Research activity information

• Mar. 2021 The Ichiro Kanehara Foundation for the Promotion of Medical Science ＆ Medical Care, Seitai-no-Kagaku Award, Molecular basis of cancer cell survival by the regulation of innate immunity

  Takashi Matozaki


• Dec. 2019 The Yasuda Medical Foundation, 安田医学賞, がん細胞の生存・維持の分子機構の解明とその臨床応用

  Takashi matozaki


• Nov. 2019 Hyogo prefecture, 兵庫県科学賞, 細胞のシグナル伝達機構の解明とその臨床応用

  Takashi Matozaki


• 1992 日本消化器病学会, 日本消化器病学会奨励賞, 英文

  MATOZAKI TAKASHI

  Official journal

• Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models

  Yasuyuki Saito, Rie Iida-Norita, Tania Afroj, Alaa Refaat, Daisuke Hazama, Satomi Komori, Shinya Ohata, Tomoko Takai, Okechi S. Oduori, Takenori Kotani, Yohei Funakoshi, Yu-Ichiro Koma, Yoji Murata, Kimikazu Yakushijin, Hiroshi Matsuoka, Hironobu Minami, Hiroshi Yokozaki, Markus G. Manz, Takashi Matozaki

  Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34⁺ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)– and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor–mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.

  Frontiers Media SA, Dec. 2023, Frontiers in Immunology, 14

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH.

  Michiko Itoh, Atsushi Tamura, Sayaka Kanai, Miyako Tanaka, Yohei Kanamori, Ibuki Shirakawa, Ayaka Ito, Yasuyoshi Oka, Isao Hidaka, Taro Takami, Yasushi Honda, Mitsuyo Maeda, Yasuyuki Saito, Yoji Murata, Takashi Matozaki, Atsushi Nakajima, Yosky Kataoka, Tomoo Ogi, Yoshihiro Ogawa, Takayoshi Suganami

  Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

  Nov. 2023, The Journal of experimental medicine, 220(11) (11), English, International magazine

  Scientific journal


• ミクログリア活性化チェックポイントSIRPα欠損による遺伝子発現変化の解析

  榛澤 春哉, 水谷 瑠依, 尾池 恵摘, 今井 武史, 浦野 江里子, 松本 映子, 神宮 大輝, 林 由里子, 的崎 尚, 大西 浩史

  (公社)日本生化学会, Oct. 2023, 日本生化学会大会プログラム・講演要旨集, 96回, [1P - 581], Japanese


• CD47 promotes peripheral T cell survival by preventing dendritic cell–mediated T cell necroptosis

  Satomi Komori, Yasuyuki Saito, Taichi Nishimura, Datu Respatika, Hiromi Endoh, Hiroki Yoshida, Risa Sugihara, Rie Iida-Norita, Tania Afroj, Tomoko Takai, Okechi S. Oduori, Eriko Nitta, Takenori Kotani, Yoji Murata, Yoriaki Kaneko, Ryo Nitta, Hiroshi Ohnishi, Takashi Matozaki

  Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has remained unclear. We here show that T cell–specific CD47-deficient ( Cd47^ΔT ) mice have a markedly reduced number of T cells in peripheral tissues. Direct interaction of CD47-deficient T cells with cDCs resulted in activation of the latter cells, which in turn induced necroptosis of the former cells. The deficiency and cell death of T cells in Cd47^ΔT mice required expression of its receptor signal regulatory protein α on cDCs. The development of CD4 ⁺ T helper cell–dependent contact hypersensitivity and inhibition of tumor growth by cytotoxic CD8 ⁺ T cells were both markedly impaired in Cd47^ΔT mice. CD47 on T cells thus likely prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function.

  Proceedings of the National Academy of Sciences, Aug. 2023, Proceedings of the National Academy of Sciences, 120(33) (33)

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 【新しいがん免疫療法研究の展開と臨床応用】自然免疫制御を介したがん免疫療法の進展 CD47-SIRPα経路の制御によるがん免疫療法

  小谷 武徳, 村田 陽二, 齊藤 泰之, 的崎 尚

  (有)科学評論社, Mar. 2023, 腫瘍内科, 31(3) (3), 327 - 333, Japanese


• Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis.

  Okamoto T, Murata Y, Hasegawa D, Yoshida M, Tanaka D, Ueda T, Hazama D, Oduori OS, Komori S, Takai T, Saito Y, Kotani T, Kosaka Y, Maniwa Y, Matozaki T

  Feb. 2023, Cancer science

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 脳白質におけるSIRPα欠損ミクログリア活性化の領域特異性解析

  尾池 恵摘, 水谷 瑠依, 今井 武史, 今田 治子, 榛澤 春哉, 正林 大地, 神宮 大輝, 林 由里子, 的崎 尚, 大西 浩史

  (公社)日本生化学会, Nov. 2022, 日本生化学会大会プログラム・講演要旨集, 95回, 1P - 367, Japanese


• 脳白質におけるSIRPα欠損ミクログリア活性化の領域特異性解析

  尾池 恵摘, 水谷 瑠依, 今井 武史, 今田 治子, 榛澤 春哉, 正林 大地, 神宮 大輝, 林 由里子, 的崎 尚, 大西 浩史

  (公社)日本生化学会, Nov. 2022, 日本生化学会大会プログラム・講演要旨集, 95回, 1P - 367, Japanese


• The Role of Type-2 Conventional Dendritic Cells in the Regulation of Tumor Immunity.

  Yasuyuki Saito, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki

  Conventional dendritic cells (cDCs) orchestrate immune responses to cancer and comprise two major subsets: type-1 cDCs (cDC1s) and type-2 cDCs (cDC2s). Compared with cDC1s, which are dedicated to the activation of CD8+ T cells, cDC2s are ontogenically and functionally heterogeneous, with their main function being the presentation of exogenous antigens to CD4+ T cells for the initiation of T helper cell differentiation. cDC1s play an important role in tumor-specific immune responses through cross-presentation of tumor-derived antigens for the priming of CD8+ T cells, whereas little is known of the role of cDC2s in tumor immunity. Recent studies have indicated that human cDC2s can be divided into at least two subsets and have implicated these cells in both anti- and pro-tumoral immune responses. Furthermore, the efficacy of cDC2-based vaccines as well as cDC2-targeted therapeutics has been demonstrated in both mouse models and human patients. Here we summarize current knowledge about the role of cDC2s in tumor immunity and address whether these cells are beneficial in the context of antitumor immune responses.

  Apr. 2022, Cancers, 14(8) (8), English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load.

  Akihiro Kaneshige, Takayuki Kaji, Lidan Zhang, Hayato Saito, Ayasa Nakamura, Tamaki Kurosawa, Madoka Ikemoto-Uezumi, Kazutake Tsujikawa, Shigeto Seno, Masatoshi Hori, Yasuyuki Saito, Takashi Matozaki, Kazumitsu Maehara, Yasuyuki Ohkawa, Michael Potente, Shuichi Watanabe, Thomas Braun, Akiyoshi Uezumi, So-Ichiro Fukada

  Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy.

  Feb. 2022, Cell stem cell, 29(2) (2), 265 - 280, English, International magazine

  Scientific journal


• Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPβ1 mediated by induction of antitumorigenic macrophages.

  Mariko Sakamoto, Yoji Murata, Daisuke Tanaka, Yuka Kakuchi, Takeshi Okamoto, Daisuke Hazama, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Masayuki Miyasaka, Masato Fujisawa, Takashi Matozaki

  The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy.

  Jan. 2022, Proceedings of the National Academy of Sciences of the United States of America, 119(1) (1), English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Protein tyrosine phosphatase Shp2 positively regulates cold stress-induced tyrosine phosphorylation of SIRPα in neurons.

  Daiki Jingu, Mika Iino, Joji Kawasaki, Eriko Urano, Shinya Kusakari, Yuriko Hayashi, Takashi Matozaki, Hiroshi Ohnishi

  The membrane protein SIRPα is a cold stress-responsive signaling molecule in neurons. Cold stress directly induces tyrosine phosphorylation of SIRPα in its cytoplasmic region, and phosphorylated SIRPα is involved in regulating experience-dependent behavioral changes in mice. Here, we examined the mechanism of cold stress-induced SIRPα phosphorylation in vitro and in vivo. The levels of activated Src family protein tyrosine kinases (SFKs), which phosphorylate SIRPα, were not increased by lowering the temperature in cultured neurons. Although the SFK inhibitor dasatinib markedly reduced SIRPα phosphorylation, low temperature induced an increase in SIRPα phosphorylation even in the presence of dasatinib, suggesting that SFK activation is not required for low temperature-induced SIRPα phosphorylation. However, in the presence of pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases), SIRPα phosphorylation was significantly reduced by lowering the temperature, suggesting that either the inactivation of PTPase(s) that dephosphorylate SIRPα or increased protection of phosphorylated SIRPα from the PTPase activity is important for low temperature-induced SIRPα phosphorylation. Inactivation of PTPase Shp2 by the allosteric Shp2 inhibitor SHP099, but not by the competitive inhibitor NSC-87877, reduced SIRPα phosphorylation in cultured neurons. Shp2 knockout also reduced SIRPα phosphorylation in the mouse brain. Our data suggest that Shp2, but not SFKs, positively regulates cold stress-induced SIRPα phosphorylation in a PTPase activity-independent manner.

  Sep. 2021, Biochemical and biophysical research communications, 569, 72 - 78, English, International magazine

  Scientific journal


• CD47および関連分子を標的としたがん治療の可能性

  齊藤 泰之, 村田 陽二, 的崎 尚

  (株)メディカルレビュー社, Sep. 2021, がん分子標的治療, 19(1) (1), 82 - 88, Japanese


• 免疫系ヒト化マウスモデルによるヒトマクロファージを標的としたがん免疫療法の開発

  齊藤 泰之, 飯田 理恵, 羽間 大祐, 小谷 武徳, 村田 陽二, 横崎 宏, 的崎 尚

  (一社)日本癌学会, Sep. 2021, 日本癌学会総会記事, 80回, [E2 - 6], English


• Role of Ras in regulation of intestinal epithelial cell homeostasis and crosstalk with Wnt signaling.

  Takenori Kotani, Noriko Ihara, Saki Okamoto, Jajar Setiawan, Tasuku Konno, Yasuyuki Saito, Yoji Murata, Takashi Matozaki

  Cross talk between different signaling pathways is thought to be important for regulation of homeostasis of, as well as oncogenesis of, the intestinal epithelium. Expression of an active form of K-Ras specifically in intestinal epithelial cells (IECs) of mice (IEC-RasDA mice) resulted in the development of hyperplasia in the small intestine and colon of mice. IEC-RasDA mice also manifested the increased proliferation of IECs. In addition, the number of goblet cells markedly increased, while that of Paneth cells decreased in IEC-RasDA mice. Development of intestinal organoids was markedly enhanced for IEC-RasDA mice compared with control mice. Whereas, the expression of Wnt target genes was significantly reduced in the in intestinal crypts from IEC-RasDA mice compared with that apparent for the control. Our results thus suggest that K-Ras promotes the proliferation of IECs as well as generation of goblet cells. By contrast, Ras counter-regulates the Wnt signaling and thereby contribute to the proper regulation of intestinal epithelial cell homeostasis.

  2021, PloS one, 16(8) (8), e0256774, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Roles of Src family kinase, Ras, and mTOR signaling in intestinal epithelial homeostasis and tumorigenesis.

  Takashi Matozaki, Takenori Kotani, Yoji Murata, Yasuyuki Saito

  The turnover of intestinal epithelial cells (IECs) is relatively rapid (3-5 days in mouse and human), and this short existence and other aspects of the homeostasis of IECs are tightly regulated by various signaling pathways including Wnt-β-catenin signaling. Dysregulation of IEC homeostasis likely contributes to the development of intestinal inflammation and intestinal cancer. The roles of receptor protein tyrosine kinases and their downstream signaling molecules such as Src family kinases, Ras, and mTOR in homeostatic regulation of IEC turnover have recently been evaluated. These signaling pathways have been found to promote not only the proliferation of IECs but also the differentiation of progenitor cells into secretory cell types such as goblet cells. Of note, signaling by Src family kinases, Ras, and mTOR has been shown to oppose the Wnt-β-catenin signaling pathway and thereby to limit the number of Lgr5+ intestinal stem cells or of Paneth cells. Such cross-talk of signaling pathways is important not only for proper regulation of IEC homeostasis but for the development of intestinal tumors and potentially for anticancer therapy.

  Jan. 2021, Cancer science, 112(1) (1), 16 - 21, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 免疫系ヒト化マウスモデルによるヒトマクロファージを標的としたがん免疫療法の開発

  齋藤 泰之, 飯田 理恵, 羽間 大祐, 小谷 武徳, 村田 陽二, 的崎 尚

  (一社)日本癌学会, Oct. 2020, 日本癌学会総会記事, 79回, OE2 - 4, English


• SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis.

  Taichi Nishimura, Yasuyuki Saito, Ken Washio, Satomi Komori, Datu Respatika, Takenori Kotani, Yoji Murata, Hiroshi Ohnishi, Satoshi Mizobuchi, Takashi Matozaki

  Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c+ cells of mice (SirpaΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of SirpaΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of SirpaΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c+ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c+ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.

  Oct. 2020, European journal of immunology, 50(10) (10), 1560 - 1570, English, International magazine

  Scientific journal


• Blockade of CD47 or SIRPα: a new cancer immunotherapy.

  Yoji Murata, Yasuyuki Saito, Takenori Kotani, Takashi Matozaki

  The CD47-Signal regulatory protein α (SIRPα) singling axis acts as a crucial regulator that limits the phagocytic activity of professional phagocytes such as macrophages. Recent studies have demonstrated that the interaction between CD47 on tumor cells and SIRPα on macrophages is implicated in the ability of tumors to evade immunosurveillance. Targeting the CD47-SIRPα interaction is therefore considered to be a promising approach for cancer therapy. Herein, we review some of studies displaying the potential clinical application of antibodies and other modalities that target the CD47-SIRPα interaction. Current limitations of the CD47-SIRPα-targeted immunotherapeutic approaches are also discussed as well as other avenues for future study to improve the current strategies in targeting the CD47-SIRPα signaling axis for cancer immunotherapy.

  Oct. 2020, Expert opinion on therapeutic targets, 24(10) (10), 945 - 951, English, International magazine


• Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy.

  Daisuke Hazama, Yizhen Yin, Yoji Murata, Makoto Matsuda, Takeshi Okamoto, Daisuke Tanaka, Naohiro Terasaka, Jinxuan Zhao, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Atsushi Nakagawa, Hiroaki Suga, Takashi Matozaki

  Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy.

  Sep. 2020, Cell chemical biology, 27(9) (9), 1181 - 1191, English, International magazine

  Scientific journal


• Regulation of colonic epithelial cell homeostasis by mTORC1.

  Takenori Kotani, Jajar Setiawan, Tasuku Konno, Noriko Ihara, Saki Okamoto, Yasuyuki Saito, Yoji Murata, Tetsuo Noda, Takashi Matozaki

  Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTOR, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CECs. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3β were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium-induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CECs and thereby contributes to colonic organogenesis and homeostasis.

  Aug. 2020, Scientific reports, 10(1) (1), 13810 - 13810, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Importance of methodology in the evaluation of renal mononuclear phagocytes and analysis of a model of experimental nephritis with Shp1 conditional knockout mice.

  Mitsuharu Watanabe, Yoriaki Kaneko, Yuko Ohishi, Masato Kinoshita, Toru Sakairi, Hidekazu Ikeuchi, Akito Maeshima, Yasuyuki Saito, Hiroshi Ohnishi, Yoshihisa Nojima, Takashi Matozaki, Keiju Hiromura

  Tissue resident mononuclear phagocytes (Mophs), comprising monocytes, macrophages, and dendritic cells (DCs), play important roles under physiological and pathological conditions. The presence of these cells in the kidney has been known for decades, and studies of renal Mophs (rMophs) are currently underway. Since no unified procedure has been identified to isolate rMophs, results of flow cytometric analysis of rMophs have been inconsistent among studies. We therefore first evaluated a preparative method for rMophs using collagenous digestion. The yield of rMophs greatly increased after the collagenase digestion. In particular, F4/80high rMophs, which were positive for CD11c, a specific marker of DCs, dramatically increased. In addition, since neutrophils are sometimes mixed among rMophs in the analysis of flow cytometry, we established a gating strategy for eliminating neutrophils. To determine the contribution of rMophs to the development of autoimmune nephritis, we analyzed an experimental model of autoimmune nephritis that was applied to Shp1 conditional knockout mice (Shp1 CKO). This knockout strain is generated by crossing a mouse line carrying floxed Shp1 allele to mice expressing Cre recombinase under the control of the CD11c promoter. Shp1 CKO therefore specifically lack Shp1 in cells expressing CD11c. As a result, Shp1 CKO were susceptible to that experimental glomerulonephritis and F4/80high rMophs of Shp1 CKO increased dramatically. In conclusion, our preparative methods for collagenase digestion and gating strategy for neutrophils are necessary for the analysis of rMophs, and Shp1 suppresses the development of autoimmune nephritis through the control of rMophs.

  Jul. 2020, Biochemistry and biophysics reports, 22, 100741 - 100741, English, International magazine

  Scientific journal


• Tetrameric glycoprotein complex gH/gL/gQ1/gQ2 is a promising vaccine candidate for human herpesvirus 6B.

  Bochao Wang, Kouichi Hara, Akiko Kawabata, Mitsuhiro Nishimura, Aika Wakata, Lidya Handayani Tjan, Anna Lystia Poetranto, Chisato Yamamoto, Yasunari Haseda, Taiki Aoshi, Lisa Munakata, Ryo Suzuki, Masato Komatsu, Ryuko Tsukamoto, Tomoo Itoh, Chikako Nishigori, Yasuyuki Saito, Takashi Matozaki, Yasuko Mori

  Primary infection of human herpesvirus 6B (HHV-6B) occurs in infants after the decline of maternal immunity and causes exanthema subitum accompanied by a high fever, and it occasionally develops into encephalitis resulting in neurological sequelae. There is no effective prophylaxis for HHV-6B, and its development is urgently needed. The glycoprotein complex gH/gL/gQ1/gQ2 (called 'tetramer of HHV-6B') on the virion surface is a viral ligand for its cellular receptor human CD134, and their interaction is thus essential for virus entry into the cells. Herein we examined the potency of the tetramer as a vaccine candidate against HHV-6B. We designed a soluble form of the tetramer by replacing the transmembrane domain of gH with a cleavable tag, and the tetramer was expressed by a mammalian cell expression system. The expressed recombinant tetramer is capable of binding to hCD134. The tetramer was purified to homogeneity and then administered to mice with aluminum hydrogel adjuvant and/or CpG oligodeoxynucleotide adjuvant. After several immunizations, humoral and cellular immunity for HHV-6B was induced in the mice. These results suggest that the tetramer together with an adjuvant could be a promising candidate HHV-6B vaccine.

  Public Library of Science (PLoS), Jul. 2020, PLoS pathogens, 16(7) (7), e1008609 - e1008609, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• An Animal Model That Mimics Human Herpesvirus 6B Pathogenesis.

  Bochao Wang, Yasuyuki Saito, Mitsuhiro Nishimura, Zhenxiao Ren, Lidya Handayani Tjan, Alaa Refaat, Rie Iida-Norita, Ryuko Tsukamoto, Masato Komatsu, Tomoo Itoh, Takashi Matozaki, Yasuko Mori

  Human herpesvirus 6B (HHV-6B), a T-lymphotropic virus, infects almost exclusively humans. An animal model of HHV-6B has not been available. Here, we report the first animal model to mimic HHV-6B pathogenesis; the model is based on humanized mice in which human immune cells were engrafted and maintained. For HHV-6B replication, adequate human T-cell activation (which becomes susceptible to HHV-6B) is necessary in this murine model. Here, we found that an additional transfer of human mononuclear cells to humanized mice resulted in an explosive proliferation of human activated T cells, which could be representative of graft-versus-host disease (GVHD) because the primary transfer of human cells was not sufficient to increase the number and ratio of human T cells. Mice infected with HHV-6B became weak and/or died approximately 7 to 14 days later. Quantitative PCR analysis revealed that the spleen and lungs were the major sites of HHV-6B replication in this model, and this was corroborated by the detection of viral proteins in these organs. Histological analysis also revealed the presence of megakaryocytes, indicating HHV-6B infection. Multiplex analysis of cytokines/chemokines in sera from the infected mice showed secretions of human cytokines/chemokines as reported for both in vitro infection and clinical samples, indicating that the secreted cytokines could affect pathogenesis. This is the first animal model showing HHV-6B pathogenesis, and it will be useful for elucidating the pathogenicity of HHV-6B, which is related to GVHD and idiopathic pneumonia syndrome.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a ubiquitous virus that establishes lifelong latent infection only in humans, and the infection can reactivate, with severe complications that cause major problems. A small-animal model of HHV-6B infection has thus been desired for research regarding the pathogenicity of HHV-6B and the development of antiviral agents. We generated humanized mice by transplantation with human hematopoietic stem cells, and here, we modified the model by providing an additional transfer of human mononuclear cells, providing the proper conditions for efficient HHV-6B infection. This is the first humanized mouse model to mimic HHV-6B pathogenesis, and it has great potential for research into the in vivo pathogenesis of HHV-6B.

  Feb. 2020, Journal of virology, 94(6) (6), English, International magazine

  [Refereed]

  Scientific journal


• SIRPα on Mouse B1 Cells Restricts Lymphoid Tissue Migration and Natural Antibody Production.

  Katka Franke, Saravanan Y Pillai, Mark Hoogenboezem, Marion J J Gijbels, Hanke L Matlung, Judy Geissler, Hugo Olsman, Chantal Pottgens, Patrick J van Gorp, Maria Ozsvar-Kozma, Yasuyuki Saito, Takashi Matozaki, Taco W Kuijpers, Rudi W Hendriks, Georg Kraal, Christoph J Binder, Menno P J de Winther, Timo K van den Berg

  The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective, we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.

  2020, Frontiers in immunology, 11, 570963 - 570963, English, International magazine

  Scientific journal


• Deletion of SIRPα (signal regulatory protein-α) promotes phagocytic clearance of myelin debris in Wallerian degeneration, axon regeneration, and recovery from nerve injury.

  Gerard Elberg, Sigal Liraz-Zaltsman, Fanny Reichert, Takashi Matozaki, Michael Tal, Shlomo Rotshenker

  BACKGROUND: Recovery of function from traumatic nerve injury depends on the ability of severed axons to grow/regenerate back to their target tissues. This is achieved by successfully crossing the lesion site where physical impact severed axons, determined by the type of trauma, followed by successfully growing throughout the Wallerian degenerating nerve segment located distal to and beyond the lesion site, determined by the nature of Wallerian degeneration. The protracted removal of myelin debris in Wallerian degeneration, which leads residual myelin debris to slow down axon growth, impedes recovery of function. We focused in this study on mechanism(s) that delay the removal of myelin debris in Wallerian degeneration and so impede recovery. Previously, we showed that myelin debris inhibited its own phagocytosis in primary cultured macrophages and microglia as CD47 on myelin ligated SIRPα (signal regulatory protein-α) on phagocytes, and sequentially, SIRPα generated "don't eat me" signaling. We also demonstrated that serum inhibited phagocytosis in a SIRPα-dependent manner. Herein, we aimed to determine whether SIRPα-dependent inhibition of phagocytosis in macrophages impedes the in vivo removal of myelin debris in Wallerian degeneration, further leading to impaired healing. METHODS: Using SIRPα null (SIRPα-/-) and littermate wild-type (SIRPα+/+) mice, we studied the recovery of sensory and motor functions from nerve injury and, further, axon regeneration, SIRPα expression, myelin debris removal, and the phagocytic capacity and presence of macrophages in Wallerian degeneration. RESULTS: Myelin debris removal, axon regeneration, and the recovery of functions were all faster in SIRPα-/- mice than in wild-type mice. Between the two cell types that mostly scavenge myelin debris, macrophages but not Schwann cells expressed SIRPα in wild-type mice, and furthermore, SIRPα-/- macrophages phagocytosed significantly more than wild-type macrophages. CONCLUSIONS: Our findings suggest an intrinsic normally occurring SIRPα-dependent mechanism that impedes the in vivo removal of myelin debris in Wallerian degeneration by inhibiting the phagocytosis of myelin debris in macrophages, hence preventing fast growing axons from fully implementing their regenerative potential. Thus, accelerating the removal of myelin debris by eliminating SIRPα-dependent inhibition of phagocytosis will most likely advance recovery of functions from nerve injury.

  Dec. 2019, Journal of neuroinflammation, 16(1) (1), 277 - 277, English, International magazine

  Scientific journal


• SIRPα+ dendritic cells promote the development of fibroblastic reticular cells in murine peripheral lymph nodes.

  Satomi Komori, Yasuyuki Saito, Datu Respatika, Taichi Nishimura, Takenori Kotani, Yoji Murata, Takashi Matozaki

  Nonhematopoietic stromal cells contribute to the organization and homeostasis of secondary lymphoid organs by producing cytokines and chemokines. The development and maintenance of these stromal cells are thought to be regulated by innate immune cells. Indeed, we recently showed that signal regulatory protein α (SIRPα)-positive dendritic cells (DCs) are essential for the proliferation and survival of podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) in mouse spleen. We have now established an in vitro culture system for lymph node stromal cells (LNSCs) isolated from mouse peripheral LNs. Activated DCs and TNF-α each promoted the proliferation of cultured LNSCs, most of which were found to be Pdpn+ FRCs. Furthermore, ablation of SIRPα in CD11c+ cells attenuated this effect of DCs on LNSC proliferation. Transplantation of activated DCs together with cultured LNSCs into the renal subcapsular space markedly increased the number of ER-TR7+ stromal cells as well as induced the accumulation of T cells and increased the expression of Ccl19 in the transplants. Ablation of SIRPα in CD11c+ cells greatly impaired the development of LN-like structure in the transplants. Our findings thus suggest that SIRPα+ DCs are important for the proliferation and differentiation of Pdpn+ FRCs in peripheral LNs.

  Wiley, Sep. 2019, European journal of immunology, 49(9) (9), 1364 - 1371, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter.

  Miho Sato-Hashimoto, Tomomi Nozu, Riho Toriba, Ayano Horikoshi, Miho Akaike, Kyoko Kawamoto, Ayaka Hirose, Yuriko Hayashi, Hiromi Nagai, Wakana Shimizu, Ayaka Saiki, Tatsuya Ishikawa, Ruwaida Elhanbly, Takenori Kotani, Yoji Murata, Yasuyuki Saito, Masae Naruse, Koji Shibasaki, Per-Arne Oldenborg, Steffen Jung, Takashi Matozaki, Yugo Fukazawa, Hiroshi Ohnishi

  A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced the emergence of CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα-knockout mice exhibited the same phenotype, suggesting that an interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRPα did not cause detectable damage to the white matter, but resulted in the increased expression of genes whose expression is characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.

  Mar. 2019, eLife, 8(. pii) (. pii), e42025, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Role of lysophosphatidic acid in proliferation and differentiation of intestinal epithelial cells.

  Tasuku Konno, Takenori Kotani, Jajar Setiawan, Yuka Nishigaito, Naoki Sawada, Shinya Imada, Yasuyuki Saito, Yoji Murata, Takashi Matozaki

  Intestinal epithelial cells (IECs) are regenerated continuously from intestinal stem cells (ISCs) near the base of intestinal crypts in order to maintain homeostasis and structural integrity of intestinal epithelium. Epidermal growth factor (EGF) is thought to be important to drive the proliferation and differentiation of IECs from ISCs, it remains unknown whether other growth factors or lipid mediators are also important for such regulation, however. Here we show that lysophosphatidic acid (LPA), instead of EGF, robustly promoted the development of intestinal organoids prepared from the mouse small intestine. Indeed, LPA exhibited the proliferative activity of IECs as well as induction of differentiation of IECs into goblet cells, Paneth cells, and enteroendocrine cells in intestinal organoids. Inhibitors for LPA receptor 1 markedly suppressed the LPA-promoted development of intestinal organoids. LPA also promoted the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in intestinal organoids, whereas inhibition of mitogen-activated protein kinase/ERK kinase (MEK) 1/2 significantly suppressed the development of, as well as the proliferative activity and differentiation of, intestinal organoids in response to LPA. Our results thus suggest that LPA is a key factor that drives the proliferation and differentiation of IECs.

  2019, PloS one, 14(4) (4), e0215255, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice

  Abe T, Tanaka Yuka, Piao J, Tanimine N, Oue N, Hinoi T, Garcia NV, Miyasaka M, MATOZAKI TAKASHI, Yasui W, Ohdan H

  Sep. 2018, Ann Gastroenterol Surg, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Role of Csk in intestinal epithelial barrier function and protection against colitis

  Sun C, MURATA YOJI, Imada S, Konno T, KOTANI TAKENORI, Saito Y, Yamada Hideto, Matozaki T

  Intestinal epithelial cells (IECs) play a pivotal role in the maintenance of the integrity and barrier function of the intestinal epithelium. Dysfunctions of IECs are thought to participate in the disruption of the intestinal epithelial barrier, resulting in gastrointestinal diseases, such as colitis and colorectal cancer. Here we show that IEC-specific COOH-terminal Src kinase (Csk)-deficient mice (Csk CKO mice) manifested the increased susceptibility to dextran sodium sulfate (DSS)-induced colitis, a model of inflammatory bowel disease. DSS-treated Csk CKO mice also exhibited the significantly elevated intestinal permeability. Following DSS treatment, Csk CKO mice exhibited the higher proliferative activity of colonic epithelial cells and the increased number of apoptotic cells in the colon compared with that apparent for control mice. Moreover, the abundance of the tight junction protein occludin, which regulates cell-cell adhesion as well as epithelial permeability, was markedly reduced in the colon of DSS-treated Csk CKO mice. These results thus suggest that Csk in IECs plays important roles in the regulation of the intestinal epithelial barrier function and protection against colitis.

  Sep. 2018, Biochem Biophys Res Commun, 504(1) (1), 109 - 114, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis.

  Hanke L Matlung, Liane Babes, Xi Wen Zhao, Michel van Houdt, Louise W Treffers, Dieke J van Rees, Katka Franke, Karin Schornagel, Paul Verkuijlen, Hans Janssen, Pasi Halonen, Cor Lieftink, Roderick L Beijersbergen, Jeanette H W Leusen, Jaap J Boelens, Ingrid Kuhnle, Jutte van der Werff Ten Bosch, Karl Seeger, Sergio Rutella, Daria Pagliara, Takashi Matozaki, Eiji Suzuki, Catharina Willemien Menke-van der Houven van Oordt, Robin van Bruggen, Dirk Roos, Rene A W van Lier, Taco W Kuijpers, Paul Kubes, Timo K van den Berg

  Elsevier B.V., Jun. 2018, Cell reports, 23(13) (13), 3946 - 3959, English, International magazine

  [Refereed]

  Scientific journal


• Anti-human SIRPα antibody is a new tool for cancer immunotherapy

  Yoji Murata, Daisuke Tanaka, Daisuke Hazama, Tadahiko Yanagita, Yasuyuki Saito, Takenori Kotani, Per-Arne Oldenborg, Takashi Matozaki

  Blackwell Publishing Ltd, May 2018, Cancer Science, 109(5) (5), 1300 - 1308, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Regulation by commensal bacteria of neurogenesis in the subventricular zone of adult mouse brain.

  Naoki Sawada, Takenori Kotani, Tasuku Konno, Jajar Setiawan, Yuka Nishigaito, Yasuyuki Saito, Yoji Murata, Ken-Ichi Nibu, Takashi Matozaki

  In the mouse olfactory bulb (OB), interneurons such as granule cells and periglomerular cells are continuously replaced by adult-born neurons, which are generated in the subventricular zone (SVZ) of the brain. We have now investigated the role of commensal bacteria in regulation of such neuronal cell turnover in the adult mouse brain. Administration of mixture of antibiotics to specific pathogen-free (SPF) mice markedly attenuated the incorporation of bromodeoxyuridine (BrdU) into the SVZ cells. The treatment with antibiotics also reduced newly generated BrdU-positive neurons in the mouse OB. In addition, the incorporation of BrdU into the SVZ cells of germ-free (GF) mice was markedly reduced compared to that apparent for SPF mice. In contrast, the reduced incorporation of BrdU into the SVZ cells of GF mice was recovered by their co-housing with SPF mice, suggesting that commensal bacteria promote the incorporation of BrdU into the SVZ cells. Finally, we found that administration of ampicillin markedly attenuated the incorporation of BrdU into the SVZ cells of SPF mice. Our results thus suggest that ampicillin-sensitive commensal bacteria regulate the neurogenesis in the SVZ of adult mouse brain.

  Apr. 2018, Biochemical and biophysical research communications, 498(4) (4), 824 - 829, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Corrigendum to: SHPS-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress: SHPS-1 deficiency induces robust neuroprotection (Journal of Neurochemistry, (2012), 122, 4, (834-843), 10.1111/j.1471-4159.2012.07818.x)

  Lang Wang, Yanyun Lu, Shan Deng, Yan Zhang, Li Yang, Yu Guan, Takashi Matozaki, Hiroshi Ohnishi, Hong Jiang, Hongliang Li

  Blackwell Publishing Ltd, Dec. 2017, Journal of Neurochemistry, 122(4) (4), 834 - 843, English

  [Refereed]

  Scientific journal


• SIRP alpha(+) dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Yasuyuki Saito, Datu Respatika, Satomi Komori, Ken Washio, Taichi Nishimura, Takenori Kotani, Yoji Murata, Hideki Okazawa, Hiroshi Ohnishi, Yoriaki Kaneko, Katsuyuki Yui, Koji Yasutomo, Chikako Nishigori, Yoshihisa Nojima, Takashi Matozaki

  Nov. 2017, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114(47) (47), E10151 - E10160, English

  [Refereed]

  Scientific journal


• Microvillus-Specific Protein Tyrosine Phosphatase SAP-1 Plays a Role in Regulating the Intestinal Paracellular Transport of Macromolecules

  Shingo Mori, Noriyasu Kamei, Yoji Murata, Kozo Takayama, Takashi Matozaki, Mariko Takeda-Morishita

  Sep. 2017, JOURNAL OF PHARMACEUTICAL SCIENCES, 106(9) (9), 2904 - 2908, English

  [Refereed]

  Scientific journal


• Role of SIRPα in Homeostatic Regulation of T Cells and Fibroblastic Reticular Cells in the Spleen

  Respatika Datu, Saito Yasuyuki, Washio Ken, Komori Satomi, Kotani Takenori, Okazawa Hideki, Murata Yoji, Matozaki Takashi

  Signal regulatory protein α (SIRPα), is an immunoglobulin superfamily protein that is predominantly expressed in macrophages and dendritic cells (DCs), especially CD4+ conventional DCs (cDCs). In this study, we demonstrated that, in addition to the reduced number of CD4+ cDCs, the number of T cells was significantly decreased in the spleen of Sirpa–/– mice, in which full-length

  神戸大学医学部, Aug. 2017, The Kobe journal of the medical sciences, 63(1) (1), 22 - 29, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Role of SIRPα in Homeostatic Regulation of T Cells and Fibroblastic Reticular Cells in the Spleen

  RespatikaD, SaitoY, WashioK, KomoriS, Kotani Takenori, OkazawaH, Murata Yoji, Matozaki Takashi

  Signal regulatory protein α (SIRPα), is an immunoglobulin superfamily protein that is predominantly expressed in macrophages and dendritic cells (DCs), especially CD4+ conventional DCs (cDCs). In this study, we demonstrated that, in addition to the reduced number of CD4+ cDCs, the number of T cells was significantly decreased in the spleen of Sirpa-/- mice, in which full-length of SIRPα protein was systemically ablated. The size of the T cell zone was markedly reduced in the spleen of Sirpa-/- mice. In addition, Sirpa-/- mice revealed a marked reduction of CCL19, CCL21, and IL-7 expression, which are thought to be important for homeostasis of T cells in the spleen. Consistently, the abundance of fibroblastic reticular cells (FRCs), a subset of stromal cells in the T cell zone, was markedly reduced in the spleen of Sirpa-/- mice compared with Sirpaf/f mice. Moreover, we demonstrated that the mRNA expression of Lymphotoxin (LT) α, LTβ, and LIGHT was significantly reduced in the spleen of Sirpa-/- mice. These data thus suggest that SIRPα is essential for steady-state homeostasis of T cells and FRCs in the spleen.

  Aug. 2017, Kobe J Med Sci, 63(1) (1), E22 - E29, English, Domestic magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Donor SIRPα polymorphism modulates the innate immune response to allogeneic grafts

  DaiH, FridayAJ, Abou-DayaKI, WilliamsAL, Mortin-TothS, NicotraML, RothsteinDM, ShlomchikWD, Matozaki Takashi, IsenbergJS, OberbarnscheidtMH, DanskaJS, LakkisFG

  Jun. 2017, Sci Immunol, 2(12) (12), English

  [Refereed]

  Scientific journal


• Prion pathogenesis is unaltered in the absence of SIRP alpha-mediated "don't-eat-me" signaling

  Mario Nuvolone, Marta Paolucci, Silvia Sorce, Veronika Kana, Rita Moos, Takashi Matozaki, Adriano Aguzzi

  May 2017, PLOS ONE, 12(5) (5), e0177876, English

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells

  MeindertsSM, OldenborgPA, BeugerBM, KleiTRL, JohanssonJ, KuijpersTW, Matozaki Takashi, HuismanEJ, deHaasM, vandenBergTK, vanBruggenR

  May 2017, Blood Adv, 1(14) (14), 875 - 886, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

  YanagitaT, Murata Yoji, TanakaD, MotegiSI, AraiE, DaniwijayaEW, HazamaD, WashioK, SaitoY, Kotani Takenori, OhnishiH, OldenborgPA, GarciaNV, MiyasakaM, IshikawaO, KanaiY, Komori Takahide, Matozaki Takashi

  Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8+ T cells. In addition, the anti-SIRPα Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPα-nonexpressing tumor cells. Anti-SIRPα Abs thus warrant further study as a potential new therapy for a broad range of cancers.

  Jan. 2017, JCI Insight, 2(1) (1), e89140, English, International magazine

  [Refereed]

  Scientific journal


• Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

  Shinya Imada, Yoji Murata, Takenori Kotani, Masaki Hatano, Chunxiao Sun, Tasuku Konno, Jung-ha Park, Yasuaki Kitamura, Yasuyuki Saito, Hideki Ohdan, Takashi Matozaki

  Nov. 2016, MOLECULAR AND CELLULAR BIOLOGY, 36(22) (22), 2811 - 2823, English

  [Refereed]

  Scientific journal


• Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation

  Cecilia Koskinen Holm, Sara Engman, Rima Sulniute, Takashi Matozaki, Per-Arne Oldenborg, Pernilla Lundberg

  Sep. 2016, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 478(1) (1), 268 - 273, English

  [Refereed]

  Scientific journal


• Promotion of Intestinal Epithelial Cell Turnover by Commensal Bacteria: Role of Short-Chain Fatty Acids

  Jung-ha Park, Takenori Kotani, Tasuku Konno, Jajar Setiawan, Yasuaki Kitamura, Shinya Imada, Yutaro Usui, Naoya Hatano, Masakazu Shinohara, Yasuyuki Saito, Yoji Murata, Takashi Matozaki

  May 2016, PLOS ONE, 11(5) (5), English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Tyrosine Phosphorylation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 20 and Its Functional Role

  Edwin Widyanto Daniwijaya, Yoji Murata, Takenori Kotani, Yasuaki Kitamura, Kemala Isnainiasih Mantilidewi, Shinya Kusakari, Hiroshi Ohnishi, Hideki Okazawa, Takashi Matozaki

  Mar. 2016, The Kobe journal of medical sciences, 59(5) (5), E172 - E183, English

  Scientific journal


• Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium

  Yoji Murata, Takenori Kotani, Yana Supriatna, Yasuaki Kitamura, Shinya Imada, Kohichi Kawahara, Miki Nishio, Edwin Widyanto Daniwijaya, Hisanobu Sadakata, Shinya Kusakari, Munemasa Mori, Yoshitake Kanazawa, Yasuyuki Saito, Katsuya Okawa, Mariko Takeda-Morishita, Hideki Okazawa, Hiroshi Ohnishi, Takeshi Azuma, Akira Suzuki, Takashi Matozaki

  Aug. 2015, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(31) (31), E4264 - E4271, English

  [Refereed]

  Scientific journal


• Regulation by gut commensal bacteria of carcinoembryonic antigen-related cell adhesion molecule expression in the intestinal epithelium

  Yasuaki Kitamura, Yoji Murata, Jung-ha Park, Takenori Kotani, Shinya Imada, Yasuyuki Saito, Hideki Okazawa, Takeshi Azuma, Takashi Matozaki

  Jul. 2015, GENES TO CELLS, 20(7) (7), 578 - 589, English

  [Refereed]

  Scientific journal


• Non-Hematopoietic and Hematopoietic SIRP alpha Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen

  Shrikant Shantilal Kolan, Kristina Lejon, Cecilia Koskinen Holm, Rima Sulniute, Pernilla Lundberg, Takashi Matozaki, Per-Arne Oldenborg

  Jul. 2015, PLOS ONE, 10(7) (7), English

  [Refereed]

  Scientific journal


• Dendritic cell SIRP regulates homeostasis of dendritic cells in lymphoid organs

  Ken Washio, Takenori Kotani, Yasuyuki Saito, Datu Respatika, Yoji Murata, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Atsushi Fukunaga, Chikako Nishigori, Takashi Matozaki

  Jun. 2015, GENES TO CELLS, 20(6) (6), 451 - 463, English

  [Refereed]

  Scientific journal


• Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs

  Ken Washio, Takenori Kotani, Yasuyuki Saito, Datu Respatika, Yoji Murata, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Atsushi Fukunaga, Chikako Nishigori, Takashi Matozaki

  Blackwell Publishing Ltd, Jun. 2015, Genes to Cells, 20(6) (6), 451 - 463, English

  [Refereed]

  Scientific journal


• Regulation of Phagocyte Migration by Signal Regulatory Protein-Alpha Signaling

  Julian Alvarez-Zarate, Hanke L. Matlung, Takashi Matozaki, Taco W. Kuijpers, Isabelle Maridonneau-Parini, Timo K. van den Berg

  Jun. 2015, PLOS ONE, 10(6) (6), English

  [Refereed]

  Scientific journal


• Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

  Shinya Kusakari, Fumihito Saitow, Yukio Ago, Koji Shibasaki, Miho Sato-Hashimoto, Yasunori Matsuzaki, Takenori Kotani, Yoji Murata, Hirokazu Hirai, Toshio Matsuda, Hidenori Suzuki, Takashi Matozaki, Hiroshi Ohnishi

  May 2015, MOLECULAR AND CELLULAR BIOLOGY, 35(9) (9), 1557 - 1572, English

  [Refereed]

  Scientific journal


• Lack of non-hematopoietic SIRP alpha signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells

  Shrikant S. Kolan, Andreas Boman, Takashi Matozaki, Kristina Lejon, Per-Arne Oldenborg

  May 2015, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 460(3) (3), 645 - 650, English

  [Refereed]

  Scientific journal


• Protein-tyrosine Phosphatase Shp2 Positively Regulates Macrophage Oxidative Burst

  Xing Jun Li, Charles B. Goodwin, Sarah C. Nabinger, Briana M. Richine, Zhenyun Yang, Helmut Hanenberg, Hiroshi Ohnishi, Takashi Matozaki, Gen-Sheng Feng, Rebecca J. Chan

  Feb. 2015, JOURNAL OF BIOLOGICAL CHEMISTRY, 290(7) (7), 3894 - 3909, English

  [Refereed]

  Scientific journal


• Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

  Satoshi Yoshino, Tetsurou Satoh, Masanobu Yamada, Koshi Hashimoto, Takuya Tomaru, Akiko Katano-Toki, Satoru Kakizaki, Shuichi Okada, Hiroyuki Shimizu, Atsushi Ozawa, Takafumi Tuchiya, Hayato Ikota, Yoichi Nakazato, Munemasa Mori, Takashi Matozaki, Tsutomu Sasaki, Tadahiro Kitamura, Masatomo Mori

  Sep. 2014, ENDOCRINOLOGY, 155(9) (9), 3459 - 3472, English

  [Refereed]

  Scientific journal


• The CD47-SIRP alpha signalling system: its physiological roles and therapeutic application

  Yoji Murata, Takenori Kotani, Hiroshi Ohnishi, Takashi Matozaki

  Jun. 2014, JOURNAL OF BIOCHEMISTRY, 155(6) (6), 335 - 344, English

  [Refereed]

  Scientific journal


• SLEの病態と治療 樹状細胞とSLE 樹状細胞特異的SHP-1欠損マウスの解析

  廣村 桂樹, 渡辺 光治, 大石 裕子, 金子 和光, 斎藤 泰之, 金子 哲也, 高岸 憲二, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本リウマチ学会, Mar. 2014, 日本リウマチ学会総会・学術集会プログラム・抄録集, 58回, 214 - 214, Japanese


• The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment

  Chika Iwamoto, Katsuto Takenaka, Shingo Urata, Takuji Yamauchi, Takahiro Shima, Takuro Kuriyama, Shinya Daitoku, Yasuyuki Saito, Toshihiro Miyamoto, Hiromi Iwasaki, Issay Kitabayashi, Katsuhiko Itoh, Junji Kishimoto, Daisuke Kohda, Takashi Matozaki, Koichi Akashi

  Mar. 2014, EXPERIMENTAL HEMATOLOGY, 42(3) (3), 163 - 171, English

  [Refereed]

  Scientific journal


• Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation

  Kemala Isnainiasih Mantilidewi, Yoji Murata, Munemasa Mori, Chihiro Otsubo, Takenori Kotani, Shinya Kusakari, Hiroshi Ohnishi, Takashi Matozaki

  Mar. 2014, JOURNAL OF BIOLOGICAL CHEMISTRY, 289(10) (10), 6451 - 6461, English

  [Refereed]

  Scientific journal


• Role of the Protein Tyrosine Phosphatase Shp2 in Homeostasis of the Intestinal Epithelium

  Hironori Yamashita, Takenori Kotani, Jung-ha Park, Yoji Murata, Hideki Okazawa, Hiroshi Ohnishi, Yonson Ku, Takashi Matozaki

  Mar. 2014, PLOS ONE, 9(3) (3), English

  [Refereed]

  Scientific journal


• Comprehensive Behavioral Analysis of Cluster of Differentiation 47 Knockout Mice

  Hisatsugu Koshimizu, Keizo Takao, Takashi Matozaki, Hiroshi Ohnishi, Tsuyoshi Miyakawa

  Feb. 2014, PLOS ONE, 9(2) (2), English

  [Refereed]

  Scientific journal


• Autoimmune animal models in the analysis of the CD47-SIRP alpha signaling pathway

  Yoji Murata, Yasuyuki Saito, Tetsuya Kaneko, Takenori Kotani, Yoriaki Kaneko, Hiroshi Ohnishi, Takashi Matozaki

  Jan. 2014, METHODS, 65(2) (2), 254 - 259, English

  [Refereed]

  Scientific journal


• Signal Regulatory Protein Alpha Is Present in Several Neutrophil Granule Populations and Is Rapidly Mobilized to the Cell Surface to Negatively Fine-Tune Neutrophil Accumulation in Inflammation

  Asa Stenberg, Anna Karlsson, Elisabeth Feuk-Lagerstedt, Karin Christenson, Johan Bylund, Anna Oldenborg, Liselotte Vesterlund, Takashi Matozaki, Janove Sehlin, Per-Arne Oldenborg

  2014, JOURNAL OF INNATE IMMUNITY, 6(4) (4), 553 - 560, English

  [Refereed]

  Scientific journal


• BALB/c- Specific L29V Polymorphism In SIRPA Determines The Efficient Engraftment Of Human Hematopoiesis In Xenogeneic Model

  Chika Iwamoto, Katsuto Takenaka, Shingo Urata, Takahiro Shima, Takuji Yamauchi, Takuro Kuriyama, Shinya Daitoku, Yasuyuki Saito, Katsuhiko Itoh, Junji Kishimoto, Daisuke Kohda, Takashi Matozaki, Koichi Akashi

  Nov. 2013, BLOOD, 122(21) (21), English

  [Refereed]


• Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein alpha (SIRP alpha) Signaling

  Cecilia Koskinen, Emelie Persson, Paul Baldock, Asa Stenberg, Ingrid Bostrom, Takashi Matozaki, Per-Arne Oldenborg, Pernilla Lundberg

  Oct. 2013, JOURNAL OF BIOLOGICAL CHEMISTRY, 288(41) (41), 29333 - 29344, English

  [Refereed]

  Scientific journal


• SIRPα signaling regulates podocyte structure and function

  Satoshi Takahashi, Mai Tomioka, Keiju Hiromura, Toru Sakairi, Hiroko Hamatani, Mitsuharu Watanabe, Hidekazu Ikeuchi, Yoriaki Kaneko, Akito Maeshima, Takeo Aoki, Hiroshi Ohnishi, Takashi Matozaki, Yoshihisa Nojima

  Sep. 2013, American Journal of Physiology - Renal Physiology, 305(6) (6), F861 - F870, English

  [Refereed]

  Scientific journal


• SIRP alpha signaling regulates podocyte structure and function

  Satoshi Takahashi, Mai Tomioka, Keiju Hiromura, Toru Sakairi, Hiroko Hamatani, Mitsuharu Watanabe, Hidekazu Ikeuchi, Yoriaki Kaneko, Akito Maeshima, Takeo Aoki, Hiroshi Ohnishi, Takashi Matozaki, Yoshihisa Nojima

  Sep. 2013, AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 305(6) (6), F861 - F870, English

  [Refereed]

  Scientific journal


• Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

  Takuji Yamauchi, Katsuto Takenaka, Shingo Urata, Takahiro Shima, Yoshikane Kikushige, Takahito Tokuyama, Chika Iwamoto, Mariko Nishihara, Hiromi Iwasaki, Toshihiro Miyamoto, Nakayuki Honma, Miki Nakao, Takashi Matozaki, Koichi Akashi

  Feb. 2013, BLOOD, 121(8) (8), 1316 - 1325, English

  [Refereed]

  Scientific journal


• Tyrosine phosphorylation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 20 and its functional roles

  Matozaki Takashi

  Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20 is an immunoglobulin-superfamily transmembrane protein that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region. However, the mechanism for tyrosine phosphorylation of, or the physiological function of, this protein remains largely unknown. Here we have shown that CEACAM20 is indeed tyrosine-phosphorylated by either treatment with pervanadate or forced expression of c-Src. In addition, Tyr522, Tyr559 or Tyr570, the latter two of which are within the ITAM, is likely important for such tyrosine phosphorylation. Forced expression of Myc-tagged wild-type CEACAM20 promoted the phagocytic activity of cultured cells for microbeads coupled with anti-Myc antibodies. By contrast, such phagocytic activity was markedly reduced when a mutant form of CEACAM20, in which Tyr559 and Tyr570 were substituted with phenylalanine, was expressed. Furthermore, the CEACAM20-mediated phagocytic activity was markedly prevented by the treatment with an inhibitor for either Src family kinases (SFKs), Syk, phosphoinositide 3-kinase (PI3K) or phospholipase C-γ (PLCγ). Inhibition of actin polymerization by Cytochalasin D significantly inhibited the CEACAM20-mediated phagocytosis. These results thus suggest that tyrosine phosphorylation of CEACAM20 likely promotes phagocytic activity of the cells. The CEACAM20-mediated phagocytic activity requires the activation of SFKs, Syk, PI3K or PLCγ.

  2013, Kobe J Med Sci, 59(1) (1), E172-E183, English, Domestic magazine

  [Refereed]

  Scientific journal


• Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state

  Ke Zen, Yalan Guo, Zhen Bian, Zhiyuan Lv, Dihan Zhu, Hiroshi Ohnishi, Takashi Matozaki, Yuan Liu

  2013, Nature Communications, 4, English

  [Refereed]

  Scientific journal


• Macrophages require Skap2 and Sirp alpha for integrin-stimulated cytoskeletal rearrangement

  Francis J. Alenghat, Quentin J. Baca, Nooreen T. Rubin, Lily I. Pao, Takashi Matozaki, Clifford A. Lowell, David E. Golan, Benjamin G. Neel, Kenneth D. Swanson

  Nov. 2012, JOURNAL OF CELL SCIENCE, 125(22) (22), 5535 - 5545, English

  [Refereed]

  Scientific journal


• Hypothermia-dependent and -independent effects of forced swim on the phosphorylation states of signaling molecules in mouse hippocampus

  Yuriko Hayashi, Shinya Kusakari, Miho Sato-Hashimoto, Eriko Urano, Masahiro Shigeno, Tsuneo Sekijima, Takenori Kotani, Yoji Murata, Hirokazu Murakami, Takashi Matozaki, Hiroshi Ohnishi

  Nov. 2012, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 428(4) (4), 475 - 481, English

  [Refereed]

  Scientific journal


• SIRP alpha Controls the Activity of the Phagocyte NADPH Oxidase by Restricting the Expression of gp91(phox)

  Ellen M. van Beek, Julian Alvarez Zarate, Robin van Bruggen, Karin Schornagel, Anton T. J. Tool, Takashi Matozaki, Georg Kraal, Dirk Roos, Timo K. van den Berg

  Oct. 2012, CELL REPORTS, 2(4) (4), 748 - 755, English

  [Refereed]

  Scientific journal


• The Absence of CD47 Promotes Nerve Fiber Growth from Cultured Ventral Mesencephalic Dopamine Neurons

  Franziska Marschinke, Sanaz Hashemian, Takashi Matozaki, Per-Arne Oldenborg, Ingrid Stromberg

  Sep. 2012, PLOS ONE, 7(9) (9), English

  [Refereed]

  Scientific journal


• SHPS-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress

  Lang Wang, Yanyun Lu, Shan Deng, Yan Zhang, Li Yang, Yu Guan, Takashi Matozaki, Hiroshi Ohnishi, Hong Jiang, Hongliang Li

  Aug. 2012, JOURNAL OF NEUROCHEMISTRY, 122(4) (4), 834 - 843, English

  [Refereed]

  Scientific journal


• Hypothermia-induced tyrosine phosphorylation of SIRPa in the brain

  Toshi Maruyama, Shinya Kusakari, Miho Sato-Hashimoto, Yuriko Hayashi, Takenori Kotani, Yoji Murata, Hideki Okazawa, Per-Arne Oldenborg, Shoji Kishi, Takashi Matozaki, Hiroshi Ohnishi

  Jun. 2012, JOURNAL OF NEUROCHEMISTRY, 121(6) (6), 891 - 902, English

  [Refereed]

  Scientific journal


• Dendritic Cell-Specific Ablation of the Protein Tyrosine Phosphatase Shp1 Promotes Th1 Cell Differentiation and Induces Autoimmunity

  Tetsuya Kaneko, Yasuyuki Saito, Takenori Kotani, Hideki Okazawa, Hiroko Iwamura, Miho Sato-Hashimoto, Yoshitake Kanazawa, Satoshi Takahashi, Keiju Hiromura, Shinya Kusakari, Yoriaki Kaneko, Yoji Murata, Hiroshi Ohnishi, Yoshihisa Nojima, Kenji Takagishi, Takashi Matozaki

  Jun. 2012, JOURNAL OF IMMUNOLOGY, 188(11) (11), 5397 - 5407, English

  [Refereed]

  Scientific journal


• The Rho kinase pathway regulates the migration of dendritic cells through SIRP-alpha

  Kanako Ogura, Atsushi Fukunaga, Kumiko Taguchi, Hiroshi Nagai, Xijun Yu, Shuntaro Oniki, Hideki Okazawa, Takashi Matozaki, Tatsuya Horikawa, Chikako Nishigori

  Apr. 2012, JOURNAL OF DERMATOLOGICAL SCIENCE, 66(1) (1), 74 - 76, English

  [Refereed]

  Scientific journal


• The Efficient Engraftment of Human Hematopoiesis in the Balb/c Strain Is Mounted by Balb/c-Specific SIRPA Polymorphism That Enhances Binding Affinity to Human CD47

  Chika Iwamoto, Katsuto Takenaka, Shingo Urata, Takahiro Shima, Katsuhiko Itoh, Junji Kishimoto, Toshihiro Miyamoto, Takashi Matozaki, Koichi Akashi

  Nov. 2011, BLOOD, 118(21) (21), 1714 - 1714, English

  [Refereed]


• CD47-signal regulatory protein-alpha (SIRP alpha) interactions form a barrier for antibody-mediated tumor cell destruction

  Xi Wen Zhao, Ellen M. van Beek, Karin Schornagel, Hans Van der Maaden, Michel Van Houdt, Marielle A. Otten, Pascal Finetti, Marjolein Van Egmond, Takashi Matozaki, Georg Kraal, Daniel Birnbaum, Andrea van Elsas, Taco W. Kuijpers, Francois Bertucci, Timo K. van den Berg

  Nov. 2011, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108(45) (45), 18342 - 18347, English

  [Refereed]

  Scientific journal


• SIRP alpha/CD172a Regulates Eosinophil Homeostasis

  Noel Verjan Garcia, Eiji Umemoto, Yasuyuki Saito, Mikako Yamasaki, Erina Hata, Takashi Matozaki, Masaaki Murakami, Yun-Jae Jung, So-Youn Woo, Ju-Young Seoh, Myoung Ho Jang, Katsuyuki Aozasa, Masayuki Miyasaka

  Sep. 2011, JOURNAL OF IMMUNOLOGY, 187(5) (5), 2268 - 2277, English

  [Refereed]

  Scientific journal


• Signal Regulatory Protein alpha Regulates the Homeostasis of T Lymphocytes in the Spleen

  Miho Sato-Hashimoto, Yasuyuki Saito, Hiroshi Ohnishi, Hiroko Iwamura, Yoshitake Kanazawa, Tetsuya Kaneko, Shinya Kusakari, Takenori Kotani, Munemasa Mori, Yoji Murata, Hideki Okazawa, Carl F. Ware, Per-Arne Oldenborg, Yoshihisa Nojima, Takashi Matozaki

  Jul. 2011, JOURNAL OF IMMUNOLOGY, 187(1) (1), 291 - 297, English

  [Refereed]

  Scientific journal


• SIRPαシグナル経路の遮断は糖尿病性腎症を増悪させる

  高橋 哲史, 廣村 桂樹, 浜谷 博子, 加藤 麻衣, 坂入 徹, 櫻井 則之, 池内 秀和, 前嶋 明人, 黒岩 卓, 青木 武生, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本腎臓学会, May 2011, 日本腎臓学会誌, 53(3) (3), 379 - 379, Japanese


• Essential roles of SIRP alpha in homeostatic regulation of skin dendritic cells

  Hiroko Iwamura, Yasuyuki Saito, Miho Sato-Hashimoto, Hiroshi Ohnishi, Yoji Murata, Hideki Okazawa, Yoshitake Kanazawa, Tetsuya Kaneko, Shinya Kusakari, Takenori Kotani, Yoshihisa Nojima, Takashi Matozaki

  Mar. 2011, IMMUNOLOGY LETTERS, 135(1-2) (1-2), 100 - 107, English

  [Refereed]

  Scientific journal


• Role of SIRP alpha in regulation of mucosal immunity in the intestine

  Yoshitake Kanazawa, Yasuyuki Saito, Yana Supriatna, Hiroyuki Tezuka, Takenori Kotani, Yoji Murata, Hideki Okazawa, Hiroshi Ohnishi, Yoshitaka Kinouchi, Yoshihisa Nojima, Toshiaki Ohteki, Tooru Shimosegawa, Takashi Matozaki

  Dec. 2010, GENES TO CELLS, 15(12) (12), 1189 - 1200, English

  [Refereed]

  Scientific journal


• Regulation by SIRP alpha of dendritic cell homeostasis in lymphoid tissues

  Yasuyuki Saito, Hiroko Iwamura, Tetsuya Kaneko, Hiroshi Ohnishi, Yoji Murata, Hideki Okazawa, Yoshitake Kanazawa, Miho Sato-Hashimoto, Hisae Kobayashi, Per-Arne Oldenborg, Makoto Naito, Yoriaki Kaneko, Yoshihisa Nojima, Takashi Matozaki

  Nov. 2010, BLOOD, 116(18) (18), 3517 - 3525, English

  [Refereed]

  Scientific journal


• Requirement of SIRP alpha for protective immunity against Leishmania major

  Naoko Morimoto, Yoji Murata, Sei-ichiro Motegi, Kazutomo Suzue, Yasuyuki Saito, Hideki Okazawa, Hiroshi Ohnishi, Takenori Kotani, Shinya Kusakari, Osamu Ishikawa, Takashi Matozaki

  Oct. 2010, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 401(3) (3), 385 - 389, English

  [Refereed]

  Scientific journal


• 樹状細胞分子SHPS-1による皮膚免疫制御とその皮膚アレルギーへの治療的応用

  Matozaki Takashi

  Sep. 2010, コスメトロジー研究報告, 18巻, , pp. 57-61, Japanese

  [Refereed]

  Scientific journal


• 脳におけるSIRPαチロシンリン酸化の解析

  Matozaki Takashi

  Aug. 2010, The Kitakanto Medical Journal, 60巻, 3号, pp. 302-303, Japanese

  International conference proceedings


• Stress-Evoked Tyrosine Phosphorylation of Signal Regulatory Protein alpha Regulates Behavioral Immobility in the Forced Swim Test

  Hiroshi Ohnishi, Takaaki Murata, Shinya Kusakari, Yuriko Hayashi, Keizo Takao, Toshi Maruyama, Yukio Ago, Ken Koda, Feng-Jie Jin, Katsuya Okawa, Per-Arne Oldenborg, Hideki Okazawa, Yoji Murata, Nobuhiko Furuya, Toshio Matsuda, Tsuyoshi Miyakawa, Takashi Matozaki

  Aug. 2010, JOURNAL OF NEUROSCIENCE, 30(31) (31), 10472 - 10483, English

  [Refereed]

  Scientific journal


• Promotion of Cell Spreading and Migration by Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) in Cooperation With Integrins

  Munemasa Mori, Yoji Murata, Takenori Kotani, Shinya Kusakari, Hiroshi Ohnishi, Yasuyuki Saito, Hideki Okazawa, Tamotsu Ishizuka, Masatomo Mori, Takashi Matozaki

  Jul. 2010, JOURNAL OF CELLULAR PHYSIOLOGY, 224(1) (1), 195 - 204, English

  [Refereed]

  Scientific journal


• Tyrosine phosphorylation of R3 subtype receptor-type protein tyrosine phosphatases and their complex formations with Grb2 or Fyn

  Yoji Murata, Munemasa Mori, Takenori Kotani, Yana Supriatna, Hideki Okazawa, Shinya Kusakari, Yasuyuki Saito, Hiroshi Ohnishi, Takashi Matozaki

  May 2010, GENES TO CELLS, 15(5) (5), 513 - 524, English

  [Refereed]

  Scientific journal


• SIRP-αは糸球体上皮細胞の形態と蛋白尿制御に関与する

  Matozaki Takashi

  (一社)日本腎臓学会, May 2010, 日本腎臓学会誌, 52巻, 3号, pp. 343-343(3) (3), 343 - 343, Japanese

  International conference proceedings


• Expression of PTPRO in the Interneurons of Adult Mouse Olfactory Bulb

  Takenori Kotani, Yoji Murata, Hiroshi Ohnishi, Munemasa Mori, Shinya Kusakari, Yasuyuki Saito, Hideki Kazawa, John L. Bixby, Takashi Matozaki

  Jan. 2010, JOURNAL OF COMPARATIVE NEUROLOGY, 518(2) (2), 119 - 136, English

  [Refereed]

  Scientific journal


• Protein tyrosine phosphatase SHP-2: A proto-oncogene product that promotes Ras activation

  Takashi Matozaki, Yoji Murata, Yasuyuki Saito, Hideki Okazawa, Hiroshi Ohnishi

  Oct. 2009, CANCER SCIENCE, 100(10) (10), 1786 - 1793, English

  [Refereed]

  Scientific journal


• 糖尿病性腎症におけるSHPS-1シグナル経路に関する検討

  高橋 哲史, 廣村 桂樹, 富岡 麻衣, 竹内 茂, 前嶋 明人, 黒岩 卓, 金子 和光, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本腎臓学会, Apr. 2009, 日本腎臓学会誌, 51(3) (3), 260 - 260, Japanese


• SAP-1 is a microvillus-specific protein tyrosine phosphatase that modulates intestinal tumorigenesis

  Hisanobu Sadakata, Hideki Okazawa, Takashi Sato, Yana Supriatna, Hiroshi Ohnishi, Shinya Kusakari, Yoji Murata, Tomokazu Ito, Uichi Nishiyama, Takashi Minegishi, Akihiro Harada, Takashi Matozaki

  Mar. 2009, GENES TO CELLS, 14(3) (3), 295 - 308, English

  [Refereed]

  Scientific journal


• Functions and molecular mechanisms of the CD47-SIRP alpha signalling pathway

  Takashi Matozaki, Yoji Murata, Hideki Okazawa, Hiroshi Ohnish

  Feb. 2009, TRENDS IN CELL BIOLOGY, 19(2) (2), 72 - 80, English

  [Refereed]

  Scientific journal


• Expression of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 in Pancreatic beta-Cells and Its Role in Promotion of Insulin Secretion and Protection against Diabetes

  Masaki Kobayashi, Hiroshi Ohnishi, Hideki Okazawa, Yoji Murata, Yuriko Hayashi, Hisae Kobayashi, Tadahiro Kitamura, Takashi Matozaki

  Nov. 2008, ENDOCRINOLOGY, 149(11) (11), 5662 - 5669, English

  [Refereed]

  Scientific journal


• Essential roles of SHPS-1 in induction of contact hypersensitivity of skin

  Sei-Ichiro Motegi, Hideki Okazawa, Yoji Murata, Yoshitake Kanazawa, Yasuyuki Saito, Hisae Kobayashi, Hiroshi Ohnishi, Per-Arne Oldenborg, Osamu Ishikawa, Takashi Matozaki

  Nov. 2008, IMMUNOLOGY LETTERS, 121(1) (1), 52 - 60, English

  [Refereed]

  Scientific journal


• Resistance to collagen-induced arthritis in SHPS-1 mutant mice

  Chie Okuzawa, Yoriaki Kaneko, Yoji Murata, Astuko Miyake, Yasuyuki Saito, Jun Okajo, Takeshi Tomizawa, Yuka Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Takashi Matozaki, Yoshihisa Nojima

  Jul. 2008, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 371(3) (3), 561 - 566, English

  [Refereed]

  Scientific journal


• Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages

  Shoko Kuroda, Miki Nishio, Takehiko Sasaki, Yasuo Horie, Koichi Kawahara, Masato Sasaki, Miyuki Natsui, Takashi Matozaki, Hiroyuki Tezuka, Toshiaki Ohteki, Irmgard Foerster, Tak W. Mak, Toru Nakano, Akira Suzuki

  May 2008, EUROPEAN JOURNAL OF IMMUNOLOGY, 38(5) (5), 1331 - 1340, English

  [Refereed]

  Scientific journal


• Impaired proliferation and Th1 differentiation of CD4+ T cells of SHPS-1 mutant mice

  Yuka Kaneko, Yoriaki Kaneko, Hiroshi Ohnishi, Takeshi Tomizawa, Jun Okajo, Yasuyuki Saito, Chie Okuzawa, Yoji Murata, Hideki Okazawa, Yoshihisa Nojima, Koichi Okamoto, Takashi Matozaki

  May 2008, Kitakanto Medical Journal, 58(2) (2), 133 - 139, English

  [Refereed]

  Scientific journal


• SHPS-1は糸球体上皮細胞に発現し、障害時の蛋白尿の制御に関与する

  富岡 麻衣, 廣村 桂樹, 竹内 茂, 坂入 徹, 奥沢 千絵, 岡上 準, 冨澤 健史, 前嶋 明人, 黒岩 卓, 金子 和光, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本腎臓学会, Apr. 2008, 日本腎臓学会誌, 50(3) (3), 365 - 365, Japanese


• Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system

  Shinya Kusakari, Hiroshi Ohnishi, Feng-Jie Jin, Yuka Kaneko, Takaaki Murata, Yoji Murata, Hideki Okazawa, Takashi Matozaki

  Apr. 2008, JOURNAL OF CELL SCIENCE, 121(8) (8), 1213 - 1223, English

  [Refereed]

  Scientific journal


• Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages

  Atsuko Miyake, Yoji Murata, Hideki Okazawa, Hiroshi Ikeda, Yuriko Niwayama, Hiroshi Ohnishi, Yukio Hirata, Takashi Matozaki

  Feb. 2008, GENES TO CELLS, 13(2) (2), 209 - 219, English

  [Refereed]

  Scientific journal


• Structural insight into the specific interaction between murine SHPS-1/SIRP alpha and its ligand CD47

  Aki Nakaishi, Mayumi Hirose, Masato Yoshimura, Chitose Oneyama, Kazunobu Saito, Nobuharu Kuki, Makoto Matsuda, Nakayuki Honma, Hiroshi Ohnishi, Takashi Matozaki, Masato Okada, Atsushi Nakagawa

  Jan. 2008, JOURNAL OF MOLECULAR BIOLOGY, 375(3) (3), 650 - 660, English

  [Refereed]

  Scientific journal


• 自己免疫性関節炎におけるSHPS-1の機能解析

  奥沢 千絵, 金子 和光, 村田 陽二, 冨澤 健史, 岡上 準, 斉藤 泰之, 池内 秀和, 坂入 徹, 山下 真, 前嶋 明人, 黒岩 卓, 廣村 桂樹, 的崎 尚, 野島 美久

  (一社)日本臨床免疫学会, Aug. 2007, 日本臨床免疫学会会誌, 30(4) (4), 312 - 312, Japanese


• Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice

  Takeshi Tomizawa, Yuka Kaneko, Yoriaki Kaneko, Yasuyuki Saito, Hiroshi Ohnishi, Jun Okajo, Chie Okuzawa, Tomomi Ishikawa-Sekigami, Yoji Murata, Hideki Okazawa, Koichi Okamoto, Yoshihisa Nojima, Takashi Matozaki

  Jul. 2007, JOURNAL OF IMMUNOLOGY, 179(2) (2), 869 - 877, English

  [Refereed]

  Scientific journal


• Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of alpha-galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells

  Jun Okajo, Yoriaki Kaneko, Yoji Murata, Takeshi Tomizawa, Chie Okuzawa, Yasuyuki Saito, Yuka Kaneko, Tomomi Ishikawa-Sekigami, Hideki Okazawa, Hiroshi Ohnishi, Takashi Matozaki, Yoshihisa Nojima

  May 2007, JOURNAL OF IMMUNOLOGY, 178(10) (10), 6164 - 6172, English

  [Refereed]

  Scientific journal


• CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42

  Takaaki Murata, Hiroshi Ohnishi, Hideki Okazawa, Yoji Murata, Shinya Kusakari, Yuriko Hayashi, Motoaki Miyashita, Hiroshi Itoh, Per-Arne Oldenborg, Nobuhiko Furuya, Takashi Matozaki

  Nov. 2006, JOURNAL OF NEUROSCIENCE, 26(48) (48), 12397 - 12407, English

  [Refereed]

  Scientific journal


• Mutational analysis of the mechanism of negative regulation by Src homology 2 domwin-containing protein tyrosine phosphatase substrate-1 of phagocytosis in macrophages

  Hiroshi Ikeda, Hideki Okazawa, Hiroshi Ohnishi, Yoji Murata, Per-Arne Oldenborg, Takashi Matozaki

  Sep. 2006, JOURNAL OF IMMUNOLOGY, 177(5) (5), 3123 - 3132, English

  [Refereed]

  Scientific journal


• CD47 regulation of epithelial cell spreading and migration, and its signal transduction

  Masahiko Shinohara, Naoko Ohyama, Yoji Murata, Hideki Okazawa, Hiroshi Ohnishi, Osamu Ishikawa, Takashi Matozaki

  Sep. 2006, CANCER SCIENCE, 97(9) (9), 889 - 895, English

  [Refereed]

  Scientific journal


• Enhanced phagocytosis of CD47-deficient red blood cells by splenic macrophages requires SHPS-1

  T Ishikawa-Sekigami, Y Kaneko, Y Saito, Y Murata, H Okazawa, H Ohnishi, PA Oldenborg, Y Nojima, T Matozaki

  May 2006, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 343(4) (4), 1197 - 1200, English

  [Refereed]

  Scientific journal


• Engagement of CD47 inhibits the contact hypersensitivity response via the suppression of motility and B7 expression by Langerhans cells

  Xijun Yu, Atsushi Fukunaga, Hiroshi Nagai, Shuntaro Oniki, Nakayuki Honma, Masamitsu Ichihashi, Takashi Matozaki, Chikako Nishigori, Tatsuya Horikawa

  Apr. 2006, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 126(4) (4), 797 - 807, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Crystallization and preliminary X-ray analysis of rat SHPS-1

  A Nagata, H Ohnishi, M Yoshimura, A Ogawa, S Ujita, H Adachi, M Okada, T Matozaki, A Nakagawa

  Mar. 2006, ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, 62, 189 - 191, English

  [Refereed]

  Scientific journal


• SHPチロシンホスファターゼによる細胞運動・細胞接着制御

  村田 陽二, MATOZAKI TAKASHI

  2006, 実験医学, 第24巻(第13号) (第13号), 1951 - 1959, Japanese

  [Refereed]

  Scientific journal


• SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages

  T Ishikawa-Sekigami, Y Kaneko, H Okazawa, T Tomizawa, J Okajo, Y Saito, C Okuzawa, M Sugawara-Yokoo, L Nishiyama, H Ohnishi, T Matozaki, Y Nojima

  Jan. 2006, BLOOD, 107(1) (1), 341 - 348, English

  [Refereed]

  Scientific journal


• Crystallization and preliminary X-ray analysis of rat SHPS-1

  Aki Nagata, Hiroshi Ohnishi, Masato Yoshimura, Akira Ogawa, Sayuri Ujita, Hiroaki Adachi, Masato Okada, Takashi Matozaki, Atsushi Nakagawa

  2006, Acta Crystallographica Section F: Structural Biology and Crystallization Communications, 62(3) (3), 189 - 191, English

  [Refereed]

  Scientific journal


• A nomenclature for signal regulatory protein family members

  TK van den Berg, EM van Beek, HJ Buhring, M Colonna, M Hamaguchi, CJ Howard, M Kasuga, Y Liu, T Matozaki, BG Neel, CA Parkos, S Sano, A Vignery, E Vivier, M Wright, R Zawatzky, AN Barclay

  Dec. 2005, JOURNAL OF IMMUNOLOGY, 175(12) (12), 7788 - 7789, English

  [Refereed]

  Scientific journal


• SHP tyrosine phosphatases and a novel cell-signaling system

  T Matozaki, H Ohnishi

  Oct. 2005, SEIKAGAKU, 77(10) (10), 1299 - 1307, Japanese

  [Refereed]

  Scientific journal


• Differential localization of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 and CD47 and its molecular mechanisms in cultured hippocampal neurons

  H Ohnishi, Y Kaneko, H Okazawa, M Miyashita, R Sato, A Hayashi, K Tada, S Nagata, M Takahashi, T Matozaki

  Mar. 2005, JOURNAL OF NEUROSCIENCE, 25(10) (10), 2702 - 2711, English

  [Refereed]

  Scientific journal


• Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system

  H Okazawa, SI Motegi, N Ohyama, H Ohnishi, T Tomizawa, Y Kaneko, PA Oldenborg, O Ishikawa, T Matozaki

  Feb. 2005, JOURNAL OF IMMUNOLOGY, 174(4) (4), 2004 - 2011, English

  [Refereed]

  Scientific journal


• SHPチロシンホスファターゼと新たなシグナル伝達機構

  大西 浩史, MATOZAKI TAKASHI

  2005, 生化学, 第77巻(第10号) (第10号), 1299 - 1307, Japanese

  [Refereed]

  Scientific journal


• Promotion of neurite and filopodium formation by CD47: Roles of integrins, Rac, and Cdc42

  M Miyashita, H Ohnishi, H Okazawa, H Tomonaga, A Hayashi, TT Fujimoto, N Furuya, T Matozaki

  Aug. 2004, MOLECULAR BIOLOGY OF THE CELL, 15(8) (8), 3950 - 3963, English

  [Refereed]

  Scientific journal


• Positive regulation of phagocytosis by SIRP beta and its signaling mechanism in macrophages

  A Hayashi, H Ohnishi, H Okazawa, S Nakazawa, H Ikeda, S Motegi, N Aoki, S Kimura, M Mikuni, T Matozaki

  Jul. 2004, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(28) (28), 29450 - 29460, English

  [Refereed]

  Scientific journal


• Ectodomain shedding of SHPS-1 and its role in regulation of cell migration

  H Ohnishi, H Kobayashi, H Okazawa, Y Ohe, K Tomizawa, R Sato, T Matozaki

  Jul. 2004, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(27) (27), 27878 - 27887, English

  [Refereed]

  Scientific journal


• Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 regulates the migration of Langerhans cells from the epidermis to draining lymph nodes

  A Fukunaga, H Nagai, T Noguchi, H Okazawa, T Matozaki, XJ Yu, CF Lagenaur, N Honma, M Ichihashi, M Kasuga, C Nishigori, T Horikawa

  Apr. 2004, JOURNAL OF IMMUNOLOGY, 172(7) (7), 4091 - 4099, English

  [Refereed]

  Scientific journal


• Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis

  T Koga, M Inui, K Inoue, S Kim, A Suematsu, E Kobayashi, T Iwata, H Ohnishi, T Matozaki, T Kodama, T Taniguchi, H Takayanagi, T Takai

  Apr. 2004, NATURE, 428(6984) (6984), 758 - 763, English

  [Refereed]

  Scientific journal


• Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress

  R Murai-Takebe, T Noguchi, T Ogura, T Mikami, K Yanagi, K Inagaki, H Ohnishi, T Matozaki, M Kasuga

  Mar. 2004, JOURNAL OF BIOLOGICAL CHEMISTRY, 279(12) (12), 11616 - 11625, English

  [Refereed]

  Scientific journal


• 新規細胞間シグナル伝達システムCD47-SHPS-1系の機能

  大西 浩史, 岡澤 秀樹, MATOZAKI TAKASHI

  2004, 細胞工学, 23(5) (5), 546 - 550, Japanese

  [Refereed]

  Scientific journal


• Regulation of multiple functions of SHPS-1, a transmembrane glycoprotein, by its cytoplasmic region

  R Sato, H Ohnishi, H Kobayashi, D Kiuchi, A Hayashi, Y Kaneko, N Honma, H Okazawa, Y Hirata, T Matozaki

  Sep. 2003, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 309(3) (3), 584 - 590, English

  [Refereed]

  Scientific journal


• Interaction of SAP-1, a transmembrane-type protein-tyrosine phosphatase, with the tyrosine kinase Lck - Roles in regulation of T cell function

  T Ito, H Okazawa, K Maruyama, K Tomizawa, S Motegi, H Ohnishi, H Kuwano, A Kosugi, T Matozaki

  Sep. 2003, JOURNAL OF BIOLOGICAL CHEMISTRY, 278(37) (37), 34854 - 34863, English

  [Refereed]

  Scientific journal


• Characterization of nucleotide pyrophosphatase-5 as an oligomannosidic glycoprotein in rat brain

  Y Ohe, H Ohnishi, H Okazawa, K Tomizawa, H Kobayashi, K Okawa, T Matozaki

  Sep. 2003, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 308(4) (4), 719 - 725, English

  [Refereed]

  Scientific journal


• Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma

  H Nagano, T Noguchi, K Inagaki, S Yoon, T Matozaki, H Itoh, M Kasuga, Y Hayashi

  Jul. 2003, ONCOGENE, 22(30) (30), 4656 - 4663, English

  [Refereed]

  Scientific journal


• Role of the CD47-SHPS-1 system in regulation of cell migration

  S Motegi, H Okazawa, H Ohnishi, R Sato, Y Kaneko, H Kobayashi, K Tomizawa, T Ito, N Honma, HJ Buhring, O Ishikawa, T Matozaki

  Jun. 2003, EMBO JOURNAL, 22(11) (11), 2634 - 2644, English

  [Refereed]

  Scientific journal


• Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1

  T Yamao, T Noguchi, O Takeuchi, U Nishiyama, H Morita, T Hagiwara, H Akahori, T Kato, K Inagaki, H Okazawa, Y Hayashi, T Matozaki, K Takeda, S Akira, M Kasuga

  Oct. 2002, JOURNAL OF BIOLOGICAL CHEMISTRY, 277(42) (42), 39833 - 39839, English

  [Refereed]

  Scientific journal


• Induction of apoptosis by stomach cancer-associated protein-tyrosine phosphatase-1

  T Takada, T Noguchi, K Inagaki, T Hosooka, K Fukunaga, T Yamao, W Ogawa, T Matozaki, M Kasuga

  Sep. 2002, JOURNAL OF BIOLOGICAL CHEMISTRY, 277(37) (37), 34359 - 34366, English

  [Refereed]

  Scientific journal


• Regulation of Ras and Rho small G proteins by SHP-2

  A Kodama, T Matozaki, M Shinohara, A Fukuhara, K Tachibana, M Ichihashi, H Nakanishi, Y Takai

  Oct. 2001, GENES TO CELLS, 6(10) (10), 869 - 876, English

  [Refereed]

  Scientific journal


• Inhibition of the motility and growth of B16F10 mouse melanoma cells by dominant negative mutants of Dok-1

  T Hosooka, T Noguchi, H Nagai, T Horikawa, T Matozaki, M Ichihashi, M Kasuga

  Aug. 2001, MOLECULAR AND CELLULAR BIOLOGY, 21(16) (16), 5437 - 5446, English

  [Refereed]

  Scientific journal


• Analysis of tyrosine phosphorylation-dependent protein-protein interactions in TrkB-mediated intracellular signaling using modified yeast two-hybrid system

  M Yamada, K Suzuki, M Mizutani, A Asada, T Matozaki, T Ikeuchi, S Koizumi, H Hatanaka

  Jul. 2001, JOURNAL OF BIOCHEMISTRY, 130(1) (1), 157 - 165, English

  [Refereed]

  Scientific journal


• Roles of cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1

  M Shinohara, A Kodama, T Matozaki, A Fukuhara, K Tachibana, H Nakanishi, Y Takai

  Jun. 2001, JOURNAL OF BIOLOGICAL CHEMISTRY, 276(22) (22), 18941 - 18946, English

  [Refereed]

  Scientific journal


• Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130(cas)

  T Noguchi, M Tsuda, H Takeda, T Takada, K Inagaki, T Yamao, K Fukunaga, T Matozaki, M Kasuga

  May 2001, JOURNAL OF BIOLOGICAL CHEMISTRY, 276(18) (18), 15216 - 15224, English

  [Refereed]

  Scientific journal


• Small GTP-binding proteins

  Y Takai, T Sasaki, T Matozaki

  Jan. 2001, PHYSIOLOGICAL REVIEWS, 81(1) (1), 153 - 208, English

  [Refereed]

  Scientific journal


• SHPS-1 regulates integrin-mediated cytoskeletal reorganization and cell motility

  K Inagaki, T Yamao, T Noguchi, T Matozaki, K Fukunaga, T Takada, T Hosooka, S Akira, M Kasuga

  Dec. 2000, EMBO JOURNAL, 19(24) (24), 6721 - 6731, English

  [Refereed]

  Scientific journal


• Multiple downstream signalling pathways from ROCK, a target molecule of Rho small G protein, in reorganization of the actin cytoskeleton in Madin-Darby canine kidney cells

  K Takaishi, T Matozaki, K Nakano, Y Takai

  Nov. 2000, GENES TO CELLS, 5(11) (11), 929 - 936, English

  [Refereed]

  Scientific journal


• 細胞の運動と接着のシグナル伝達機構

  高井 義美, 中西 宏之, 萬代 研二, 的崎 尚

  日本癌学会, Sep. 2000, 日本癌学会総会記事, 59回, 445 - 445, Japanese


• Small G-protein networks - Their crosstalk and signal cascades

  T Matozaki, H Nakanishi, Y Takai

  Aug. 2000, CELLULAR SIGNALLING, 12(8) (8), 515 - 524, English

  [Refereed]

  Scientific journal


• Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering

  A Kodama, T Matozaki, A Fukuhara, M Kikyo, M Ichihashi, Y Takai

  Aug. 2000, MOLECULAR BIOLOGY OF THE CELL, 11(8) (8), 2565 - 2575, English

  [Refereed]

  Scientific journal


• Cell-cell adhesion-mediated tyrosine phosphorylation of nectin-2 delta, an immunoglobulin-like cell adhesion molecule at adherens junctions

  M Kikyo, T Matozaki, A Kodama, H Kawabe, H Nakanishi, Y Takai

  Aug. 2000, ONCOGENE, 19(35) (35), 4022 - 4028, English

  [Refereed]

  Scientific journal


• Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH2-terminal kinase

  K Fukunaga, T Noguchi, H Takeda, T Matozaki, Y Hayashi, H Itoh, M Kasuga

  Feb. 2000, JOURNAL OF BIOLOGICAL CHEMISTRY, 275(7) (7), 5208 - 5213, English

  [Refereed]

  Scientific journal


• Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering.

  Kodama, A, Matozaki, T, Fukuhara, A, Kikyo, M, Ichihashi, M, Takai, Y

  2000, Mol. Biol. Cell, 11(5) (5), 1875 - 1886

  [Refereed]


• Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant

  K Inagaki, T Noguchi, T Matozaki, T Horikawa, K Fukunaga, M Tsuda, M Ichihashi, M Kasuga

  Jan. 2000, ONCOGENE, 19(1) (1), 75 - 84, English

  [Refereed]

  Scientific journal


• Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion in MDCK cells - regulation by Rho, Rac and Rab small G proteins

  T Kamei, T Matozaki, T Sakisaka, A Kodama, S Yokoyama, YF Peng, K Nakano, K Takaishi, Y Takai

  Nov. 1999, ONCOGENE, 18(48) (48), 6776 - 6784, English

  [Refereed]

  Scientific journal


• The distribution and characterization of SHPS-1, that binds protein tyrosine phosphatase SHP-2, in the human and rat brain

  K Fukunaga, T Matozaki, Y Hayashi, Y Fujioka, M Tsuda, T Takada, T Noguchi, M Kasuga, H Ito

  Aug. 1999, BIOMEDICAL RESEARCH-TOKYO, 20(4) (4), 197 - 203, English

  [Refereed]

  Scientific journal


• Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration

  T Noguchi, T Matozaki, K Inagaki, M Tsuda, K Fukunaga, Y Kitamura, T Kitamura, K Shii, Y Yamanashi, M Kasuga

  Apr. 1999, EMBO JOURNAL, 18(7) (7), 1748 - 1760, English

  [Refereed]

  Scientific journal


• PI 3-kinase gamma and protein kinase C-zeta mediate RAS-independent activation of MAP kinase by a G(i) protein-coupled receptor

  H Takeda, T Matozaki, T Takada, T Noguchi, T Yamao, M Tsuda, F Ochi, K Fukunaga, K Inagaki, M Kasuga

  Jan. 1999, EMBO JOURNAL, 18(2) (2), 386 - 395, English

  [Refereed]

  Scientific journal


• Differential expression of SHP2, a protein-tyrosine phosphatase with SRC homology-2 domains, in various types of renal tumour

  N Kuroda, Y Hayashi, T Matozaki, K Hanioka, A Gotoh, WP Wang, H Uchida, K Hashimoto, Y Iwai, K Kawasaki, Y Imai, M Kasuga, H Itoh

  Oct. 1998, VIRCHOWS ARCHIV-AN INTERNATIONAL JOURNAL OF PATHOLOGY, 433(4) (4), 331 - 339, English

  [Refereed]

  Scientific journal


• Lysophosphatidic acid-induced association of SHP-2 with SHPS-1: roles of RHO, FAK, and a SRC family kinase

  H Takeda, T Matozaki, Y Fujioka, T Takada, T Noguchi, T Yamao, M Tsuda, F Ochi, K Fukunaga, S Narumiya, T Yamamoto, M Kasuga

  Jun. 1998, ONCOGENE, 16(23) (23), 3019 - 3027, English

  [Refereed]

  Scientific journal


• Integrin-mediated tyrosine phosphorylation of SHPS-1 and its association with SHP-2 - Roles of Fak and Src family kinases

  M Tsuda, T Matozaki, K Fukunaga, Y Fujioka, A Imamoto, T Noguchi, T Takada, T Yamao, H Takeda, F Ochi, T Yamamoto, M Kasuga

  May 1998, JOURNAL OF BIOLOGICAL CHEMISTRY, 273(21) (21), 13223 - 13229, English

  [Refereed]

  Scientific journal


• Roles of the complex formation of SHPS-1 with SHP-2 in insulin-stimulated mitogen-activated protein kinase activation

  T Takada, T Matozaki, H Takeda, K Fukunaga, T Noguchi, Y Fujioka, Okazaki, I, M Tsuda, T Yamao, F Ochi, M Kasuga

  Apr. 1998, JOURNAL OF BIOLOGICAL CHEMISTRY, 273(15) (15), 9234 - 9242, English

  [Refereed]

  Scientific journal


• The signal transduction of receptor tyrosine kinase

  T. Takada, T. Matozaki, M. Kasuga

  1998, Nippon rinsho. Japanese journal of clinical medicine, 56(7) (7), 1756 - 1762, Japanese

  Scientific journal


• Epidermal growth factor stimulates the tyrosine phosphorylation of SHPS-1 and association of SHPS-1 with SHP-2, a SH2 domain-containing protein tyrosine phosphatase

  F Ochi, T Matozaki, T Noguchi, Y Fujioka, T Yamao, T Takada, M Tsuda, H Takeda, K Fukunaga, Y Okabayashi, M Kasuga

  Oct. 1997, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 239(2) (2), 483 - 487, English

  [Refereed]

  Scientific journal


• Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain

  M Adachi, M Ishino, T Torigoe, Y Minami, T Matozaki, T Miyazaki, T Taniguchi, Y Hinoda, K Imai

  Apr. 1997, ONCOGENE, 14(13) (13), 1629 - 1633, English

  [Refereed]

  Scientific journal


• Mouse and human SHPS-1: Molecular cloning of cDNAs and chromosomal localization of genes

  T Yamao, T Matozaki, K Amano, Y Matsuda, N Takahashi, F Ochi, Y Fujioka, M Kasuga

  Feb. 1997, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 231(1) (1), 61 - 67, English

  [Refereed]

  Scientific journal


• Overexpression of SAP-1, a transmembrane-type protein tyrosine phosphatase, in human colorectal cancers

  Y Seo, T Matozaki, M Tsuda, Y Hayashi, H Itoh, M Kasuga

  Feb. 1997, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 231(3) (3), 705 - 711, English

  [Refereed]

  Scientific journal


• A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion

  Y Fujioka, T Matozaki, T Noguchi, A Iwamatsu, T Yamao, N Takahashi, M Tsuda, T Takada, M Kasuga

  Dec. 1996, MOLECULAR AND CELLULAR BIOLOGY, 16(12) (12), 6887 - 6899, English

  [Refereed]

  Scientific journal


• Characterization of a 115-kDa protein that binds to SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in Chinese hamster ovary cells

  T Noguchi, T Matozaki, Y Fujioka, T Yamao, M Tsuda, T Takada, M Kasuga

  Nov. 1996, JOURNAL OF BIOLOGICAL CHEMISTRY, 271(44) (44), 27652 - 27658, English

  [Refereed]

  Scientific journal


• Effects of growth factors and gut hormones on proliferation of primary cultured gastric mucous cells of guinea pig

  K Matsuda, C Sakamoto, Y Konda, O Nakano, T Matozaki, H Nishisaki, T Suzuki, T Uchida, K Wada, T Fujimori, S Maeda, M Kasuga

  Aug. 1996, JOURNAL OF GASTROENTEROLOGY, 31(4) (4), 498 - 504, English

  [Refereed]

  Scientific journal


• LOCALIZATION AND SUBCELLULAR-DISTRIBUTION OF SH-PTP2, A PROTEIN-TYROSINE-PHOSPHATASE WITH SRC HOMOLOGY-2 DOMAINS, IN RAT-BRAIN

  T SUZUKI, T MATOZAKI, A MIZOGUCHI, M KASUGA

  Jun. 1995, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 211(3) (3), 950 - 959, English

  [Refereed]

  Scientific journal


• ROLE OF SH-PTP2, A PROTEIN-TYROSINE-PHOSPHATASE WITH SRC HOMOLOGY-2 DOMAINS, IN INSULIN-STIMULATED RAS ACTIVATION

  T NOGUCHI, T MATOZAKI, K HORITA, Y FUJIOKA, M KASUGA

  Oct. 1994, MOLECULAR AND CELLULAR BIOLOGY, 14(10) (10), 6674 - 6682, English

  [Refereed]

  Scientific journal


• SRC KINASE TYROSINE PHOSPHORYLATES PTP1C, A PROTEIN-TYROSINE-PHOSPHATASE CONTAINING SRC HOMOLOGY-2 DOMAINS THAT DOWN-REGULATES CELL-PROLIFERATION

  T MATOZAKI, T UCHIDA, Y FUJIOKA, M KASUGA

  Oct. 1994, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 204(2) (2), 874 - 881, English

  [Refereed]

  Scientific journal


• INSULIN STIMULATES THE PHOSPHORYLATION OF TYR(538) AND THE CATALYTIC ACTIVITY OF PTP1C, A PROTEIN-TYROSINE-PHOSPHATASE WITH SRC HOMOLOGY-2 DOMAINS

  T UCHIDA, T MATOZAKI, T NOGUCHI, T YAMAO, K HORITA, T SUZUKI, Y FUJIOKA, C SAKAMOTO, M KASUGA

  Apr. 1994, JOURNAL OF BIOLOGICAL CHEMISTRY, 269(16) (16), 12220 - 12228, English

  [Refereed]

  Scientific journal


• EGF STIMULATES BOTH CYCLOOXYGENASE ACTIVITY AND CELL-PROLIFERATION OF CULTURED GUINEA-PIG GASTRIC MUCOUS CELLS

  C SAKAMOTO, K MATSUDA, O NAKANO, Y KONDA, T MATOZAKI, H NISHISAKI, M KASUGA

  1994, JOURNAL OF GASTROENTEROLOGY, 29, 73 - 76, English

  [Refereed]

  Scientific journal


• MOLECULAR-CLONING OF A HUMAN TRANSMEMBRANE-TYPE PROTEIN-TYROSINE-PHOSPHATASE AND ITS EXPRESSION IN GASTROINTESTINAL CANCERS

  T MATOZAKI, T SUZUKI, T UCHIDA, J INAZAWA, T ARIYAMA, K MATSUDA, K HORITA, H NOGUCHI, H MIZUNO, C SAKAMOTO, M KASUGA

  Jan. 1994, JOURNAL OF BIOLOGICAL CHEMISTRY, 269(3) (3), 2075 - 2081, English

  [Refereed]

  Scientific journal


• PHORBOL ESTER STIMULATES THE ACTIVITY OF A PROTEIN-TYROSINE-PHOSPHATASE CONTAINING SH(2) DOMAINS (PTP1C) IN HL-60 LEUKEMIA-CELLS BY INCREASING GENE-EXPRESSION

  T UCHIDA, T MATOZAKI, K MATSUDA, T SUZUKI, S MATOZAKI, O NAKANO, K WADA, Y KONDA, C SAKAMOTO, M KASUGA

  Jun. 1993, JOURNAL OF BIOLOGICAL CHEMISTRY, 268(16) (16), 11845 - 11850, English

  [Refereed]

  Scientific journal


• PGE2 PROTECTS ISOLATED CELLS AGAINST INJURY THROUGH MULTIPLE MECHANISMS

  C SAKAMOTO, K MATSUDA, Y KONDA, H NISHISAKI, O NAKANO, T MATOZAKI, K WADA, T SUZUKI, T UCHIDA, H NOGUCHI, H MIZUNO, M KASUGA

  May 1993, GASTROENTEROLOGIA JAPONICA, 28, 122 - 126, English

  [Refereed]

  Scientific journal


• Effect of prostaglandin E2 on the proliferation of cultured guinea pig gastric mucous cells.

  NAKANO Osamu, SAKAMOTO Choitsu, KONDA Yoshitaka, MATSUDA Kohei, MATOZAKI Takashi, NISHISAKI Hogara, WADA Ken, SUZUKI Toshiya, UCHIDA Toru, NAGAO Munehiko, KASUGA Masato

  To understand the mechanism by which prostaglandins (PGs) preserve gastric mucosal integrity, we established a primary cultured monolayer of guinea pig gastric mucous cells, and by using this culture system, we studied whether endogenously released PGE₂ could influence the proliferation of the mucous cells. By the histochemical and morphological analysis at 24h of the culture periods, the cells were recognized to contain PAS-positive mucous granules with only 3% of them being parietal cells. Although the cells which were simultaneously labeled with [³H] arachidonic acid in 0.5% serum-containing medium synthesized and released radiolabeled PGE₂, PGI₂ and PGA₂, the release of PGE₂ was more markedly observed and was partially dependent upon arachidonic acid added to the ulture medium. By radioimmunoassay of the culture media, the mucous cells were found to release PGE₂ in a time-dependent manner in response to 10% serum.
  Pretreatment of the cells with 10^-4M indomethacin not only inhibited PGE₂ release but also inhibited increase in cell number. However, the addition of PGE₂ dose-dependently restored the indomethacin-induced inhibition of cell growth with the maximal increase almost to the control level at 10^-6M PGE₂. These results suggest that PGE₂ endogenously released from the cells may exert a proliferative effect on gastric mucous cells.

  The Japanese Society of Gastroenterology, 1993, Nippon Shokakibyo Gakkai Zasshi, 90(1) (1), 9 - 15, Japanese


• EXPRESSION OF 2 TYPES OF NEUROFIBROMATOSIS TYPE-1 GENE TRANSCRIPTS IN GASTRIC CANCERS AND COMPARISON OF GAP ACTIVITIES

  T UCHIDA, T MATOZAKI, T SUZUKI, K MATSUDA, K WADA, O NAKANO, Y KONDA, H NISHISAKI, M NAGAO, C SAKAMOTO, M KASUGA

  Aug. 1992, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 187(1) (1), 332 - 339, English

  [Refereed]

  Scientific journal


• P53 GENE-MUTATIONS IN HUMAN GASTRIC-CANCER - WILD-TYPE P53 BUT NOT MUTANT P53 SUPPRESSES GROWTH OF HUMAN GASTRIC-CANCER CELLS

  T MATOZAKI, C SAKAMOTO, T SUZUKI, K MATSUDA, T UCHIDA, O NAKANO, K WADA, H NISHISAKI, Y KONDA, M NAGAO, M KASUGA

  Aug. 1992, CANCER RESEARCH, 52(16) (16), 4335 - 4341, English

  [Refereed]

  Scientific journal


• Protective effect of prostaglandin E2 on ethanol-induced injury of chief cells isolated from guinea pig may be associated with diacylglycerol formation

  K. Matsuda, C. Sakamoto, Y. Konda, H. Nishisaki, T. Matozaki, O. Nakano, K. Wada, M. Kasuga

  1992, Therapeutic Research, 13(1) (1), 102 - 106, Japanese

  International conference proceedings


• The inhibitory effect of cholecystokinin on phosphatidylcholine synthesis in isolated rat pancreatic acini. (II).

  MATOZAKI Takashi, SAKAMOTO Choitsu, NISHISAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, MATSUDA Kohei, WADA Ken, SUZUKI Toshiya, UCHIDA Tohru, NAGAO Munehiko, KASUGA Masato

  To better understand the mechanism underlying the inhibition induced by cholecystokinin (CCK) of phosphatidylcholine (PC) synthesis, the effects of CCK treatment on the activities of enzyme involved in PC synthesis via CDP-choline pathway were studied in isolated rat pancreatic acini. CCK treatment of acini reduced CTP: phosphocholine cytidylyltransferase activity in both cytosolic and particulate fraction. However, CCK treatment of acini did not alter the activities of choline kinase and phosphocholinetransferase in acini. When acini were labeled with [³H] myristic acid and chased, CCK8 (1nM) reduced the synthesis of [³H] myristic acid labeled-PC to 27% of control after 60min-chase period. This inhibition of PC synthesis induced by CCK was accompanied by a delayed disappearance of [³H] diacylglycerol (DAG), the radioactivity of which was 225% of control at 60 min. CCK also induced an increase in [³H] triacylglycerol and [³H] phosphatidic acid in acini. These results suggest that CCK inhibits PC synthesis by inducing the inhibition of CTP: phosphocholine cytidylyltransferase activity. The inhibition by CCK of PC synthesis may contribute to the sustained accumulation of DAG in pancreatic acinar cells.

  The Japanese Society of Gastroenterology, 1992, Nippon Shokakibyo Gakkai Zasshi, 89(2) (2), 517 - 521, Japanese


• MISSENSE MUTATIONS AND A DELETION OF THE P53-GENE IN HUMAN GASTRIC-CANCER

  T MATOZAKI, C SAKAMOTO, K MATSUDA, T SUZUKI, Y KONDA, O NAKANO, K WADA, T UCHIDA, H NISHISAKI, M NAGAO, M KASUGA

  Jan. 1992, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 182(1) (1), 215 - 223, English

  [Refereed]

  Scientific journal


• DISTRIBUTION OF SMG-P25A AND SMG-P21S, RAS-P21-LIKE GUANINE NUCLEOTIDE-BINDING PROTEINS, IN THE RAT STOMACH

  K MATSUDA, C SAKAMOTO, O NAKANO, Y KONDA, T MATOZAKI, K WADA, M KASUGA, A MIZOGUCHI, A KIKUCHI, Y TAKAI

  Jan. 1992, AMERICAN JOURNAL OF PHYSIOLOGY, 262(1) (1), G69 - G73, English

  [Refereed]

  Scientific journal


• CHOLECYSTOKININ INHIBITS PHOSPHATIDYLCHOLINE SYNTHESIS VIA A CA2+-CALMODULIN-DEPENDENT PATHWAY IN ISOLATED RAT PANCREATIC ACINI - A POSSIBLE MECHANISM FOR DIACYLGLYCEROL ACCUMULATION

  T MATOZAKI, C SAKAMOTO, H NISHISAKI, T SUZUKI, K WADA, K MATSUDA, O NAKANO, Y KONDA, M NAGAO, M KASUGA

  Nov. 1991, JOURNAL OF BIOLOGICAL CHEMISTRY, 266(33) (33), 22246 - 22253, English

  [Refereed]

  Scientific journal


• LECITHIN-CHOLESTEROL ACYLTRANSFERASE (LCAT) DEFICIENCY WITH A MISSENSE MUTATION IN EXON-6 OF THE LCAT GENE

  E MAEDA, Y NAKA, T MATOZAKI, M SAKUMA, Y AKANUMA, G YOSHINO, M KASUGA

  Jul. 1991, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 178(2) (2), 460 - 466, English

  [Refereed]

  Scientific journal


• INTRACELLULAR MEDIATORS OF BOMBESIN ACTION ON RAT PANCREATIC ACINAR-CELLS

  T MATOZAKI, WY ZHU, Y TSUNODA, B GOKE, JA WILLIAMS

  Jun. 1991, AMERICAN JOURNAL OF PHYSIOLOGY, 260(6) (6), G858 - G864, English

  [Refereed]

  Scientific journal


• CHARACTERIZATION OF CHOLECYSTOKININ RECEPTORS ON GUINEA-PIG GASTRIC CHIEF CELL-MEMBRANES

  T MATOZAKI, C SAKAMOTO, M NAGAO, H NISHISAKI, Y KONDA, O NAKANO, K MATSUDA, K WADA, T SUZUKI, M KASUGA

  Feb. 1991, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 174(3) (3), 1055 - 1063, English

  [Refereed]

  Scientific journal


• The inhibitory effect of cholecystokinin on phosphatidylcholine synthesis in isotlated rat pancreatic acini.

  MATOZAKI Takashi, SAKAMOTO Choitsu, NISHISAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, MATSUDA Kohei, WADA Ken, SUZUKI Toshiya, NAGAO Munehiko, KASUGA Masato

  The effects of cholecystokinin (CCK) and other pancreatic secretagogues on phosphatidylcholine (PC) synthesis were studied in isolated rat pancreatic acini. When acini were incubated with [³H] choline in the presence of 1nM CCK-octapeptide (CCK8) for 60min, the incorporations of [³H] choline to both water soluble choline metabolites and PC in acini were reduced by CCK8 to 74% and 41% of control, respectively. Pulse-chase study revealed that CCK reduced both the disappearance of phosphocholine and the synthesis of PC. Ca²⁺-mobilizing secretagogues such as carbamylcholine and Ca²⁺ ionophore A23187 also reduced PC synthesis to the same extent as CCK8. By contrast, neither cAMP-dependent secretagogues such as secretin and dibutyryl cAMP nor a phorbol ester had any effect on PC synthesis in acini. These results suggest that CCK inhibits PC synthesis by inducing both the reduction of choline uptake into acini and the inhibition of CTP: phosphocholine cytidylyltransferase activity. This hormonal regulation of PC synthesis via CDP-choline pathway appears to be mediated by Ca²⁺-dependent pathway but not by cAMP- or protein kinase C-dependent pathway.

  The Japanese Society of Gastroenterology, 1991, Nippon Shokakibyo Gakkai Zasshi, 88(7) (7), 1442 - 1446, Japanese


• Protective effect of prostaglandin E2 on ethanol-induced injury of chief cells isolated from guinea pig.

  KONDA Yoshitaka, NISHISAKI Hogara, NAKANO Osamu, MATSUDA Kohei, WADA Ken, MATOZAKI Takashi, NAGAO Munehiko, SAKAMOTO Choitsu

  The mechanism by which PGE₂ directly protects individual gastric cells from ethanol-induced injury was studied by using isolated gastric chief cells from guinea pig. Ethanol dose-dependently caused chief cell injury which was estimated by the release of lactate dehydrogenase (LDH) from chief cells. Pretreatment of chief cells with PGE₂ reduced the cell damage caused by ethanol in time- and dose-dependent manner. The pretreatment at 37°C and pH 7.4 with PGE₂ maximally reduced the cell damage. This protective effect was reduced when the pretreatment was performed at either acid or alkaline pH or at reduced temperature. PGE₂ did not stimulate any increase in cytosolic free Ca²⁺ concentration and initial Ca²⁺ influx rate. On the other hand, PGE₂ stimulated an increase of cAMP accumulation in chief cells. However, pretreatment of chief cells with secretion, VIP, dbcAMP or forskolin failed to reduce subsequent injury caused by ethanol. These results suggest that PGE₂ may protect chief cells against ethanol-caused injury probably via PGE type receptors coupled to as yet unidentified signal in gastric chief cells.

  The Japanese Society of Gastroenterology, 1991, Nippon Shokakibyo Gakkai Zasshi, 88(6) (6), 1281 - 1287, Japanese


• Characterization of muscarinic acetylcholine receptors in the isolated gastric chief cells from guinea pig.

  WADA K., NISHISAKI H., KONDA Y., MATOZAKI T., NAKANO O., MATSUDA K., NAGAO M., SAKAMOTO C.

  The muscarinic receptor system involved in perpsinogen secretion from isolated guinea pig gastric chief cells was investigated by assessing the effect of muscarinic receptor antagonists on carbamylcholine (CCh)-induced pepsinogen secretion. CCh stimulated pepsinogen secretion in a dose dependent manner with the maximal and the half-maximal stimulatory concentrations at 10^-4 and 3×10^-6M, respectively. Each of five different muscarinic receptor antagonists such as atropine, pirenzepine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX116 and scopolamine reduced pepsinogen secretion stimulated by graded concentration of CCh, but did not alter the maximum secretion. The increase in concentration of each antagonist caused parallel rightward shift of the dose response curve to CCh. Schild analysis of the inhibition of CCh-induced pepsinogen secretion by the antagonists showed that pA₂ values of atropine, scopolamine and 4-DAMP are 8.8, 9.2 and 9.0, respectively. On the other hand, pA₂ values of pirenzepine and AF-DX116 are 6.5 and 5.9, respectively, suggesting that the muscarinic receptore mediating pepsinogen secretion from chief cells has a intermediate affinity for pirenzepine and a low affinity for AF-DX116. These results suggest that the muscarinic acetylcholine receptor mediating pepsinogen secretion from gastric chief cells is the M₃ subtype

  The Japanese Society of Gastroenterology, 1991, Nippon Shokakibyo Gakkai Zasshi, 88(1) (1), 28 - 32, Japanese


• Difference in Effects of Sodium Fluoride and Cholecystokinin on Pepsinogen Secretion from Isolated Guinea Pig Gastric Chief Cells

  NAKANO Osamu, SAKAMOTO Choitsu, NISHISAKI Hogara, KONDA Yoshitaka, MATSUDA Kohei, WADA Ken, NAGAO Munehiko, MATOZAKI Takashi, KASUGA Masato

  In order to further investigate the precise mechanisms of cholecystokinin (CCK)-induced pepsinogen secretion from gastric chief cells, we compared the signal transducing mechanisms activated by CCK with those activated by sodium fluoride (NaF) in isolated guinea pig gastric chief cells. NaF stimulated a monophasic increase in diacylglycerol accumulation with a peak value observed at 15 sec, while CCK strongly stimulated its biphasic accumulation. NaF evoked an increase in initial Ca²⁺ influx rate with a slow and smooth increase in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) monitored by fura-2, while CCK stimulated a rapid increase in [Ca²⁺]_i followed by a late sustained phase of [Ca²⁺]_i increase. Lanthanum chloride (La³⁺) effectively (unlike either nifedipine or verapamil) blocked NaF-stimulated increase in [Ca²⁺]_i, but it blocked only CCK-stimulated late sustained phase of [Ca²⁺]_i increase. La³⁺ reduced NaF-or CCK-stimulated maximal pepsinogen secretion to 57.0±2.5% and 73.1±3.1% of control, respectively. These results suggest that NaF activates a signal transducing mechanism which seems to be distinct from that activated by CCK, thereby inducing an increase in diacylglycerol accumulation, Ca²⁺ influx and pepsinogen secretion in guinea pig gastric chief cells.

  The Japan Endocrine Society, 1991, Folia Endocrinologica Japonica, 67(3) (3), 214 - 221, Japanese


• Prostaglandin protects isolated guinea pig chief cells against ethanol injury via an increase in diacylglycerol

  Y. Konda, H. Nishisaki, O. Nakano, K. Matsuda, K. Wada, M. Nagao, T. Matozaki, C. Sakamoto

  1990, Journal of Clinical Investigation, 86(6) (6), 1897 - 1903, English

  Scientific journal


• Effects of ethanol on pepsinogen release from isolated guinea pig gastric chief cells.

  KONDA Yoshitaka, SAKAMOTO Choitsu, NISHISAKI Hogara, NAKANO Osamu, MATSUDA Kohei, WADA Ken, NAGAO Munehiko, MATOZAKI Takashi

  The effects of ethanol on pepsinogen release from isolated guinea pig gastric chief cells were investigated. Ethanol, at concentrations of 300mM to 900mM, dose-dependently stimulated increases in pepsinogen release, initial Ca influx rate and intracellular free Ca concentration ([Ca²⁺]i) without affecting chief cells' viability. The increases in all parameters were inhibited by La³⁺ or EGTA, but not by nifedipine or verapamil.
  COOH-terminal octapeptide of cholecystokinin (CCK8) also stimulated increases in pepsinogen release, initial Ca influx rate and [Ca²⁺]i. However, the increases were dependent on not only extracellular Ca²⁺ but also intracellular Ca²⁺ mobilization. These results suggest that ethanol stimulates Ca²⁺ influx via the mechanism different from that of CCK8 and thereby stimulates pepsinogen release from isolated ginea pig gastric chief cells.

  The Japanese Society of Gastroenterology, 1990, Nippon Shokakibyo Gakkai Zasshi, 87(6) (6), 1350 - 1356, Japanese


• Cholecystokinin receptors on guinea pig gastric chief cell membranes.

  SAKAMOTO Choitsu, MATOZAKI Takashi, NAGAO Munehiko, NISHISAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, MATSUDA Kohei, WADA Ken

  Cholecystokinin (CCK) binding to its receptors on guinea pig gastric chief cell membranes was characterized with ¹²⁵I-COOH terminal octapeptide of CCK (¹²⁵I-CCK8). Specific binding of ¹²⁵I-CCK8 to chief cell membranes was maximal at pH 6.0 and 30°C after 180min of incubation and reversible upon the addition of 10^-7M unlabeled CCK8. CCK analogs such as CCK8, gastrin-I, and COOH-terminal tetrapeptide of CCK (CCK4) competitively inhibited the labeled CCK8 binding with the half maximal inhibitory concentration of 10^-10M, 3×10^-7M and 10^-6M, respectively. Furthermore, guanine nucleotide analogs such as GTPγS and Gpp(NH)p also inhibited the labeled CCK8 binding to chief cell membranes. Scatchard analysis of the binding data at pH6.0 revealed two orders of the binding sites and GTPγS decreased the binding by converting two binding sites of the receptors to only one site of lower affinity. These results suggest that there are specific receptors for CCK, which are coupled to a guanine nucleotide regulatory protein on guiea pig gastric chief cell membranes.

  The Japanese Society of Gastroenterology, 1990, Nippon Shokakibyo Gakkai Zasshi, 87(11) (11), 2429 - 2433, Japanese


• Structural Characterization of the Somatostatin Receptors on Rat Cerebrocortical Membranes

  NAGAO Munehiko, SAKAMOTO Choitsu, MATOZAKI Takashi, NISHIZAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, BABA Shigeaki

  We characterized structually the receptors for somatostatin in rat cerebral cortex by affinity labeling with [¹²⁵I-Tyr¹] somatostatin. [¹²⁵I-Tyr¹] somatostatin was cross-linked to cerebrocortical membranes using photoreactive cross-linker: N-5-azido-2-nitrobenzoyloxy-succinimide. Analysis by autoradiography revealed a broad band centered at Mr=72,000 in the presence or absence of dithiothreitol. Affinity labeling of and specific [¹²⁵I-Tyr¹] somatostatin binding to cerebrocortical membranes were decreased similarly by adding unlabeled somatostatin or nonhydrolyzable guanine nucleotide analogue, guanyl-5′-yl imidodiphosphate, in a dose dependent manner. The pretreatment of cerebrocortical membranes with islet activating protein resulted in a decrease in subsequent affinity labeling of the protein. The cross-linked protein could be solubilized with Zwittergent 3-12 and poorly with digitonin, triton X-100 and NP-40. When exposed to agarose-coupled lectins, the solubilized labeled protein was absorbed to wheat germ agglutinin, partially to ricin communis-II, and not to concanavalin A or lentil lectin. The Mr=72,000 protein bound to wheat germ agglutinin-agarose was eluted with not only N, N′, N″-triacetylchitotriose but also N-acetylglucosamine. These results suggest that somatostatin receptors on cerebrocortical membranes are a monomeric glycoprotein with a Mr=70,000 containing no disulfide-linked binding subunit, which is coupled to islet activating protein-sensitive guanine nucleotide regulatory protein.

  The Japan Endocrine Society, 1990, Folia Endocrinologica Japonica, 66(10) (10), 1108 - 1116, Japanese


• A NEW CCK ANALOG DIFFERENTIATES 2 FUNCTIONALLY DISTINCT CCK RECEPTORS IN RAT AND MOUSE PANCREATIC ACINI

  T MATOZAKI, J MARTINEZ, JA WILLIAMS

  Oct. 1989, AMERICAN JOURNAL OF PHYSIOLOGY, 257(4) (4), G594 - G600, English

  [Refereed]

  Scientific journal


• Effect of palmitate and phorbol ester on synthesis of phosphatidylcholine in isolated guinea pig gastric glands

  H. Nishisaki, C. Sakamoto, Y. Konda, O. Nakano, M. Nagao, T. Matozaki, S. Baba

  1989, Japanese Journal of Gastroenterology, 86(11) (11), 1 - 6, Japanese

  Scientific journal


• Characterization of cholecystokinin receptors in gastric chief cells - Effect of CCK analogs and CCK receptor antagonists on chief cells.:Effect of CCK analogs and CCK receptor antagonists on chief cells

  MATOZAKI Takashi, SAKAMOTO Choitsu, NAGAO Munehiko, NISHIZAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, BABA Shigeaki

  In isolated guinea pig gastric chief cells, gatrin-I and cholecystokinin-hexapeptide (CCK-4) stimulated pepsinogen release. However, the efficacies of these two peptide were 51% of that observed with CCK-octapeptide (CCK8). CR1409 and L-364718, both of which are new CCK receptor antagonists in pancreatic acinar cells, also inhibited 10^-8M CCK8-stimulated pepsinogen release with a half-maximal inhibitory concentration (IC₅₀) observed at 3×10^-9M, respectively. The dose response curve to CCK8 for pepsinogen release shifted to the right in the presence of CR1409 or, L-364718. The IC₅₀ of these two antagonists for the CCK8-stimulated increase in cytosolic Ca²⁺ concentration monitored by Fura-2 were equal to those for CCK8-stimulated pepsinogen release. By contrast, the IC₅₀ of dibutyryl cyclic GMP, a well-known CCK receptor antagonist, for CCK8-stimulated pepsinogen release was less than that for CCK8-stimulated increase in cytosolic Ca²⁺ concentration. Results suggested that CCK receptors in gastric chief cells are unique and may be different from CCK receptors in other tissues previously repoted.

  The Japanese Society of Gastroenterology, 1989, Nippon Shokakibyo Gakkai Zasshi, 86(7) (7), 1424 - 1428, Japanese


• Coupling of Inhibitory GTP Binding Protein to Somatostatin Receptors on Rat Cerebrocortical Membranes

  NAGAO Munehiko, SAKAMOTO Choitsu, MATOZAKI Takashi, NISHIZAKI Hogara, KONDA Yoshitaka, NAKANO Osamu, BABA Shigeaki

  We studied the interaction between somatostatin receptors and inhibitory GTP binding protein in rat cerebrocortical membranes. Guanine nucleotides reduced [¹²⁵I-Tyr¹] somato-statin binding to cerebrocortical membranes in a dose-dependent manner with rank order of potency being guanyl-5′-yl-imidodiphosphate (Gpp (NH) p) >GTP>GMP. Maximum reduction of the binding to 32% of control was observed in the presence of 10^-5M Gpp (NH) p. Scatchard analysis of the labeled somatostatin binding revealed that the decrease in the binding by Gpp (NH) p was due to the decrease in the binding affinity for somatostatin. Divalent cations, such as Mg⁺⁺, Mn⁺⁺ and Ca⁺⁺, caused an increase in labeled somatostatin binding to membranes with the maximum binding observed at a concentration of 10, 10, 1 mM, respectively. However, Na⁺ decreased a labeled somatostatin binding in a dose-dependent manner, and half maximum inhibition of the binding was observed at 10mM Na⁺. Moreover, Gpp (NH) p and Na⁺ lowered labeled somatostatin binding in an additive fashion. When cerebrocortical membranes were treated at 37°C for 40min with various concentrations of Islet-Activating-Protein (IAP), which had been preactivated with dithiothreitol, sub-sequent labeled somatostatin binding to the membranes was decreased in a dose-dependent manner. 30μ/ml TAP treatment caused a decrease in the binding to 50% of control, which was characterized by the decreased binding affinity without a significant change in the binding capacity. Furthermore, exposure of IAP plus NAD to cerebrocortical membranes caused ADP-ribosylation of a membrane protein with Mr=41,000 on autoradiogram. Such an TAP treatment of cerebrocortical membranes abolished the inhibitory effect of somatostatin on vasoactive intestinal peptide-stimulated increase in adenylate cyclase activity. These results suggest that somatostatin receptors in the brain couple to inhibitory GTP binding protein, which mediates adenylate cyclase inhibition by somatostatin.

  The Japan Endocrine Society, 1989, Folia Endocrinologica Japonica, 65(12) (12), 1357 - 1366, Japanese


• Role of a Guanine Nucleotide Regulatory Protein in Exocrine Pancreatic Secretion:Effects of Cholera Toxin and Pertussis Toxin on Cholecystokinin Action

  MATOZAKI Takashi, SAKAMOTO Choitsu, NAGAO Munehiko, NISHISAKI Hogara, KONDA Yoshitaka, BABA Shigeaki

  We have recently shown that F^- can mimic the actions of cholecystokinin (CCK) on amylase release, Ca²⁺ mobilization and inositol phosphate generation in pancreatic acinar cells. We have concluded, therefore, that pancreatic CCK receptors may be coupled to the activation of polyphosphoinositide hydrolysis by a guanine nucleotide regulatory protein (N protein), which seems to be sensitive to F^-. In the present study, in order to further characterize this N protein coupled to pancreatic CCK receptors, we have examined the effects of bacterial toxins, pertussis toxin (PT) and cholera toxin (CT) on both CCK-and NaF-induced cellular responses in isolated rat pancreatic acini. Neither PT or CT pretreatment of acini affected both CCK-and NaF-stimulated increases in intracellular Ca²⁺ concentration monitored by quin2. Furthermore, pretreatments of acini with PT and CT didn't alter the effects of CCK on inositol phosphate generation in acini. Similarly, NaF-induced inositol phosphate generation was not changed by these toxin treatments. However, pretreatment procedures employed in this study were considered to catalize complete ADP-ribosylation of α-subunit of the stimulatory (Ns) and inhibitory (Ni) N protein. These results, therefore, strongly suggest that a N protein coupling pancreatic CCK receptors to the breakdown of polyphosphoinositide may be distinct from Ns or Ni like protein.

  The Japan Endocrine Society, 1989, Folia Endocrinologica Japonica, 65(8) (8), 743 - 749, Japanese


• G-PROTEIN IN STIMULATION OF PI-HYDROLYSIS BY CCK IN ISOLATED RAT PANCREATIC ACINAR-CELLS

  T MATOZAKI, C SAKAMOTO, M NAGAO, H NISHIZAKI, S BABA

  Nov. 1988, AMERICAN JOURNAL OF PHYSIOLOGY, 255(5) (5), E652 - E659, English

  [Refereed]

  Scientific journal


• Pancreatic secretagogues regulate somatostatin binding to acinar cell membranes via two-functionally distinct pathways

  T. Matozaki, C. Sakamoto, M. Nagao, S. Baba

  1988, Hormone and Metabolic Research, 20(3) (3), 141 - 144, English

  Scientific journal


• Effect of COOH-terminal octapeptide of cholecystokinin or carbachol on free cytosolic Ca++ concentration and pepsinogen secretion in the isolated guinea pig gastric chief cells.

  SAKAMOTO Choitsu, NAGAO Munehiko, MATOZAKI Takashi, KONDA Yoshitaka, NISHISAKI Hogara, BABA Shigeaki

  Stimulation with COOH-terminal octapeptide of cholecystokinin (CCK8) or carbachol resulted in a rapid increase in Quin-2 fluorescence of isolated guinea pig gastric chief cells, whereas histamine, vasoactive intestinal peptide, secretin and forskolin had no effect.
  The minimum effective dose of CCK8 or carbachol to elicit the rise in Quin-2 fluoresecence was very close to that for pepsinogen secretion. Removal of Ca⁺⁺ from extracellular medium or Ca⁺⁺ channel blockers did not affect CCK8- or carbachol-induced increase in Quin-2 fluorescence. Moreover, following the addition of CCK8, carbachol was unable to stimulate a second increase in Quin-2 fluorescence.
  These results suggest that CCK8 and carbachol share common Ca⁺⁺ pools and an increase in free cytosolic Ca⁺⁺ concentration may mediate CCK8- or carbachol-induced pepsinogen secretion from gastric cheif cells.

  The Japanese Society of Gastroenterology, 1988, Nippon Shokakibyo Gakkai Zasshi, 85(7) (7), 1347 - 1352, Japanese


• Role of a Guanine Nucleotide Regulatory Protein in Stimulation of Exocrine Pancreatic Secretion by Cholecystokinin in Isolated Rat Pancreatic Acini

  MATOZAKI Takashi

  To clarify the possible role of a guanine nucleotide regulatory protein in the signal transducing system activated by cholecystokinin (CCK), the actions of CCK on rat pancreatic acini were compared with those of NaF, which is a well-known activator of stimulatory and inhibitory guanine nucleotide regulatory proteins. Guanine nucleotides reduced the binding of ¹²⁵I-CCK-octapeptide (CCK8) to acinar cell membranes, with the rank order of potency being guanyl-5′-yl imidodiphosphate (Gpp (NH) p) >GTP>GDP>GMP. Scatchard analysis of labeled CCK binding revealed that the decrease in CCK binding caused by Gpp (NH) p was due to the decrease in an affinity constant of CCK for its receptors with no signficant change in the maximal binding capacity.
  When acini were incubated with increasing concentrations of either CCK8 or NaF, maximal stimulation of amylase release occurred at 100 pM CCK8 or 10 mM NaF, respectively, and supramaximal concentrations of CCK8 or NaF caused its submaximal stimulation. Further, CCK and NaF similarly stimulated the hydrolysis of polyphosphoinositide in acini and the release of Ca²⁺ from the intracellular Ca²⁺ store into the cytoplasm although there was a lag period prior to any detectable stimulation by NaF. The doses of NaF necessary for Ca²⁺ mobilization and inositol phosphate generation were nearly the same, with a maximal stimulation at 20 mM NaF. NaF, at concentrations up to 20 mM, a supramaximal concentration for amylase release, produced no significant change in the cellular cyclic AMP level. In addition, 10 mM NaF potentiated the amylase release stimulated by VIP, a wellknown secretagogue which functions via cyclic AMP, suggesting that the stimulatory effects of NaF are independent of cellular cyclic AMP.
  Gpp (NH) p also activated the hydrolysis of polyphosphoinositide in a cell-free pancreatic acinar cell membrane preparation, with a half-maximal and a maximal stimulation at 1 μM and 10μM, respectively. Furthermore, the effects of submaximal concentrations of CCK8 on polyphosphoinositide hydrolysis were markedly potentiated in the presence of 100 μM GTP, which alone was ineffective.
  These results, therefore, strongly suggest that pancreatic CCK receptors may be coupled to the activation of polyphosphoinositide breakdown by a guanine nucleotide regulatory protein.

  The Japan Endocrine Society, 1988, Folia Endocrinologica Japonica, 64(10) (10), 1051 - 1064, Japanese


• Effect of Islet Activating Protein on Somatostatin-induced Inhibition of Cellular Cyclic AMP Content in Isolated Rat Pancreatic Acini

  MATOZAKI Takashi, SAKAMOTO Choitsu, NAGAO Munehiko, NISHIZAKI Hogara, BABA Shigeaki

  Our previous study concerning guanine nucleotides regulation of labeled somatostatin binding has suggested that somatostatin receptors on pancreatic acinar cell membranes probably couple with the inhibitory guanine nucleotide regulatory protein (Ni). In order to clarify the possible role of Ni in mediating signal transduction of somatostatin in the pancreas, we further examined the effect of pretreatment with islet activating protein (IAP) on the inhibition of VIP-stimulated cellular cyclic AMP content by somatostatin in isolated rat pancreatic acini. Increasing concentrations of somatostatin decreased VIP-stimulated cellular content of cyclic AMP in the acini, with a maximal inhibition at 10^-8M somatostatin. When pancreatic acini were pretreated with varying concentrations of IAP for 4 hours, the somatostatin-induced inhibition of cyclic AMP content was attenuated in a dose dependent manner by IAP pretreatment. Incubation of pancreatic acinar membrane with preactivated IAP and [³²P] NAD resulted in labeling of a Mr=41000 protein band, consistent with α-subunit of Ni in many other cell types previously reported. On the other hand, a Mr=41000 protein band on SDS gel was reduced in a dose dependent fashion by IAP pretreatment, when acini were pretreated with increasing concentrations of IAP. These results suggest that only the Mr=41000 protein is a specific substrate in pancreatic acinar' membranes for TAP-induced ADP-ribosylation. Futhermore, the reduction of ³²P incorporation to Mr=41000 protein by IAP pretreatment occurred in parallel to decreases in somatostatin-induced inhibition of cellular cyclic AMP contents in pancreatic acini.
  These results suggest that pretreatment of acini with IAP reverses the inhibitory effect of somatostatin on VIP-stimulated cyclic AMP content via ADP-ribosylation of the Mr=41000 protein (a subunit of Ni). In conclusion, our accumulated data suggest that Ni may play an important role in mediating the inhibitory action of somatostatin on adenylate cyclase enzyme system in pancreatic acini.

  The Japan Endocrine Society, 1988, Folia Endocrinologica Japonica, 64(6) (6), 523 - 530, Japanese


• COUPLING OF GUANINE-NUCLEOTIDE INHIBITORY PROTEIN TO SOMATOSTATIN RECEPTORS ON PANCREATIC ACINAR MEMBRANES

  C SAKAMOTO, T MATOZAKI, M NAGAO, S BABA

  Sep. 1987, AMERICAN JOURNAL OF PHYSIOLOGY, 253(3) (3), G308 - G314, English

  [Refereed]

  Scientific journal


• Protein kinase C regulates somatostatin binding to its receptors on rat pancreatic acinar cell membranes

  T. Matozaki, C. Sakamoto, M. Nagao, S. Baba

  1987, Biomedical Research, 8(1) (1), 39 - 44, English

  Scientific journal


• Coupling of Guanine Nucleotide Inhibitory Protein to Somatostatin Receptors on Rat Pancreatic Acinar Membranes

  SAKAMOTO Choitsu, MATOZAKI Takashi, NAGAO Munehiko, NISHISAKI Hogara, BABA Shigeaki

  To investigate whether somatostatin receptors couple to guanine nucleotide inhibitory protein, Ni, on rat pancreatic acinar membranes, the effects of guanine nucleotide analogs or pretreatment of acini with islet activating protein (IAP), pertussis toxin on labeled somatostatin binding were examined. Guanine nucleotides reduced labeled somatostatin binding to acinar membranes up to 80%, with rank order of potency being guanyl-5′-yl imidodiphosphate (Gpp(NH)p)>GTP>GDP>GMP. Scatchard analysis of the labeled somatostatin binding revealed that the decrease in somatostatin binding caused by Gpp(NH)p was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. The inhibitory effect of Gpp(NH)p was partially abolished in the absence of Mg²⁺ and Na⁺ also reduced labeled somatostatin binding. Furthermore, inhibitory effects of 100mM Na⁺ and Gpp(NH)p were additive in reducing labeled somatostatin binding. A half maximal inhibitory concentration of Gpp(NH)p was decreased to 10^-7M in the presence of 100mM Na⁺ and 5mM Mg²⁺ as compared to 10^-6M in the presence of 5mM Mg²⁺ alone. Results therefore suggest that Gpp(NH)p requires Mg²⁺ for Ni activation and Na⁺ increases sensitivity of Ni to guanine nucleotide analogs.
  When pancreatic acini were treated for 4 hours with varying concentrations of IAP, which has been shown to uncouple Ni-mediated communication between inhibitory receptors and adenylate cyclase catalytic unit, subsequent labeled somatostatin binding to the acinar membranes was decreased in a dose dependent manner.
  These results indicate that somatostatin receptors on pancreatic acinar membranes couple to guanine nucleotide inhibitory protein, Ni and thus somatostatin probably functions in the pancreas to regulate intracellular signal transduction via Ni.

  The Japan Endocrine Society, 1987, Folia Endocrinologica Japonica, 63(8) (8), 978 - 986, Japanese


• Phorbol Ester or Diacylglycerol Modulates Somatostatin Binding to Its Receptors on Rat Pancreatic Acinar Cell Membranes

  MATOZAKI Takashi, SAKAMOTO Choitsu, NAGAO Munehiko, BABA Shigeaki

  To clarify the precise mechanism by which unrelated peptides, cholecystokinin or carbamylcholine, modulate the somatostatin binding, the effect of a phorbol ester, 12-0-tetradecanoylphorbol-13-acetate (TPA) or a synthetic diacylglycerol analog, [¹²⁵ I-Tyr¹-oley1-2-acetylglycerol (OAG) onsomatostatin binding to pancreatic acinar cell membranes was examined.
  Pretreatment of pancreatic acini for 120 min at 37°C with 100 ng/ml TPA maximally reduced subsequent labeled somatostatin binding to acinar membranes. The inhibitory effect of TPA on the somatostatin binding was dependent on the dose used, or the time and temperature of pretreatment. These effects of TPA were almost mimicked by the treatment of acini with OAG. Scatchard analysis of [¹²⁵I-Tyr¹ somatostatin binding demonstrated that the decrease in the labeled somatostatin binding induced by TPA or OAG pretreatment was due to the decrease in the maximum binding capacity without a significant change in the binding affinity.
  A specifically labeled single band of the Mr = 90 K obtained with a photoaffinity crosslinking study indicates that the somatostatin binding sites are the same somatostatin receptor as previously described. Moreover, the intensity of the Mr = 90 K band was dramatically decreased when acini were treated with increasing concentrations of TPA, a finding consistent with TPA-induced decrease in binding capacity. Such an inhibitory effect of TPA was abolished when pretreatment of acini with TPA was performed in the presence of Ca ²⁺ chelating compounds such as EDTA and EGTA.
  Interestingly, the combined treatment of TPA and Ca²⁺ionophore A23187 caused synergistic inhibition of the subsequent labeled somatostatin binding to acinar membranes, although Ca²⁺ionophore itself almost failed to affect the somatostatin binding.
  These results suggest, therefore, that 1) TPA or OAG can modulate somatostatin binding to its receptors on rat pancreatic acinar cell membranes, presumably through activation of Ca²⁺-activated, phospholipid-dependent protein kinase (protein kinase C) and 2) the activated protein kinase C and intracellular Ca²⁺mobilization presumably act to modulate pancreatic acinar somatostatin receptors synergistically.

  The Japan Endocrine Society, 1986, Folia Endocrinologica Japonica, 62(7) (7), 807 - 817, Japanese


• Effects of Various Pancreatic Secretagogues on SomatostatinEffects of Various Pancreatic Secretagogues on Somatostatin Binding to Rat Pancreatic Acinar Cell Plasma Membranes

  MATOZAKI Takashi, SAKAMOTO Choitsu, NAGAO Munehiko, BABA Shigeaki

  The effects of pretreatment with pancreatic secretagogues and subsequently activated cellular events on [¹²⁵ I-Tyr¹] somatostatin binding to acinar membranes were studied. Pretreatment of pancreatic acini with bombesin at increasing concentrations for 120 min reduced labeled somatostatin binding to the acinar membranes in a dose-dependent fashion with a maximal reduction of binding at 10^-8M bombesin (44.3 ± 1.8% of control). The maximal inhibition of labeled somatostatin binding by pretreatment with bombesin was almost comparable to that with COOH-terminal octapeptide cholecystokinin (CCK₈) or carbamylcholine (carbachol). Furthermore, pretreatment of acini with vasoactive intestinal peptide (VIP) as well as secretin resulted in a small, but significant decrease of subsequent labeled somatostatin binding. In addition, adenosine 3′, 5′ cyclic nucleotide derivatives or a phosphodiesterase inhibitor mimicked the effect of VIP or secretin. The effect of simultaneous pretreatment of acini with VIP and carbachol on subsequent labeled somatostatin binding appeared to be almost equal to the calculated additive value for each peptide.These results suggest that the binding of somatostatin to its receptors in the pancreatic acini may be regulated via two functionally distinct pathways.

  The Japan Endocrine Society, 1986, Folia Endocrinologica Japonica, 62(12) (12), 1376 - 1383, Japanese


• PHORBOL ESTER OR DIACYLGLYCEROL MODULATES SOMATOSTATIN BINDING TO ITS RECEPTORS ON RAT PANCREATIC ACINAR CELL-MEMBRANES

  T MATOZAKI, C SAKAMOTO, M NAGAO, S BABA

  Jan. 1986, JOURNAL OF BIOLOGICAL CHEMISTRY, 261(3) (3), 1414 - 1420, English

  [Refereed]

  Scientific journal

• 異なる週齢のマウスにおいて受容体型分子SIRPα欠損がミクログリア活性化に与える影響の解析

  榛澤春哉, 尾池恵摘, 守家優佳, 本澤拓郎, 松本映子, 浦野江里子, 林由里子, 的崎尚, 大西浩史

  2024, 日本分子生物学会年会プログラム・要旨集(Web), 47th


• 膜型分子SIRPαによるCD11c陽性ミクログリア誘導制御メカニズムの解析

  守家優佳, 尾池恵摘, 榛澤春哉, 仲丸優香, 松本映子, 浦野江里子, 小林良祐, 堀居拓郎, 畑田出穂, 林由里子, 的崎尚, 大西浩史

  2024, 日本分子生物学会年会プログラム・要旨集(Web), 47th


• 加齢による運動学習能低下が改善するミクログリア特異的SIRPα欠損マウスにおける遺伝子発現解析

  水谷瑠依, 富山飛鳥, 今井武史, 松下紗世子, 森田紋子, 浦野江里子, 橋本美穂, 林由里子, 的崎尚, 大西浩史

  2022, 日本神経化学会大会抄録集(Web), 65th


• CD47-SIRPαシグナル系を標的としたマクロファージによるがん細胞排除を促進する新規大環状ペプチドの開発(A novel macrocyclic peptide targets the CD47-SIRPalpha axis and enhances the macrophage-mediated tumor killing)

  羽間 大祐, 村田 陽二, 田中 大介, 岡本 武士, 齊藤 泰之, 小谷 武徳, 西村 善博, 的崎 尚

  日本癌学会, Sep. 2019, 日本癌学会総会記事, 78回, P - 2169, English


• Regulation of Small Intestinal Epithelial Homeostasis by Tsc2-mTORC1 Signaling.

  Jajar Setiawan, Takenori Kotani, Tasuku Konno, Yasuyuki Saito, Yoji Murata, Tetsuo Noda, Takashi Matozaki

  Mammalian target of rapamycin complex 1 (mTORC1), a protein complex containing the serine/threonine kinase mTOR, integrates various growth stimulating signals. mTORC1 is expressed in intestinal epithelial cells (IECs), whereas the physiological roles of this protein complex in homeostasis of IECs remain virtually unknown. We here generated mice, in which tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, was specifically ablated in IECs (Tsc2 CKO mice). Ablation of Tsc2 enhanced the phosphorylation of mTORC1 downstream molecules such as ribosomal S6 protein and 4E-BP1 in IECs. Tsc2 CKO mice manifested the enhanced proliferative activity of IECs in intestinal crypts as well as the promoted migration of these cells along the crypt-villus axis. The mutant mice also manifested the increased apoptotic rate of IECs as well as the increased ectopic Paneth cells, which are one of the major differentiated IECs. In addition, in vitro study showed that ablation of Tsc2 promoted the development of intestinal organoids without epidermal growth factor, while mTORC1 inhibitor, rapamycin, diminished this phenotype. Our results thus suggest that Tsc2-mTORC1 signaling regulates the proliferation, migration, and positioning of IECs, and thereby contributes to the proper regulation of intestinal homeostasis.

  12 Apr. 2019, The Kobe journal of medical sciences, 64(6) (6), E200-E209, English, Domestic magazine


• SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells in the adult spleen

  SAITO Yasuyuki, KOMORI Satomi, DATU Respatika, WASHIO Ken, NISHIMURA Taichi, KOTANI Takenori, MURATA Yoji, MATOZAKI Takashi

  30 Sep. 2018, 臨床血液, 59(9) (9), 1687, English


• 常在細菌による成体マウス脳室下帯におけるニューロン新生の制御

  澤田直樹, 澤田直樹, 小谷武徳, 金野祐, ジャジャル セティアワン, 齊藤泰之, 村田陽二, 丹生健一, 的崎尚

  (公社)日本生化学会, Sep. 2018, 日本生化学会大会(Web), 91回, [2T13m - 325)], Japanese


• CD47-signal regulatory protein α signaling system and its application to cancer immunotherapy.

  Yoji Murata, Yasuyuki Saito, Takenori Kotani, Takashi Matozaki

  Tumor cells evade immune surveillance through direct or indirect interactions with various types of immune cell, with much recent attention being focused on modifying immune cell responses as the basis for the development of new cancer treatments. Signal regulatory protein α (SIRPα) and CD47 are both transmembrane proteins that interact with each other and constitute a cell-cell communication system. SIRPα is particularly abundant in myeloid cells such as macrophages and dendritic cells, whereas CD47 is expressed ubiquitously and its expression level is elevated in cancer cells. Recent studies have shown that blockade of CD47-SIRPα interaction enhances the phagocytic activity of phagocytes such as macrophages toward tumor cells in vitro as well as resulting in the efficient eradication of tumor cells in a variety of xenograft or syngeneic mouse models of cancer. Moreover, CD47 blockade has been shown to promote the stimulation of tumor-specific cytotoxic T cells by macrophages or dendritic cells. Biological agents, such as Abs and recombinant proteins, that target human CD47 or SIRPα have been developed and are being tested in preclinical models of human cancer or in clinical trials with cancer patients. Preclinical studies have also suggested that CD47 or SIRPα blockade may have a synergistic antitumor effect in combination with immune checkpoint inhibitors that target the adaptive immune system. Targeting of the CD47-SIRPα signaling system is thus a promising strategy for cancer treatment based on modulation of both innate and acquired immune responses to tumor cells.

  Aug. 2018, Cancer science, 109(8) (8), 2349 - 2357, English, International magazine

  [Refereed]

  Link to Kobe Univ. Repository (Kernel)


• Srcファミリーキナーゼの炎症性腸疾患における重要性

  SUN Chunxiao, SUN Chunxiao, MURATA Yoji, IMADA Shinya, KOTANI Takenori, SAITO Yasuyuki, YAMADA Hideto, MATOZAKI Takashi

  2018, 日本生化学会大会(Web), 91st, ROMBUNNO.1P‐297 (WEB ONLY), English


• 腸上皮細胞の恒常生維持に関わるチロシンリン酸化シグナルの意義

  的崎尚, 村田陽二, 小谷武徳, 齊藤泰之

  2018, 日本生化学会大会(Web), 91st, ROMBUNNO.1S03e‐02 (WEB ONLY), Japanese


• CD47/SIRPαシグナルを標的としたがん免疫療法

  MURATA YOJI, MATOZAKI TAKASHI

  Jan. 2018, がん分子標的治療, 15(4) (4), 414 - 419, Japanese

  Introduction scientific journal


• SHPS- 1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative (vol 122, pg 834, 2012)

  L. Wang, Y. Lu, S. Deng, Y. Zhang, L. Yang, Y. Guan, T. Matozaki, H. Ohnishi, H. Jiang, H. Li

  Dec. 2017, JOURNAL OF NEUROCHEMISTRY, 143(6) (6), 761 - 761, English

  Others


• SIRP alpha(+) dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Yasuyuki Saito, Satomi Komori, Datu Respatika, Ken Washio, Takenori Kotani, Yoji Murata, Hiroshi Ohnishi, Katsuyuki Yui, Koji Yasutomo, Takashi Matozaki

  Dec. 2017, CYTOKINE, 100, 55 - 55, English

  Summary international conference


• 腸上皮の恒常性制御におけるTsc2‐mTORC1シグナルの役割

  SETIAWAN Jajar, KOTANI Takenori, KONNO Tasuku, IMADA Shinya, PARK Jung‐ha, SAWADA Naoki, SAITO Yasuyuki, MURATA Yoji, MATOZAKI Takashi

  2017, 日本生化学会大会(Web), 90th, ROMBUNNO.2P‐0458 (WEB ONLY), English


• Anti‐SIRPα antibodies provide a basis for new approaches to cancer immunotherapy

  MATOZAKI Takashi, MURATA Yoji, YANAGITA Tadahiko, SAITO Yasuyuki, KOTANI Takenori

  2017, 日本癌学会学術総会抄録集(Web), 76th, ROMBUNNO.S5‐3 (WEB ONLY), English


• Establishment of a potential new PDX mouse model for personalized cancer immunotherapy

  SAITO Yasuyuki, MURATA Yoji, KOTANI Takenori, FLAVELL Richard A, MANZ Markus G, MATOZAKI Takashi

  2017, 日本癌学会学術総会抄録集(Web), 76th, ROMBUNNO.J‐1040 (WEB ONLY), English


• Regulation of intestinal epithelial homeostasis by Src family kinases through Rac and YAP

  MURATA Yoji, IMAGE Shinya, KOTANI Takenori, SUN Chunxiao, SAITO Yasuyuki, MATOZAKI Takashi

  2017, 日本癌学会学術総会抄録集(Web), 76th, ROMBUNNO.E‐1007 (WEB ONLY), English


• Role of Tsc2‐mTORC1 signaling in intestinal homeostasis

  KOTANI Takenori, JAJAR Setiawan, KONNO Tasuku, IMADA Shinya, SAWADA Naoki, MURATA Yoji, SAITO Yasuyuki, MATOZAKI Takashi

  2017, 日本癌学会学術総会抄録集(Web), 76th, ROMBUNNO.P‐3032 (WEB ONLY), English


• がん‐マクロファージ間相互作用を標的とした新規がん免疫療法の開発

  村田陽二, 柳田匡彦, 田中大介, 羽間大祐, 齊藤泰之, 小谷武徳, 大西浩史, 的崎尚

  2017, 日本生化学会大会(Web), 90th, ROMBUNNO.3AT26‐02(3P‐0901) (WEB ONLY), Japanese


• Future therapeutic potential of SAP-1 in inflammatory bowel diseases

  Takenori Kotani, Yoji Murata, Yasuyuki Saito, Takashi Matozaki

  Dec. 2016, Expert Review of Gastroenterology & Hepatology, 10(12) (12), 1313 - 1315, English

  [Refereed]

  Others


• Accumulation of dysregulated renal mononuclear phagocytes (rMoPh) and Th1 cells in the kidney of CD11c‐specific Shp‐1 knockout mice

  WATANABE Mitsuharu, KANEKO Yoriaki, HIROMURA Keiju, KINOSHITA Masato, OHISHI Yuko, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa

  14 Nov. 2016, 日本免疫学会総会・学術集会記録, 45(Proceedings) (Proceedings), 180, English


• Shp‐1 in dendritic cells controls the development of memory‐phenotype CD8⁺ T cells

  OHISHI Yuko, KANEKO Yoriaki, KINOSHITA Masato, WATANABE Mitsuharu, HIROMURA Keiju, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa

  14 Nov. 2016, 日本免疫学会総会・学術集会記録, 45(Proceedings) (Proceedings), 41, English


• 短鎖脂肪酸は腸上皮細胞のターンオーバーを調節する(Short chain fatty acids regulate the turnover of intestinal epithelial cells)

  金野 祐, 小谷 武徳, Park Jung-Ha, Setiawan Jajar, 北村 泰明, 今田 慎也, 臼井 佑太郎, 波多野 直哉, 篠原 正和, 齊藤 泰之, 村田 陽二, 的崎 尚

  (公社)日本生化学会, Sep. 2016, 日本生化学会大会プログラム・講演要旨集, 89回, [2P - 238], Japanese


• 樹状細胞特異的Shp1欠損マウスにおける自己免疫性腎炎の解析(第2報)

  渡辺 光治, 廣村 桂樹, 金子 和光, 木下 雅人, 大石 裕子, 坂入 徹, 池内 秀和, 前嶋 明人, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本腎臓学会, May 2016, 日本腎臓学会誌, 58(3) (3), 278 - 278, Japanese


• The anti‐SIRPα antibody prevents tumor formation: a novel strategy for cancer therapy

  YANAGITA Tadahiko, MURATA Yoji, TANAKA Daisuke, SAITO Yasuyuki, KOTANI Takenori, KOMORI Takahide, MATOZAKI Takashi

  2016, 日本癌学会学術総会抄録集(Web), 75th, ROMBUNNO.J‐1004 (WEB ONLY), English


• SIRPα欠損マウスはLPS投与によって誘導される低体温症が重症化する

  HASHIMOTO Miho, NOZU Tomomi, URANO Eriko, SAITO Yasuyuki, KOTANI Takenori, MURATA Yoji, MATOZAKI Takashi, ONISHI Hiroshi

  2016, 日本生物学的精神医学会(Web), 38th, 154 (WEB ONLY), English


• SIRPα欠損マウスにおけるクプリゾン感受性の亢進

  野津智美, 橋本美穂, ELHANBALY Ruwaida, 石川達也, 齊藤泰之, 小谷武徳, 村田陽二, 深澤有吾, 的崎尚, 大西浩史

  2016, 北関東医学会総会プログラム・抄録, 63rd, 27‐28, Japanese


• 細胞間シグナルCD47‐SIRPα系の生理機能とその臨床応用

  的崎尚, 村田陽二, 齊藤泰之, 小谷武徳, 柳田匡彦, 田中大介, 大西浩史

  2016, 日本生化学会大会(Web), 89th, ROMBUNNO.1S10‐6 (WEB ONLY), Japanese


• 白質におけるミクログリア恒常性制御

  野津智美, 橋本美穂, ELHANBALY Ruwaida, 石川達也, 齊藤泰之, 小谷武徳, 村田陽二, 深澤有吾, 的崎尚, 大西浩史

  2016, 日本生物学的精神医学会(Web), 38th, 149 (WEB ONLY), Japanese


• Dendritic cell‐specific ablation of the protein tyrosine phosphatase Shp1 induces enhanced production of inflammatory cytokines by toll‐like receptor‐mediated stimulation

  OHISHI Yuko, KANEKO Yoriaki, WATANABE Mitsuharu, KINOSHITA Masato, HIROMURA Keiju, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa

  30 Oct. 2015, 日本免疫学会総会・学術集会記録, 44(Proceedings) (Proceedings), 160, English


• Dendritic cell‐specific ablation of the protein tyrosine phosphatase Shp‐1 induces autoimmune nephritis characterized by infiltration of dendritic cell and Th1 cell

  WATANABE Mitsuharu, KANEKO Yoriaki, HIROMURA Keiju, OHISHI Yuko, KINOSHITA Masato, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa

  30 Oct. 2015, 日本免疫学会総会・学術集会記録, 44(Proceedings) (Proceedings), 126, English


• 【細胞シグナル操作法】分子からみたシグナル操作法 キナーゼ プロテインホスファターゼ

  Kotani Takenori, Murata Yoji, Matozaki Takashi

  Oct. 2015, 生体の科学, 66(5) (5), 432 - 433, Japanese

  [Invited]

  Introduction commerce magazine


• 【プロテインホスファターゼの最先端:制御機構から医療まで】 受容体型チロシンホスファターゼの機能と病態 R3サブタイプチロシンホスファターゼを中心に

  Murata Yoji, Kotani Takenori, Matozaki Takashi

  日本生化学会, Oct. 2015, 生化学, 87(5) (5), 547 - 553, Japanese

  [Invited]

  Introduction scientific journal


• ミクログリアにおけるSIRPαシグナルの役割

  橋本美穂, 野津智美, 浦野江里子, 齊藤泰之, 小谷武徳, 村田陽二, 的崎尚, 大西浩史

  北関東医学会, 01 Aug. 2015, 北関東医学会総会プログラム・抄録, 62nd(3) (3), 20 - 21, Japanese


• 腸粘膜上皮細胞の微絨毛に局在する受容体型チロシンホスファターゼSAP‐1とCEACAM20による腸管免疫制御

  村田陽二, 小谷武徳, YANA Supriatna, 北村泰明, 今田慎也, 齊藤泰之, 大西浩史, 的崎尚

  05 Jun. 2015, 日本細胞生物学会大会要旨集, 67th, 175, Japanese


• 腸内細菌による腸上皮細胞の寿命制御

  小谷武徳, 朴貞河, 北村泰明, 北村泰明, 今田慎也, 村田陽二, 齊藤泰之, 的崎尚

  05 Jun. 2015, 日本細胞生物学会大会要旨集, 67th, 199, Japanese


• 樹状細胞特異的Shp1欠損マウスにおける自己免疫性腎炎の解析

  渡辺 光治, 廣村 桂樹, 金子 和光, 大石 裕子, 木下 雅人, 坂入 徹, 池内 秀和, 前嶋 明人, 大西 浩史, 的崎 尚, 野島 美久

  (一社)日本腎臓学会, Apr. 2015, 日本腎臓学会誌, 57(3) (3), 486 - 486, Japanese


• Importance of commensal bacteria and short‐chain fatty acids for the growth and migration of intestinal epithelial cells

  KOTANI Takenori, PARK Jung‐ha, KITAMURA Yasuaki, IMADA Shinya, MURATA Yoji, SAITO Yasuyuki, MATOZAKI Takashi

  2015, 日本癌学会学術総会抄録集(Web), 74th, J‐1203 (WEB ONLY), English


• Cell‐cell interactions via CD47‐SIRPα signal regulate microglial activation

  HASHIMOTO Miho, NOZU Tomomi, URANO Eriko, SAITO Yasuyuki, KOTANI Takenori, MURATA Yoji, MATOZAKI Takashi, OHNISHI Hiroshi

  2015, 日本神経化学会大会抄録集(Web), 58th, ROMBUNNO.2P‐34 (WEB ONLY), English


• 腸上皮細胞の増殖・移動制御における腸内細菌と短鎖脂肪酸の重要性

  KOTANI Takenori, PARK Jung‐ha, KITAMURA Yasuaki, IMADA Shinya, MURATA Yoji, SAITO Yasuyuki, MATOZAKI Takashi

  2015, 日本生化学会大会(Web), 88th, 3P0174 (WEB ONLY), English


• 腸上皮組織の恒常性制御におけるCskとSrcファミリーキナーゼの役割

  IMADA Shinya, IMADA Shinya, MURATA Yoji, KITAMURA Yasuaki, PARK Jung‐ha, HATANO Masaki, KONNO Tasuku, KOTANI Takenori, SAITO Yasuyuki, OHDAN Hideki, MATOZAKI Takashi

  2015, 日本生化学会大会(Web), 88th, 2T21P-14(2P0206) (WEB ONLY), English


• Role of C‐terminal Src kinase (Csk) and Src family kinases in homeostasis of the intestinal epithelium

  IMADA Shinya, IMADA Shinya, MURATA Yoji, KITAMURA Yasuaki, PARK Jung‐ha, KOTANI Takenori, SAITO Yasuyuki, OHDAN Hideki, MATOZAKI Takashi

  2015, 日本癌学会学術総会抄録集(Web), 74th, J‐1283 (WEB ONLY), English


• Essential role of SIRP α on dendritic cells in organization and homeostasis of the spleen

  WASHIO Ken, KOTANI Takenori, RESPATIKA Datu, MURATA Yoji, SAITO Yasuyuki, KANEKO Yoriaki, OKAZAWA Hideki, OHNISHI Hiroshi, FUKUNAGA Atsushi, NISHIGORI Chikako, MATOZAKI Takashi

  18 Nov. 2014, 日本免疫学会総会・学術集会記録, 43(Proceedings) (Proceedings), 38, English


• 細胞間コミュニケーションシステムCD47‐SIRPα系による血液・免疫系の制御

  小谷武徳, 鷲尾健, ダトゥレス パティカ, 村田陽二, 齊藤泰之, 的崎尚

  2014, 日本分子生物学会年会プログラム・要旨集(Web), 37th, 2W9-3(2P-0718) (WEB ONLY), Japanese


• 細胞質型チロシンホスファターゼShp2の成熟脳における機能解析

  草刈 伸也, 橋本 美穂, 柴崎 貢志, 吾郷 由希夫, 松田 敏夫, Neel Benjamin G., 小谷 武徳, 村田 陽二, 的崎 尚, 大西 浩史

  北関東医学会, 01 Aug. 2013, The Kitakanto medical journal = 北関東医学, 63(3) (3), 321 - 322, Japanese


• SIRPαによる脾臓T細胞の恒常性の調節

  橋本美穂, 齊藤泰之, 金子哲也, 大西浩史, 草苅伸也, 小谷武徳, 村田陽二, 岡澤秀樹, 的崎尚

  北関東医学会, 01 Aug. 2013, 北関東医学会総会プログラム・抄録, 60th(3) (3), 24 - 25, Japanese


• CD47-SIRPα系の生理機能と病態

  Matozaki Takashi

  Dec. 2012, 上原記念生命科学財団研究報告集, 26, 1 - 7, Japanese

  Others


• Hypothermia-induced tyrosine phosphorylation of SIRP alpha in the brain

  S. Kusakari, T. Maruyama, M. Sato-Hashimoto, Y. Hayashi, Y. Kusakari, T. Kotani, Y. Murata, S. Kishi, T. Matozaki, H. Ohnishi

  Oct. 2012, JOURNAL OF NEUROCHEMISTRY, 123, 67 - 67, English

  Summary international conference


• Collagen-induced arthritis and SIRPα

  金子 和光, 的崎 尚, 野島 美久

  科学評論社, Jul. 2012, 臨床免疫・アレルギー科, 58(1) (1), 46 - 52, Japanese


• IMPORTANCE OF THE PROTEIN TYROSINE PHOSPHATASE SHP1 IN DENDRITIC CELLS FOR PREVENTION OF TH1 CELL DIFFERENTIATION AND AUTOIMMUNITY: A POTENTIAL TARGET FOR THE THERAPY

  T. Kaneko, Y. Saito, T. Kotani, H. Ohnishi, Y. Murata, Y. Yonemoto, K. Okamura, T. Matozaki, K. Takagishi

  Jun. 2012, ANNALS OF THE RHEUMATIC DISEASES, 71, 73 - 73, English

  Summary international conference


• 脾臓T細胞の恒常性調節へのSIRPαの関与

  橋本(佐藤)美穂, 齊藤泰之, 金子哲也, 大西浩史, 草苅伸也, 小谷武徳, 村田陽二, 岡澤秀樹, 的崎尚

  2012, 日本生化学会大会(Web), 85th, 3T29-06 (WEB ONLY), Japanese


• Src family kinases: modulators of neurotransmitter receptor function and behavior

  Hiroshi Ohnishi, Yoji Murata, Hideki Okazawa, Takashi Matozaki

  Dec. 2011, TRENDS IN NEUROSCIENCES, 34(12) (12), 629 - 637, English

  [Refereed]

  Book review


• Dendritic cell‐specific depletion of protein tyrosine phosphatase Shp1 promotes Th1 differentiation causes autoimmunit

  KANEKO Tetsuya, SAITO Yasuyuki, OHNISHI Hiroshi, SATO‐HASHIMOTO Miho, KOTANI Takenori, MURATA Yoji, OKAZAWA Hideki, TAKAGISHI Kenji, MATOZAKI Takashi

  07 Nov. 2011, 日本免疫学会総会・学術集会記録, 40, 199, English


• Signal regulatory protein alpha (SIRP α)/CD172a regulates eosinophil homeostasis

  VERJAN GARCIA Noel, UMEMOTO Eiji, SAITO Yasuyuki, HATA Erina, MATOZAKI Takashi, MURAKAMI Masaaki, JANG Myoung Ho, MIYASAKA Masayuki

  07 Nov. 2011, 日本免疫学会総会・学術集会記録, 40, 122, English


• 樹状細胞のチロシンホスファターゼSHP‐1は自己免疫疾患発症に関与する

  金子哲也, 齊藤泰之, 大西浩史, 岡邨興一, 米本由木夫, 篠崎哲也, 的崎尚, 高岸憲二

  25 Aug. 2011, 日本整形外科学会雑誌, 85(8) (8), S1299, Japanese


• SIRPαは腎糸球体上皮細胞の形態と蛋白尿制御に関与する

  高橋 哲史, 廣村 桂樹, 富岡 麻衣, 浜谷 博子, 坂入 徹, 青木 武生, 大西 浩史, 的崎 尚, 野島 美久

  北関東医学会, Aug. 2011, The Kitakanto Medical Journal, 61(3) (3), 457 - 457, Japanese


• CD47-SIRP alpha interactions form a barrier for antibody-mediated tumor cell destruction by phagocytes

  X. W. Zhao, E. M. van Beek, K. Schornagel, H. van der Made, M. van Houdt, M. A. Otten, P. Finetti, M. van Egmond, T. Matozaki, G. Kraal, A. van Elsas, T. W. Kuijpers, F. Bertucci, T. K. van den Berg

  Apr. 2011, EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 41, 36 - 36, English

  Summary international conference


• 特集を読むまえに 基礎の基礎 (特集 ホスファターゼ研究新章--創薬につながる新機能と第四の脱リン酸化酵素の発見)

  的崎 尚, 村田 陽二

  学研メディカル秀潤社, 2011, 細胞工学, 30(6) (6), 586 - 589, Japanese


• Regulation by protein tyrosine phosphorylation of depression-like behavior

  Hiroshi Ohnishi, Takashi Matozaki

  2011, NEUROSCIENCE RESEARCH, 71, E36 - E36, English

  Summary international conference


• Expression, localization, and biological function of the R3 subtype of receptor-type protein tyrosine phosphatases in mammals

  Takashi Matozaki, Yoji Murata, Munemasa Mori, Takenori Kotani, Hideki Okazawa, Hiroshi Ohnishi

  Dec. 2010, CELLULAR SIGNALLING, 22(12) (12), 1811 - 1817, English

  [Refereed]

  Book review


• Regulation by protein tyrosine phosphorylation of stress responses in the brain

  Hiroshi Ohnishi, Shinya Kusakari, Takaaki Murata, Toshi Maruyama, Yuriko Hayashi, Keizo Takao, Tsuyoshi Miyakawa, Yukio Ago, Ken Koda, Toshio Matsuda, Katsuya Okawa, Yasuyuki Saito, Yoji Murata, Takashi Matozaki

  2010, NEUROSCIENCE RESEARCH, 68, E58 - E58, English

  Summary international conference


• 血管内皮細胞のシェアストレス刺激応答におけるVE‐PTPの機能解析

  村田陽二, 森宗昌, 小谷武徳, 草苅伸也, 岡澤秀樹, 齊藤泰之, 大西浩史, 的崎尚

  2010, 生化学, ROMBUNNO.4T9-2, Japanese


• 腸微絨毛特異的な発現を示す受容体型チロシンホスファターゼSAP‐1とIL‐10による炎症性腸疾患の制御

  小谷武徳, 村田陽二, YANA Supriatna, 岡澤秀樹, 大西浩史, EDWIN Daniwijaya, 定方久延, 草苅伸也, 齊藤泰之, 大川克也, 的崎尚

  2010, 生化学, ROMBUNNO.4P-0447, Japanese


• 低温ストレスによるSIRPαチロシンリン酸化の誘導

  丸山登士, 大西浩史, 草苅伸也, 林由里子, 草苅百合子, 村田陽二, 齊藤泰之, 岸章治, 的崎尚

  2010, 生化学, ROMBUNNO.4P-0434, Japanese


• 樹状細胞の機能と関与分子 SIRPαによる樹状細胞の機能制御

  齊藤泰之, 村田陽二, 大西浩史, 的崎尚

  25 Nov. 2009, 月刊臨床免疫・アレルギー科, 52(5) (5), 494 - 498, Japanese


• Essential roles of the CD47‐SIRP α signaling in homeostasis of lymphoid tissue dendritic cells

  SAITO Yasuyuki, IWAMURA Hiroko, KANAZAWA Yoshitake, HASHIMOTO Miho, MURATA Yoji, OHNISHI Hiroshi, KANEKO Yoriaki, MATOZAKI Takashi, NOJIMA Yoshihisa

  30 Sep. 2009, 臨床血液, 50(9) (9), 907, English


• 腸微絨毛特異的な発現を示す受容体型チロシンホスファターゼSAP‐1とIL‐10による炎症性腸疾患の制御

  小谷武徳, 村田陽二, YANA Supriatna, 大西浩史, 定方久延, 草苅伸也, 齊藤泰之, 岡澤秀樹, 的崎尚

  25 Sep. 2009, 生化学, ROMBUNNO.4T5A-16, Japanese


• VE‐PTPによるRas,インテグリン依存的なラメリポディア形成の促進

  森宗昌, 村田陽二, 大西浩史, 岡澤秀樹, 齊藤泰之, 森昌朋, 的崎尚

  25 Sep. 2009, 生化学, ROMBUNNO.4T5A-18, Japanese


• Promotion by VE‐PTP of lamellipodium formation in cooperation with Ras and integrin

  MORI Munemasa, MURATA Yoji, OHNISHI Hiroshi, OKAZAWA Hideki, KOTANI Takenori, SAITO Yasuyuki, MORI Masatomo, MATOZAKI Takashi

  31 Aug. 2009, 日本癌学会学術総会記事, 68th, 246, English


• Tyrosine phosphorylation of SAP‐1, a receptor‐type protein tyrosine phosphatase, and its association with Grb2

  MURATA Yoji, KOTANI Takenori, SUPRIATNA Yana, MORI Munemasa, OKAZAWA Hideki, OHNISHI Hiroshi, SAITO Yasuyuki, MATOZAKI Takashi

  31 Aug. 2009, 日本癌学会学術総会記事, 68th, 204, English


• 2. 脳におけるSHPS-1シグナルの解析（第56回北関東医学会総会抄録 一般演題）

  林 由里子, 大西浩史, 草苅 伸也, 村田 陽二, 齊藤 泰之, 的崎 尚

  北関東医学会, 01 Aug. 2009, The Kitakanto medical journal, 59(3) (3), 322 - 322, Japanese


• 受容体型膜蛋白質SHPS‐1のインスリン分泌制御における機能解析

  小林雅樹, 大西浩史, 岡澤秀樹, 村田陽二, 林由里子, 小林久江, 北村忠弘, 的崎尚

  20 Apr. 2009, 日本内分泌学会雑誌, 85(1) (1), 305, Japanese


• CD47-signal regulatory protein alpha (SIRP alpha) interactions constitute a barrier for antibody-mediated tumor cell elimination by macrophages

  X. W. Zhao, E. M. Van Beek, K. Schornagel, M. van Egmond, T. Matozaki, G. Kraal, T. K. van den Berg

  Apr. 2009, EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 39, 33 - 33, English

  Summary international conference


• TLRシグナルの制御 TLRシグナルのホスファターゼおよびその会合分子による制御

  村田陽二, 齊藤泰之, 大西浩史, 岡澤秀樹, 的崎尚

  25 Mar. 2009, 月刊臨床免疫・アレルギー科, 51(3) (3), 232 - 241, Japanese


• 脳におけるSHPS‐1シグナルの解析

  林由里子, 大西浩史, 草苅伸也, 村田陽二, 齊藤泰之, 的崎尚

  2009, 北関東医学会総会プログラム・抄録, 56th, 14, Japanese


• 神経系における受容体型膜蛋白質SHPS‐1の機能解析

  草苅伸也, 大西浩史, 林由里子, 高雄啓三, 宮川剛, 齊藤泰之, 村田陽二, 的崎尚

  2009, 神経組織の成長・再生・移植研究会学術集会プログラム・予稿集, 24th, 64, Japanese


• シグナル伝達研究 II:現象から因子へ 6.CD47‐SHPS‐1系による樹状細胞の機能制御

  齊藤泰之, 村田陽二, 大西浩史, 的崎尚

  15 Sep. 2008, 実験医学, 26(15) (15), 2424 - 2431, Japanese


• 15.SHPS-1による樹状細胞の機能制御(一般演題,第55回北関東医学会総会抄録)

  岩村紘子, 齊藤泰之, 村田陽二, 大西浩史, 的崎尚, 金子和光, 野島美久

  北関東医学会, 01 Aug. 2008, The KITAKANTO medical journal, 58(3) (3)


• The induction of Th17 by SHPS-1-expressing dendritic cells

  金子 和光, 斎藤 泰之, 的崎 尚

  科学評論社, Jul. 2008, Clinical immunology & allergology, 50(1) (1), 1 - 8, Japanese


• 受容体型膜蛋白質SHPS‐1のインスリン分泌制御における機能解析

  小林雅樹, 大西浩史, 岡澤秀樹, 村田陽二, 林由里子, 北村忠弘, 的崎尚

  25 Apr. 2008, 糖尿病, 51(Supplement 1) (Supplement 1), S.123, Japanese


• CCR7-mediated migration of dendritic cells through activation of Rho kinase is regulated by Src homology 2 domain-containing protein tyrosine phosphatase substrate 1

  K. Ogura, S. Oniki, A. Fukunaga, H. Nagai, H. Okazawa, T. Matozaki, C. Nishigon, T. Horikawa

  Apr. 2008, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 128, S174 - S174, English

  Summary international conference


• Essential Roles of SHPS-1 in induction of contact hypersensitivity of skin

  S. Motegi, H. Okazawa, O. Ishikawa, T. Matozaki

  Apr. 2008, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 128, S158 - S158, English

  Summary international conference


• Resistance to Experimental Autoimmune Encephalomyelitis and Impaired T cell Priming by Dendritic Cells in SHPS‐1 Mutant Mice

  KANEKO Yoriaki, KANEKO Yuka, TOMIZAWA Takeshi, OHNISHI Hiroshi, OKAJO Jun, OKUZAWA Chie, SAITO Yasuyuki, SEKIGAMI Tomomi, MATOZAKI Takashi, NOJIMA Yoshihisa

  25 Oct. 2007, 日本免疫学会総会・学術集会記録, 37, 269, English


• Resistance to collagen‐induced arthritis in SHPS‐1 mutant mice

  OKUZAWA Chie, KANEKO Yoriaki, MURATA Yoji, TOMIZAWA Takeshi, KANEKO Yuka, OKAJO Jun, SAITO Yasuyuki, SEKIGAMI Tomomi, MATOZAKI Takashi, NOJIMA Yoshihisa

  25 Oct. 2007, 日本免疫学会総会・学術集会記録, 37, 134, English


• An essential role of SHPS‐1 in proper development of dendritic cells for induction of Th17‐mediated autoimmune diseases

  SAITO Yasuyuki, KANEKO Yoriaki, KANEKO Yuka, OKUZAWA Chie, SEKIGAMI Tomomi, OKAJO Jun, TOMIZAWA Takeshi, MURATA Yoji, OKAZAWA Hideki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa

  25 Oct. 2007, 日本免疫学会総会・学術集会記録, 37, 125, English


• 14. CD47-SHPS-1系におけるトランスエンドサイトーシスの役割(一般演題,第54回北関東医学会総会抄録)

  草苅伸也, 大西浩史, 村田考啓, 岡澤秀樹, 村田陽二, 的崎尚

  北関東医学会, 01 Aug. 2007, The KITAKANTO medical journal, 57(3) (3)


• SHPS-1 positively regulates T cell priming and cytokine production by dendritic cells (DCs)

  Takeshi Tomizawa, Yoriaki Kaneko, Jun Okajo, Chie Okuzawa, Yasuyuki Saito, Tomomi Sekigami, Yuka Kaneko, Takashi Matozaki, Yoshihisa Nojima

  Apr. 2007, JOURNAL OF IMMUNOLOGY, 178, English

  Summary international conference


• Regulation by SHPS-1 of alpha-GalCer-induced prevention of cancer metastasis

  Jun Okajo, Yoriaki Kaneko, Takeshi Tomizawa, Chie Okuzawa, Yasuyuki Saito, Tomomi Sekigami, Takashi Matozaki, Yoshihisa Nojima

  Apr. 2007, JOURNAL OF IMMUNOLOGY, 178, English

  Summary international conference


• マウスSHPS-1/SIRPαとそのリガンドCD47の特異的相互作用についての構造生物学的研究

  中石明希, 廣瀬まゆみ, 吉村政人, 九鬼伸治, 松田真, 大西浩史, 的崎尚, 岡田雅人, 中川敦史

  2007, 生化学


• 自己免疫性関節炎におけるSHPS-1の機能解析

  奥沢 千絵, 前嶋 明人, 黒岩 卓, 廣村 桂樹, 的崎 尚, 野島 美久, 金子 和光, 村田 陽二, 冨澤 健史, 岡上 準, 斉藤 泰之, 池内 秀和, 坂入 徹, 山下 真

  <B>【目的】</B>SHPS-1は単球系細胞に発現が認められる膜蛋白であるが、我々は最近、SHPS-1がマウスにおける実験的脳脊髄炎や接触性皮膚炎などの自己免疫性疾患の発症に必須であることを明らかにしている。そこで、今回我々は、関節リウマチのマウスモデルであるコラーゲン誘導関節炎(CIA)発症におけるSHPS-1の関与について検討した。<BR><B>【方法と結果】</B>SHPS-1の機能に重要である細胞内領域を特異的に欠失した変異SHPS-1を発現するマウス（MTマウス）をすでに作成しているので、これを用いてニワトリ由来のタイプIIコラーゲンで誘導されるCIAの発症を検討した。野生型マウスでは指、手関節を中心に累積発症率52％の割合で発症し、発症スコアーは3.0であった。一方、MTマウスでは全く発症が認められず、組織学的な解析においてもMTマウスの関節組織はほぼ正常に保たれていた。さらに、コラーゲンによって関節炎を誘導されたマウスにおける免疫応答を検討したところ、MTマウスではコラーゲン特異的な抗体産生能やT細胞の増殖能が減弱しており、炎症性サイトカインの産生低下も認められた。<BR><B>【考察】</B>MTマウスではCIAの発症が認められなかったことより、SHPS-1は抗原特異的免疫応答において重要なシグナル分子であり、リウマチ性疾患の治療を考える上で有力な標的となり得る事が示唆された。

  日本臨床免疫学会, 2007, 日本臨床免疫学会総会抄録集, 35(0) (0), 79 - 79, Japanese


• Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 regulates the induction of Langerhans cell maturation

  Atsushi Fukunaga, Hiroshi Nagai, Xijun Yu, Shuntaro Oniki, Hideki Okazawa, Sei-ichiro Motegi, Ryuji Suzuki, Nakayuki Honma, Takashi Matozaki, Chikako Nishigori, Tatsuya Horikawa

  Dec. 2006, EUROPEAN JOURNAL OF IMMUNOLOGY, 36(12) (12), 3216 - 3226, English


• Regulation by SHPS‐1 of α‐GalCer‐induced prevention of cancer metastasis

  OKAJO Jun, KANEKO Yoriaki, TOMIZAWA Takeshi, OKUZAWA Chie, SAITO Yasuyuki, SEKIGAMI Tomomi, MATOZAKI Takashi, NOJIMA Yoshihisa

  15 Nov. 2006, 日本免疫学会総会・学術集会記録, 36, 247, English


• SHPS‐1 positively regulates T cell priming and cytokine production by dendritic cells (DCs)

  TOMIZAWA Takeshi, KANEKO Yoriaki, OKAJO Jun, OKUZAWA Chie, SAITO Yasuyuki, SEKIGAMI Tomomi, KANEKO Yuka, MATOZAKI Takashi, NOJIMA Yoshihisa

  15 Nov. 2006, 日本免疫学会総会・学術集会記録, 36, 210, English


• Regulation by CD47 of epithelial cell spreading and migration and its signal transduction

  M. Shinohara, N. Ohyama, Y. Murata, H. Okazawa, H. Ohnishi, T. Matozaki

  Aug. 2006, REGULATORY PEPTIDES, 135(3) (3), 158 - 159, English

  Summary international conference


• CD47-SHPS-1シグナル系による赤血球動態の調節

  関上 智美, 金子 和光, 的崎 尚

  科学評論社, Apr. 2006, 臨床免疫, 45(4) (4), 472 - 476, Japanese


• 接着分子とマクロファージによる食作用の制御機構--CD47-SHPS-1系を中心として (特集 病態の形成・変化における細胞接着の働き)

  岡澤 秀樹, 的崎 尚

  中山書店, Dec. 2005, モレキュラ-メディシン, 42(12) (12), 1344 - 1350, Japanese


• A novel intercellular communication system, the CD47-SHPS-1 system, in neuronal network

  H Ohnishi, M Miyashita, T Murata, Y Kaneko, H Okazawa, T Matozaki

  Aug. 2005, JOURNAL OF NEUROCHEMISTRY, 94, 84 - 84, English

  Summary international conference


• 解説 新しい抑制性シグナリングシステムCD47-SHPS-1

  岡上 準, 金子 和光, 的崎 尚

  科学評論社, May 2005, 臨床免疫, 43(5) (5), 589 - 594, Japanese


• The 8th Meeting of gunma Gene Transter Research

  伊藤 知和, 桑野 博行, 岡澤 秀樹, 富澤 恭子, 的崎 尚, 丸山 浩司, 小杉 厚

  Kitakanto Medical Society, 01 Nov. 2004, The KITAKANTO medical journal, 54(4) (4), 361 - 361, Japanese


• CD47-SHPS-1シグナル系によるマクロファージの貪食機能抑制

  石川 智美, 金子 和光, 的崎 尚

  科学評論社, Aug. 2004, 臨床免疫, 42(2) (2), 231 - 234, Japanese


• 16. 変異型SHPS-1のマクロファージ貪食に対する効果(一般演題)(第51回北関東医学会総会抄録)

  池田洋, 岡澤秀樹, 富澤恭子, 大西浩史, 的崎尚

  北関東医学会, 01 Aug. 2004, The KITAKANTO medical journal, 54(3) (3)


• Role of the CD47-SHPS-1 system in regulation of cell migration and macrophage phagocytosis

  T Matozaki, H Okazawa

  2004, JOURNAL OF PHARMACOLOGICAL SCIENCES, 94, 12P - 12P, English

  Summary international conference


• A novel cell-cell communication system, which acts through tyrosine phosphatase SHP-2: Its function in the central nervous system

  H Ohnishi, T Matozaki

  2004, JOURNAL OF PHARMACOLOGICAL SCIENCES, 94, 14P - 14P, English

  Summary international conference


• SHPS-1/SIRP alpha regulates migration of Langerhans cells from epidermis to draining lymphnode

  A Fukunaga, H Nagai, XJ Yu, T Noguchi, T Matozaki, C Nishigori, T Horikawa

  Nov. 2003, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 121(5) (5), 1236 - 1236, English

  Summary international conference


• 細胞間接着によるGab‐1のチロシンリン酸化

  篠原将彦, 児玉昌子, 的崎尚, 福原淳範, 橘公一, 中西宏之, 高井義美

  26 Sep. 2001, 日本癌学会総会記事, 60th, 163, Japanese


• チロシンフォスファターゼによる細胞の運動・接着の制御機構

  的崎尚, 高井義美

  25 Nov. 2000, 日本分子生物学会年会プログラム・講演要旨集, 23rd, 301, Japanese


• 増殖因子と細胞間接着の協調作用による蛋白質チロシンリン酸化

  的崎尚, 児玉昌子, 高井義美

  01 Sep. 2000, Jpn J Cancer Res, 91(Supplement (Sept)) (Supplement (Sept)), 442, Japanese


• 細胞の運動と接着のシグナル伝達機構

  高井義美, 中西宏之, 万代研二, 的崎尚

  01 Sep. 2000, Jpn J Cancer Res, 91(Supplement (Sept)) (Supplement (Sept)), 445, Japanese


• SHP‐2チロシンホスファターゼによるRho低分子量G蛋白質の活性制御機構

  的崎尚, 児玉昌子, 高井義美

  25 Aug. 2000, 生化学, 72(8) (8), 671, Japanese


• リン酸化・脱リン酸化による高次細胞機能制御 チロシンフォスファターゼによる細胞の運動・接着の制御機構

  的崎尚, 高井義美

  2000, 日本細胞生物学会大会講演要旨集, 53rd, 23, Japanese


• 細胞内シグナル伝達の基礎と臨床 細胞の接着・運動の時空間制御機構

  児玉昌子, 的崎尚, 高井義美

  30 Nov. 1999, 細胞, 31(13) (13), 505 - 509, Japanese


• HGFによる細胞運動とチロシンホスファターゼSHP‐2

  児玉昌子, 的崎尚, 福原淳範, 桔梗充博, 高井義美

  22 Nov. 1999, 日本分子生物学会年会プログラム・講演要旨集, 22nd, 407, Japanese


• 細胞間接着破壊によるカドヘリンとc‐Metのcoendocytosis Rho,Rac,Rab低分子量G蛋白質による制御

  匂坂敏朗, 亀井尚, 的崎尚, 中野克俊, 児玉昌子, 高石健司, 高井義美

  30 Aug. 1999, 日本癌学会総会記事, 58th, 232, Japanese


• 癌転移研究の手法 細胞の接着と運動の機構

  亀井尚, 的崎尚, 高井義美

  16 Aug. 1999, 癌と化学療法, 26(9) (9), 1359 - 1366, Japanese


• Insulin-induced activation of JNK is regulated by SHP-2.

  K Fukunaga, T Matozaki, T Noguchi, T Yamao, T Takada, F Ochi, H Takeda, K Inagaki, T Hosoka, M Kasuga

  Aug. 1999, DIABETOLOGIA, 42, A179 - A179, English

  Summary international conference


• 細胞の接着と運動におけるRhoとRab低分子量G蛋白質ファミリーの協調作用

  匂坂敏朗, 的崎尚, 高石健司, 佐々木卓也, 高井義美

  1999, 日本細胞生物学会大会講演要旨集, 52nd, 1, Japanese


• Role of binding proteins to IRS-1 in insulin signalling

  W Ogawa, T Matozaki, M Kasuga

  May 1998, MOLECULAR AND CELLULAR BIOCHEMISTRY, 182(1-2) (1-2), 13 - 22, English

  Book review


• Roles of protein-tyrosine phosphatases in insulin-mediated signal transduction system

  T. Noguchi, T. Matozaki, M. Kasuga

  1998, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 43(8) (8), 1200 - 1208, Japanese

  Book review


• Roles of protein-tyrosine phosphatases in growth factor signalling

  T Matozaki, M Kasuga

  Jan. 1996, CELLULAR SIGNALLING, 8(1) (1), 13 - 19, English

  Book review


• RAS-INDEPENDENT AND WORTMANNIN-SENSITIVE ACTIVATION OF GLYCOGEN-SYNTHASE BY INSULIN IN CHO CELLS

  H SAKAUE, K HARA, T NOGUCHI, T MATOZAKI, W OGAWA, K YONEZAWA, M KASUGA

  May 1995, DIABETES, 44, A19 - A19, English

  Summary international conference


• インスリンの細胞内シグナル伝達機構とチロシンホスファタ-ゼ (プロテインホスファタ-ゼ--最近の進歩<特集>)

  的崎 尚, 春日 雅人

  金原一郎記念医学医療振興財団, Apr. 1995, 生体の科学, 46(2) (2), p127 - 134, Japanese


• Ras-independent and wortmannin-sensitive activation of glycogen synthase by insulin in Chinese hamster ovary cells

  H. Sakaue, K. Hara, T. Noguchi, T. Matozaki, K. Kotani, W. Ogawa, K. Yonezawa, M. D. Waterfield, M. Kasuga

  1995, Journal of Biological Chemistry, 270(19) (19), 11304 - 11309, English


• MOLECULAR-CLONING OF 2 NOVEL PROTEIN-TYROSINE PHOSPHATASES AND THEIR FUNCTIONS IN THE STOMACH CELL-PROLIFERATION

  T SUZUKI, T MATOZAKI, K HORITA, K MATSUDA, T UCHIDA, H NOGUCHI, Y FUJIOKA, T YAMAO, C SAKAMOTO, M KASUGA

  Apr. 1994, GASTROENTEROLOGY, 106(4) (4), A444 - A444, English

  Summary international conference


• GENE-EXPRESSION OF CYCLOOXYGENASE AND EGF-LIKE GROWTH-FACTORS IN DIFFERENT STAGES OF THE MOUSE GASTRIC-ULCER

  K MATSUDA, C SAKAMOTO, H MIZUNO, H NOGUCHI, T MATOZAKI, K WADA, T UCHIDA, Y KONDA, M KASUGA

  Apr. 1994, GASTROENTEROLOGY, 106(4) (4), A132 - A132, English

  Summary international conference


• BASIC FIBROBLAST GROWTH-FACTOR, EPIDELMAL GROWTH-FACTOR AND INSULIN STIMULATE GASTRIC CELL-GROWTH

  K MATSUDA, C SAKAMOTO, Y KONDA, O NAKANO, T MATOZAKI, H NISHISAKI, T SUZUKI, T UCHIDA, K WADA, M KASUGA

  Apr. 1993, GASTROENTEROLOGY, 104(4) (4), A634 - A634, English

  Summary international conference

• マクロファージよる生細胞貪食を制御する分子基盤の解明

  小谷 武徳, 高井智子, 齊藤泰之, 村田陽二, 的崎尚

  第10回日本プロテインホスファターゼ研究会 学術集会, Jan. 2022, Japanese

  Oral presentation


• SIRPα supports the survival of dendritic cells by regulating the NF-kB activation

  Satomi Komori, Yasuyuki Saito, Respatika Datu, Takenori Kotani, Yoji Murata, Takashi Matozaki

  第50回日本免疫学会学術集会, Dec. 2021, English

  Oral presentation


• Preclinical EPreclinical Evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy by the use of humanized micevaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy by the use of humanized mice

  Yasuyuki Saito, Rie Iida-Norita, Daisuke Hazama, Refaat Alaa, Satomi Komori, Takenori Kotani, Yoji Murata, Takashi Matozaki

  第50回日本免疫学会学術集会, Dec. 2021, English

  Oral presentation


• The novel antitumor effect of anti-SIRPα/β1 antibodies via macrophages

  村田 陽二, 坂本 茉莉子, 岡本 武士, 齊藤 泰之, 小谷 武徳, 藤澤 正人, 的崎 尚

  第44回 日本分子生物学会年会, Dec. 2021, Japanese

  Poster presentation


• A signalling switch from Gs to Gq in pancreatic β-cells determines incretin effectiveness in diabetes

  Okechi S. Oduori, Kenju Shimomura, HarumiTakahashi, Norihide Yokoi, Patrik Rorsman, Takashi Matozaki, Susumu Seino

  第20回生体機能研究会, Oct. 2021, English

  Oral presentation


• ランゲルハンス組織球症に対する治療標的候補分子SIRPα

  岡本 武士, 村田 陽二, 田中 大介, 坂本 茉莉子, 齊藤 泰之, 小谷 武徳, 的崎 尚

  第20回生体機能研究会, Oct. 2021, Japanese

  Oral presentation


• Antitumor effects of agents targeting SIRP＆alpha;, an immune eheekpoint, and their combination with other agents

  Yoji Murata, Yasuyuki Saito, Takenori Kotani, Takashi Matozaki

  The 80th Annual Meeting of the Japanese Cancer Association, Oct. 2021, English

  Oral presentation


• Impact of anti-SIRPαantibodies on Langerhans cell histiocytosis

  岡本 武士, 村田 陽二, 羽間 大祐, 坂本 茉莉子, 角地 宥香, 田中 大介, 増田 重人, 齊藤 泰之, 小谷 武徳, 眞庭 謙昌, 的崎 尚

  The 80th Annual Meeting of the Japanese Cancer Association, Sep. 2021, Japanese

  Oral presentation


• A novel humanized mouse model in vivo evaluation of cancer immunotherapy targeting human macrophages

  Yasuyuki Saito, Rie Iida, Daisuke Hazama, Takenori Kotani, Yoji Murata, Hiroshi Yokozaki, Takashi Matozaki

  The 80th Annual Meeting of the Japanese Cancer Association, Sep. 2021, English

  Oral presentation


• SIRPβ1 on macrophages as a promising target for cancer immunotherapy

  坂本 茉莉子, 村田 陽二, 角地 宥香, 岡本 武士, 田中 大介, 羽間 大祐, 増田 重人, 齊藤 泰之, 小谷 武徳, 藤澤 正人, 的崎 尚

  The 80th Annual Meeting of the Japanese Cancer Association, Japanese

  Poster presentation


• The antitumor effect of monotherapy with an anti-SIRPα antibody against bladder cancer cells

  Yoji Murata, Mariko Sakamoto, Takeshi Okamoto, Yasuyuki Saito, Takenori Kotani, Takashi Matozaki

  2021 JCA-AACR JCA-AACR Precision Cancer Medicine International Conference, English

  Poster presentation


• A novel humanized mouse model for assessing human macrophage-targeted cancer immunotherapy in vivo

  飯田 理恵, 齊藤 泰之, 羽間 大祐, 小森 里美, 小谷 武徳, 村田 陽二, 的崎 尚

  文部科学省新学術領域研究 先端モデル動物支援プラットフォーム2021年度若手支援技術講習会, Sep. 2021, Japanese

  Oral presentation


• Antibodies to SIRPα/SIRPβ as a potential tool for immunotherapy of bladder cancer

  Mariko Sakamoto, Yoji Murata, Yuka Kakuchi, Daisuke Takana, Takeshi Okamoto, Yasuyuki Saito, Takenori Kotani, Masato Fujisawa, Takashi Matozaki

  14th International Conference on Protein Phosphatase, Dec. 2020, English

  Poster presentation


• Blockade of the CD47-SIRPα interaction by SIRPα-binding macrocyclic peptides as a potential cancer immunotherapy

  Yoji Murata, Daisuke Hazama, Yizhen Yin, Mariko Sakamoto, Yasuyuki Saito, Takenori Kotani, Hiroaki Suga, Takashi Matozaki

  14th International Conference on Protein Phosphatase, Dec. 2020, English

  Oral presentation


• Roles of Shp2-Ras, Src family kinases, and mTOR signaling in intestinal epithelial homeostasis

  Takenori Kotani, Saki Okamoto, Yoji Murata, Yasuyuki Saito, Takashi Matozaki

  14th International Conference on Protein Phosphatase, Dec. 2020, English

  Oral presentation


• Role of CD47 on the regulation of peripheral T cell survival by dendritic cells

  Satomi Komori, Yasuyuki Saito, Taichi Nishimura, Hiroki Yoshida, Risa Sugihara, Rie Iida, Takenori Kotani, Yoji Murata, Takashi Matozaki

  14th International Conference on Protein Phosphatase, Dec. 2020, English

  Poster presentation


• A novel humanized mouse model for assessing human macrophage-targeted cancer immunotherapy in vivo

  Rie Iida-Norita, Yasuyuki Saito, Daisuke Hazama, Satomi Komori, Hiroki Yoshida, Risa Sugihara, Yoji Murata, Takashi Matozaki

  14th International Conference on Protein Phosphatase, Dec. 2020, English

  Poster presentation


• SIRPα targeting as a potential therapy of Langerhans cell histiocytosis

  岡本 武士, 村田 陽二, 羽間 大祐, 坂本 茉莉子, 角地 宥香, 齊藤 泰之, 小谷 武徳, 眞庭 謙昌, 的崎 尚

  The 79th Annual Meeting of the Japanese Cancer Association, Oct. 2020, Japanese

  Oral presentation


• Role of K-Ras activity in regulation of proliferation and differentiatiojn of intestinal epithelial cells

  小谷 武徳, 井原 紀子, ジャジャル セティアワン, 岡本 沙樹, 齊藤 泰之, 村田 陽二, 的崎 尚

  The 79th Annual Meeting of the Japanese Cancer Association, Oct. 2020, Japanese

  Oral presentation


• The novel antitumor effect of an antibody to SIRPα/SIRPβagainst bladder cancers-

  坂本 茉莉子, 村田 陽二, 羽間 大祐, 岡本 武士, 角地 宥香, 齊藤 泰之, 小谷 武徳, 藤沢 正人, 的崎 尚

  The 79th Annual Meeting of the Japanese Cancer Association, Oct. 2020, Japanese

  Oral presentation


• Humanized mouse models for in vivo evaluation of cancer immunotherapy targeting human macrophages

  Yasuyuki Saito, Rie Iida, Daisuke Hazama, Takenori Kotani, Yoji Murata, Takashi Matozaki

  The 79th Annual Meeting of the Japanese Cancer Association, Oct. 2020, English

  Oral presentation


• 膜型分子CD47を介した成熟T細胞の寿命制御

  小森 里美, 齊藤 泰之, 西村 太一, 吉田 弘樹, 杉原 理紗, 飯田 理恵, 小谷 武徳, 村田 陽二, 的崎 尚

  第19回生体機能研究会, Sep. 2020, Japanese

  Oral presentation


• Srcﾌｧﾐﾘｰｷﾅｰｾﾞ、Ras, ｍTORC1ｼｸﾞﾅﾙによる腸上皮細胞の恒常性制御

  小谷 武徳, 岡本 沙樹, 村田 陽二, 齊藤 泰之, 的崎 尚

  第19回生体機能研究会, Sep. 2020, Japanese

  Oral presentation


• 抗SIRPα抗体を用いた膀胱がんに対する新規がん免疫療法開発

  坂本 茉莉子, 村田 陽二, 田中 大介, 岡本 武士, 羽間 大祐, 角地 宥加, 齊藤 泰之, 小谷 武徳, 的崎 尚

  第19回生体機能研究会, Sep. 2020, Japanese

  Oral presentation


• Identification of macrocyclic peptides that regulate the CD47-SIRPαsystem, and their potential as anti-cancer drugs

  村田 陽二, 羽間 大祐, Yin Yizhen, 松田 真, 岡本 武士, 田中 大介, 坂本 茉莉子, 角地 宥香, 寺坂 尚紘, Zhao Jinxuan, 齊藤 泰之, 小谷 武徳, 中川 敦史, 菅 裕明, 的崎 尚

  The 93rd Annual Meeting of the Japanese Biochemical Society, Sep. 2020, Japanese

  Oral presentation


• Role of K-Ras activity in regulation of intestinal proliferation and differentiatiojn of intestinal epithelial cells

  小谷 武徳, 井原 紀子, ジャジャル セティアワン, 岡本 沙樹, 齊藤 泰之, 村田 陽二, 的崎 尚

  The 93rd Annual Meeting of the Japanese Biochemical Society, Sep. 2020, Japanese

  Poster presentation


• Importance of CD47-SIRPa system for regulation of macrophages in the tumor microenvironment

  Takashi Matozaki

  The 4th Taiwan-Japan Bilateral Conference on Protein Phosphatases 2019, Nov. 2019, English

  [Invited]

  Nominated symposium


• A nobel macrocycle peptide targets CD47-SIRPalpha axis and enhances the macrophage-mediated tumor killing

  Daisuke Hazama, Yoji Murata, Daisuke Tanaka, Takeshi Okamoto, Ysuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Takashi Matozaki

  第78回日本癌学会総会, Sep. 2019, Japanese

  Poster presentation


• Role of Tsc2-mTORC1 signaling in regulation of colonic epithelial homeostasis

  Takenori Kotani, Jajar Setiawan, Noriko Ihara, Saki Okamoto, Yoji Murata, Yasuyuki Saito, Takashi Matozaki

  第78回日本癌学会総会, Sep. 2019, Japanese

  Poster presentation


• SIRPα抗体を用いた新規のがん免疫療法:CD20及びPD-1抗体との併用による有効性

  Takashi Matozaki, Yoji Murata, Yasuyuki Saito, Takenori Kotani

  第78回日本癌学会総会, Sep. 2019, Japanese

  Oral presentation


• Regulation of innate immune cell functions by the SHP-1/2 binding protein SIRPα

  村田 陽二, 齊藤 泰之, 小谷 武徳, 的崎 尚

  第92回日本生化学会大会, Sep. 2019, Japanese

  Oral presentation


• Regulation by macrophages of the hematopoietic cell lifespan and its therapeutic application

  的崎 尚, 齊藤 泰之, 小谷 武徳, 村田 陽二

  第92回日本生化学会大会, Sep. 2019, Japanese

  Oral presentation


• Importance of SIRPα+ dendric cells for the development of fibroblastic reticular cells of peripheral lymph nodes

  Satomi Komori, Yasuyuki Saito, Datu Resppatika, Taichi Nishimura, Takenori Kotani, Yoji Murata, Takashi Matozaki

  第92回日本生化学会大会, Sep. 2019, Japanese

  Poster presentation


• 新規SIRPα阻害剤の開発とその抗腫瘍効果

  村田 陽二, 羽間 大祐, 田中 大介, 岡本 武士, 齊藤 泰之, 小谷 武徳, 的崎 尚

  第18回生体機能研究会, Jul. 2019, Japanese

  Oral presentation


• SIRPα陽性樹状細胞による末梢リンパ節ストローマ細胞の発達制御

  小森 里美, 齊藤 泰之, ダトゥ レスパティカ, 西村 太一, 小谷 武徳, 村田 陽二, 的崎 尚

  第9回ﾎｽﾌｧﾀｰｾﾞ研究会学術集会, Jul. 2019, Japanese

  Oral presentation


• 大腸上皮の恒常性制御におけるTsc2-mTORC1シグナルの役割

  小谷 武徳, ジャジャル セティアワン, 井原 紀子, 岡本 沙樹, 村田 陽二, 齊藤 泰之, 的崎 尚

  第9回ﾎｽﾌｧﾀｰｾﾞ研究会学術集会, Jul. 2019, Japanese

  Oral presentation


• Role of Tsc2-mTORC1 signaling in homeostasis of intestinal epithelium and its relation to inflammation and cancer

  Takenori Kotani, Jajar Setiawan, Yoji Murata, Yasuyuki Saito, Takashi Matozaki

  AACR Annual Meeting 2019, Mar. 2019, English, the American Association for Cancer Research, アトランタ, International conference

  Poster presentation


• SIRPα＋Dendritic Cells regulate organization of lymph node stromal sells in vivo

  Satomi Komori, Yasuyuki Saito, Respatika Datu, Takenori Kotani, Yoji Murata, Takashi Matozaki

  第47回日本免疫学学術集会, Dec. 2018, English, 日本免疫学会, 福岡, Domestic conference

  Oral presentation


• Importance of SIRPα on dendritic cells for the development of exprerimental autoimmune encephalomyelitis

  Taichi Nishimura, Yasuyuki Saito, Satomi Komori, Respatika Datu, Ken Washio, Takenori Kotani, Yoji Murata, Satoshi Mizobuchi, Takashi Matozaki

  第47回日本免疫学学術集会, Dec. 2018, English, 日本免疫学会, 福岡, Domestic conference

  Oral presentation


• SIRPα陽性樹状細胞による脾臓細網線維芽細胞の恒常性の制御

  SAITO YASUYUKI, 小森 里美, Datu Respatika, 鷲尾 健, 西村 太一, KOTANI TAKENORI, MURATA YOJI, MATOZAKI TAKASHI

  第80回日本血液学会学術集会, Oct. 2018, English, 日本血液学会, 大阪, Domestic conference

  Poster presentation


• Role of the tyrosine phosphorylation signal in homeostasis of intestinal epithelium and its relation to inflammation and cancer

  Takashi Matozaki, Yoji Murata, Takenori Kotani, Yasuyuki Saito

  Workshop on Frontiers in Phosphatase Research and Drug Discovery, Oct. 2018, English, 日本プロテインホスファターゼ研究会, 東京, International conference

  Oral presentation


• Critical role of SIRPαon dendritic cells for the development of experimental autoimmune encephalomyelitis

  Taichi Nishimura, Yasuyuki Saito, Ken Washio, Satomi Komori, Respatika Datu, Takenori Kotan*i, Yoji Murata, Satoshi Mizobuchi, Takashi Matozaki

  Workshop on Frontiers in Phosphatase Research and Drug Discovery, Oct. 2018, English, 日本プロテインホスファターゼ研究会, 東京, International conference

  Poster presentation


• 腸上皮細胞の恒常生維持に関わるチロシンリン酸化シグナルの意義

  MATOZAKI TAKASHI, MURATA YOJI, KOTANI TAKENORI, SAITO YASUYUKI

  第91回日本生化学会大会, Sep. 2018, English, 日本生化学会, 京都, Domestic conference

  Oral presentation


• 腸炎症制御における腸上皮Srcファミリーキナーゼの役割

  孫 春暁, MURATA YOJI, 今田 慎也, KOTANI TAKENORI, SAITO YASUYUKI, YAMADA HIDETO, MATOZAKI TAKASHI

  第77回日本癌学会学術総会, Sep. 2018, English, 日本癌学会, 大阪, Domestic conference

  Poster presentation


• 常在細菌による成体マウス脳室下帯におけるニュートロン新生の制御

  澤田 直樹, KOTANI TAKENORI, 金野 祐, ジャジャル セティアワン, SAITO YASUYUKI, MURATA YOJI, NIBU KENICHI, MATOZAKI TAKASHI

  第91回日本生化学会大会, Sep. 2018, English, 日本生化学会, 京都, Domestic conference

  Poster presentation


• Tsc2-mTORC1シグナルによる小腸上皮の恒常性制御

  ジャジャル セティアワン, KOTANI TAKENORI, 金野 祐, MURATA YOJI, SAITO YASUYUKI, MATOZAKI TAKASHI

  第77回日本癌学会学術総会, Sep. 2018, Japanese, 日本癌学会, 大阪, Domestic conference

  Poster presentation


• Srcファミリーキナーゼの炎症性腸疾患における重要性

  孫 春暁, MURATA YOJI, 今田 慎也, KOTANI TAKENORI, SAITO YASUYUKI, YAMADA HIDETO, MATOZAKI TAKASHI

  第91回日本生化学会大会, Sep. 2018, Japanese, 日本生化学会, 京都, Domestic conference

  Poster presentation


• Involvement of intestinal epithelial Src family kinases in intestinal immunity

  Sun Chunxiao, Yuka Murata, Imada Shinya, Kotani Takenori, Saito Yasuyuki, Hideto Yamada, Matozaki Takashi

  第77回日本癌学会学術総会, Sep. 2018, English, 大阪, Domestic conference

  Poster presentation


• 実験的自己免疫性脳脊髄炎の発症制御におけるCD47-SIRPα系の役割について

  西村 太一, SAITO YASUYUKI, 鷲尾 健, 小森 里美, KOTANI TAKENORI, MURATA YOJI, MIZOBUCHI SATOSHI, MATOZAKI TAKASHI

  第17回生体機能研究会, Jul. 2018, Japanese, 生体機能研究会, 渋川, Domestic conference

  Oral presentation


• 抗SIRPα抗体による新規がん免疫療法

  羽間 大祐, MURATA YOJI, 栁田 匡彦, 田中 大介, SAITO YASUYUKI, KOTANI TAKENORI, NISHIMURA YOSHIHIRO, MATOZAKI TAKASHI

  第17回生体機能研究会, Jul. 2018, Japanese, 生体機能研究会, 渋川, Domestic conference

  Oral presentation


• SIRPα＋Dendritic Cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Yasuyuki Saito, Datu Rrspatika, Satomi Komori, Ken Washio, Taichi Nishimura, Takenori Kotani, Yoji Murata, Takashi Matozaki

  15th International Symposium on Dendritic Cells, Jun. 2018, Japanese, Aachen, International conference

  Poster presentation


• Role of Csk iRole of Csk in the regulation of intestinal homeostasis and the development of inflammation in the colonn the regulation of intestinal homeostasis and the development of inflammation in the colon

  Chunxiao Sun, Yoji Murata, Shinya Imada, Takenori Kotani, Yasuyuki Saito, Hideto Yamada, Takashi Matozaki

  第65回日本生化学会近畿支部例会, May 2018, Japanese, The Japanese Biochemical Society, Kinki Branch, 西宮, Domestic conference

  Poster presentation


• SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Satomi Komori, Saito Yasuyuki, Datu Respatika, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 2nd International Joint Symposium -UW,UO,KU-, Mar. 2018, English, Center for Cell Signaling and Medical Innovation, Honolulu, USA(Hawaii), International conference

  Poster presentation


• Regulation of intestinal epithelial cell turnover by intertinal contents

  Konno Tasuku, Kotani Takenori, Jung-ha Park, Jajar Setiawan, Naoki Sawada, Yuka Nishigaito, Naoya, Hatano, Masato Okada, Shinohara Masakazu, Saito Yasuyuki, Murata Yoji, Matozaki Takashi

  The 2nd International Joint Symposium -UW,UO,KU-, Mar. 2018, English, Center for Cell Signaling and Medical Innovation, Honolulu, USA(Hawaii), International conference

  Poster presentation


• Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

  Matozaki Takashi

  The 2nd International Joint Symposium -UW,UO,KU-, Mar. 2018, English, Center for Cell Signaling and Medical Innovation, Honolulu, USA(Hawaii), International conference

  Oral presentation


• Development of a novel cancer immunotherapy targeting the interaction between tumor cells and macrophages

  Murata Yoji, Tadahiro Yanagita, Daisuke Tanaka, Daisuke Hazama, Saito Yasuyuki, Kotani Takenori, Hiroshi Ohnishi, Matozaki Takashi

  ConBio2017(The 90th Annual Meeting of the Japanese Biochemical Society, The 40th Annual Meeting of the Molecular Biology Society of Japan), Dec. 2017, Japanese, The Japanese Biochemical Society, The Molecular Biology Society of Japan, 神戸, Domestic conference

  Oral presentation


• SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Saito Yasuyuki, Satomi Komori, Datu Respatika, Washio Ken, Kotani Takenori, Murata Yoji, Hiroshi Ohnishi, Katsuyuki Yui, Koji Yasutomo, Matozaki Takashi

  The 46th Annual Meeting of The Japanese Society for Immunology, Dec. 2017, English, Japanese Society for Immunology, 仙台, Domestic conference

  Oral presentation


• Role of Tsc2-mTORC1 signaling in regulation of intestinal epithelial homeostasis

  Jajar Setiawan, Kotani Takenori, Konno Tasuku, Shinya Imada, Jung-ha Park, Naoki Sawada, Saito Yasuyuki, Murata Yoji, Matozaki Takashi

  ConBio2017(The 90th Annual Meeting of the Japanese Biochemical Society, The 40th Annual Meeting of the Molecular Biology Society of Japan), Dec. 2017, English, The Japanese Biochemical Society, The Molecular Biology Society of Japan, 神戸, Domestic conference

  Poster presentation


• Development of a novel primary culture system for lymphoid organ fibroblastic reticular cells

  Komori Satomi, Saito Yasuyuki, Datu Respatika, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 46th Annual Meeting of The Japanese Society for Immunology, Dec. 2017, English, Japanese Society for Immunology, 仙台, Domestic conference

  Poster presentation


• SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen

  Saito Yasuyuki, Satomi Komori, Datu Respatika, Washio Ken, Kotani Takenori, Murata Yoji, Hiroshi Ohnishi, Katsuyuki Yui, Koji Yasutomo, Matozaki Takashi

  The 5th Annual Meeting of the International Cytokine and Interferon Society, ICIS 2017 5th Annual Meeting of the International Cytokine and Interferon Society, ICIS 2017, Nov. 2017, English, International Cytokine and Interferon Society, 金沢, International conference

  Oral presentation


• Role of mechanistic target of rapamycin complex 1 (mTORC1) in regulation of intestinal epithelial homeostasis

  Kotani Takenori, Jajar Setiawan, Konno Tasuku, Shinya Imada, Naoki Sawada, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 3rd Japan-Taiwan Bilateral Conference on Protein Phosphatase in Sendai. The 8th Japanese Conference on Protein Phosphatase., Nov. 2017, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Oral presentation


• Blockage of CD47-SIRPαsignaling provide a novel cancer immunotherapy

  Matozaki Takashi

  The 3rd Japan-Taiwan Bilateral Conference on Protein Phosphatase in Sendai. The 8th Japanese Conference on Protein Phosphatase., Nov. 2017, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Oral presentation


• 免疫系ヒト化マウスを用いた新規がん異種移植マウスモデルの作成

  Saito Yasuyuki, 羽間 大祐, Kotani Takenori, Murata Yoji, Matozaki Takashi

  なし, Sep. 2017, Japanese, なし, 岐阜, Domestic conference

  Oral presentation


• 二次リンパ組織ストローマ細胞の新規初代培養系の樹立と増殖・制御機構の解明

  小森 里美, Saito Yasuyuki, Datu Respatika, Kotani Takenori, Murata Yoji, Matozaki Takashi

  なし, Sep. 2017, Japanese, なし, 岐阜, Domestic conference

  Oral presentation


• 腸内容物による腸上皮細胞のターンオーバー制御

  Konno Tasuku, Kotani Takenori, 朴 貞河, Jajar Setiawan, 澤田 直樹, 西垣内 佑香, Hatano Naoya, 岡田 雅人, Shinohara Masakazu, Saito Yasuyuki, Murata Yoji, Matozaki Takashi

  なし, Sep. 2017, Japanese, なし, 岐阜, Domestic conference

  Oral presentation


• Role of Tsc2-mTORC1 signaling in intestinal homeostasis

  Kotani Takenori, Jajar Setiawan, Konno Tasuku, Shinya Imada, Naoki Sawada, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 76th Annual Meeting of the Japanese Cancer Association, Sep. 2017, Japanese, The Japanese Cancer Association, 横浜, Domestic conference

  Poster presentation


• Anti-SIRPalpha antibodies provide a basis for new approaches to canser immunotherapy,

  Matozaki Takashi, Murata Yoji, Tadahiro Yanagita, Saito Yasuyuki, Kotani Takenori

  The 76th Annual Meeting of the Japanese Cancer Association, Sep. 2017, English, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• Establishment of a potential new PDX mouse model for personalized cancer immunotherapy

  Saito Yasuyuki, Murata Yoji, Kotani Takenori, Richard A. Flavell, Markus G. Manz, Matozaki Takashi

  The 76th Annual Meeting of the Japanese Cancer Association, Sep. 2017, Japanese, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• Regulation of interestinal epithelial homeostasis by Src family kinases through Rac and YAP

  Murata Yoji, Shinya Imada, Kotani Takenori, Chunxiao Sun, Saito Yasuyuki, Matozaki Takashi

  The 76th Annual Meeting of the Japanese Cancer Association, Sep. 2017, English, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• 受容体型チロシンホスファターゼSAP-1による腸管免疫制御

  Murata Yoji, Kotani Takenori, Saito Yasuyuki, Matozaki Takashi

  なし, Jul. 2017, Japanese, なし, 淡路, Domestic conference

  Oral presentation


• Role of Src family kinases in regulation of intestinal epithelial homeostasis

  Murata Yoji, Shinya Imada, Kotani Takenori, Chunxiao Sun, Saito Yasuyuki, Matozaki Takashi

  Europhosphatase 2017:Phosphatases in cell fates and decisions, Jul. 2017, English, FASEB, Paris, France, International conference

  Poster presentation


• Regulation of intestinal immunity by the microvillus-specific protein tyrosine phosphatase SAP-1 and its substrate CEACAM20

  Kotani Takenori, Murata Yoji, Yana Supriatna, Yasuaki Kitamura, Shinya Imada, Saito Yasuyuki, Hideki Okazawa, Hiroshi Ohnishi, Matozaki Takashi

  Europhosphatase 2017:Phosphatases in cell fates and decisions, Jul. 2017, English, FASEB, Paris, France, International conference

  Poster presentation


• Blockage of CD47-SIRPαsignaling provide a novel cancer immunotherapy

  Matozaki Takashi, Murata Yoji, Tadahiko Yanagita, Saito Yasuyuki, Kotani Takenori

  Europhosphatase 2017:Phosphatases in cell fates and decisions, Jul. 2017, English, FASEB, Paris, France, International conference

  Oral presentation


• Role of SIRPα on dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen

  Datu Respatika, Saito Yasuyuki, Ken Washio, Satomi Komori, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 45th Annual Meeting of the Japanese Society for Immunology, Dec. 2016, English, Japanese Society for Immunology, 宜野湾, Domestic conference

  Poster presentation


• Therapeutic application of anti-SIRPαantibody in cancer treatment

  Tadahiko Yanagita, Murata Yoji, Daisuke Tanaka, Saito Yasuyuki, Kotani Takenori, Komori Takahide, Matozaki Takashi

  The 12th International Conference on Protein Phosphatase, Oct. 2016, English, Japanese Association for Protein Phosphatase Research, 大阪, Domestic conference

  Poster presentation


• The anti-SIRPα antibody prevents tumor formation: a novel strategy for cancer therapy

  栁田 匡彦, Murata Yoji, 田中 大介, Saito Yasuyuki, Kotani Takenori, Komori Takahide, Matozaki Takashi

  The 75th Annual Meeting of the Japanese Cancer Association, Oct. 2016, Japanese, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• Role of SIRPαin the homeostasis of fibroblastic reticular cells by dendritic cells in the spleen

  Datu Respatika, Saito Yasuyuki, Ken Washio, Satomi Komori, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 12th International Conference on Protein Phosphatase, Oct. 2016, English, Japanese Association for Protein Phosphatase Research, 大阪, Domestic conference

  Poster presentation


• Human hemato-lymphoid system development in human cytokine knock-in mice engrafted with adult donor-derived CD34+ cells

  Saito Yasuyuki, Matozaki Takashi, Richard A. Flavell, Markus G. Manz

  The 12th International Conference on Protein Phosphatase, Oct. 2016, English, Japanese Association for Protein Phosphatase Research, 大阪, Domestic conference

  Oral presentation


• Development of novel cancer immunotherapy targeting tumor microenvironment

  Matozaki Takashi

  The 75th Annual Meeting of the Japanese Cancer Association, Oct. 2016, Japanese, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• 白質におけるミクログリア恒常性制御

  野津 智美, 橋本 美穂, Ruwaida Elhanbaly, 石川 達也, Saito Yasuyuki, Kotani Takenori, Murata Yoji, 深澤 有吾, Matozaki Takashi, 大西 浩史

  The 59th Annual Meeting of the Japan Neuroscience Society, Sep. 2016, Japanese, Japanese Society of Biological Psychiatry, The Japanese Society for Neurochemistry, 福岡, Domestic conference

  Poster presentation


• Role of the CD47-SIRPalpha system and its therapeutic application

  Matozaki Takashi

  なし, Sep. 2016, Japanese, なし, 神戸, Domestic conference

  Oral presentation


• Role of the CD47-SIRPalpha system and its therapeutic application

  Matozaki Takashi, Murata Yoji, Saito Yasuyuki, Kotani Takenori, 栁田 匡彦, 田中 大介, 大西 浩史

  The 89th Annual Meeting of the Japanese Biochemical Society, Sep. 2016, Japanese, The Japanese Biochemical Society, 仙台, Domestic conference

  Oral presentation


• SIRPα欠損マウスはLPS投与によって誘導される低体温症が重症化する

  橋本 美穂, 野津 智美, 浦野 江里子, Saito Yasuyuki, Kotani Takenori, Murata Yoji, Matozaki Takashi, 大西 浩史

  The 59th Annual Meeting of the Japan Neuroscience Society, Sep. 2016, Japanese, Japanese Society of Biological Psychiatry, The Japanese Society for Neurochemistry, 福岡, Domestic conference

  Poster presentation


• Short chain fatty acids regulate the turnover of intestinal epithelial cells

  Konno Tasuku, Kotani Takenori, 朴 貞河, Jajar Setiawan, 北村 泰明, 今田 慎也, 臼井 佑太郎, Hatano Naoya, Shinohara Masakazu, Saito Yasuyuki, Murata Yoji, Matozaki Takashi

  The 89th Annual Meeting of the Japanese Biochemical Society, Sep. 2016, Japanese, The Japanese Biochemical Society, 仙台, Domestic conference

  Poster presentation


• Role of SIRPαon dendritic cells in homeostatic regulation of fibroblastic reticular cells in the spleen

  Datu Respatika, Saito Yasuyuki, Ken Washio, Satomi Komori, Kotani Takenori, Murata Yoji, Matozaki Takashi

  なし, Jul. 2016, English, なし, 淡路, Domestic conference

  Oral presentation


• 成熟細胞の寿命制御とその破綻による病態に関する研究-腸上皮細胞をモデルとして-

  Matozaki Takashi

  なし, May 2016, Japanese, なし, 広島, Domestic conference

  Oral presentation


• Regulation by microbiota of the cellular life span in intestinal epithelial cells

  Kotani Takenori, 朴 貞河, 金野 祐, Jajar Setiawan, 北村 泰明, 今田 慎也, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 7th Annual Meeting of Japanese Association for Protein Phosphatase Research, Jan. 2016, Japanese, Japanese Association for Protein Phosphatase Research, 岡崎, Domestic conference

  Oral presentation


• Essential Role of SIRPα on Dendritic Cells in Homeostatic Regulation of Spleen Stromal Cells

  Datu Respatika, Saito Yasuyuki, Ken Washio, Satomi Komori, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 7th Annual Meeting of Japanese Association for Protein Phosphatase Research, Jan. 2016, English, Japanese Association for Protein Phosphatase Research, 岡崎, Domestic conference

  Poster presentation


• Role of C-terminal Src kinase(Csk) and Src family kinases in homeostasis of the intestinal epithelium

  今田 慎也, Murata Yoji, 北村 泰明, 朴 貞河, 畑野 正樹, 金野 祐, Kotani Takenori, Saito Yasuyuki, 大段 秀樹, Matozaki Takashi

  BMB2015 Biochemistry and Molecular Biology, Dec. 2015, Japanese, The Molecular Biology Society of Japan,The Japanese Biochemical Society, 神戸, Domestic conference

  Poster presentation


• Role of C-terminal Src kinase(Csk) and Src family kinases in homeostasis of the intestinal epithelium

  今田 慎也, Murata Yoji, 北村 泰明, 朴 貞河, 畑野 正樹, 金野 祐, Kotani Takenori, Saito Yasuyuki, 大段 秀樹, Matozaki Takashi

  BMB2015 Biochemistry and Molecular Biology, Dec. 2015, Japanese, The Molecular Biology Society of Japan,The Japanese Biochemical Society, 神戸, Domestic conference

  Oral presentation


• Importance of commensal bacteria and short-chain fatty acids for the growth and migration of intestinal epithelial cells

  Kotani Takenori, 朴 貞河, 北村 泰明, 今田 慎也, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  BMB2015 Biochemistry and Molecular Biology, Dec. 2015, Japanese, The Molecular Biology Society of Japan,The Japanese Biochemical Society, 神戸, Domestic conference

  Poster presentation


• Regulation of intestinal immunity by R3-subtype receptor-type protein tyrosine phosphatase SAP-1

  Murata Yoji, Kotani Takenori, 齋藤 泰之, 岡澤 秀樹, 大西 浩史, Matozaki Takashi

  BMB2015 Biochemistry and Molecular Biology, Dec. 2015, Japanese, The Molecular Biology Society of Japan,The Japanese Biochemical Society, 神戸, Domestic conference

  Public symposium


• Role of C-terminal Src kinase(Csk) and Src family kinases in homeostasis of the intestinal epithelium

  今田 慎也, Murata Yoji, 北村 泰明, 朴 貞河, Kotani Takenori, Saito Yasuyuki, 大段 秀樹, Matozaki Takashi

  The 74th Annual Meeting of the Japanese Cancer Association, Oct. 2015, Japanese, The Japanese Cancer Association, 名古屋, Domestic conference

  Oral presentation


• Importance of commensal bacteria and short-chain fatty acids for the growth and migration of intestinal epithelial cells

  Kotani Takenori, 朴 貞河, 北村 泰明, 今田 慎也, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 74th Annual Meeting of the Japanese Cancer Association, Oct. 2015, Japanese, The Japanese Cancer Association, 名古屋, Domestic conference

  Oral presentation


• SAP-1 and CEACAM20 protect against colitis in the intestinal epithelium

  Murata Yoji, Kotani Takenori, Yana Supriatna, Yasuaki Kitamura, Shinya Imada, Saito Yasuyuki, Hideki Okazawa, Hiroshi Ohnishi, Matozaki Takashi

  2015 FASEB Science Research Conferences, Aug. 2015, English, FASEB, SteamboatSprings, USA, International conference

  Poster presentation


• Role of C-terminal Src kinase(Csk) and Src family kinases in homeostasis of the intestinal epithelium

  Shinya Imada, Murata Yoji, Yasuaki Kitamura, Jung-ha Park, Masaki Hatano, Kotani Takenori, Saito Yasuyuki, Hideki Ohdan, Matozaki Takashi

  2015 FASEB Science Research Conferences, Aug. 2015, English, FASEB, SteamboatSprings, USA, International conference

  Poster presentation


• Regulation of intestinal immunity by the microvillus-specific protein tyrosine phosphatase SAP-1 and CEACAM20

  Murata Yoji, Kotani Takenori, Yana Supriatna, 北村 泰明, 今田 慎也, Saito Yasuyuki, 大西 浩史, Matozaki Takashi

  The 67th Annual Meeting of the Japan Society for Cell Biology, Jul. 2015, Japanese, The Japan Society for Cell Biology, 東京, Domestic conference

  Poster presentation


• Regulation by microbiota of the cellular life span in intestinal epithelial cells

  Kotani Takenori, 朴 貞河, 北村 泰明, 今田 慎也, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 67th Annual Meeting of the Japan Society for Cell Biology, Jul. 2015, Japanese, The Japan Society for Cell Biology, 東京, Domestic conference

  Poster presentation


• Behavioral analysis of forebrain neuron-specific Shp2 conditional knockout mice

  Hiroshi Ohnishi, Shinya Kusakari, Miho Hashimoto, Shuya Ishikawa, Eriko Urano, Kotani Takenori, Murata Yoji, Matozaki Takashi

  The 38th Annual Meeting of the Japan Neuroscience Society, Jul. 2015, English, The Japan Neuroscience Society, 神戸, Domestic conference

  Poster presentation


• 細胞間シグナル伝達システムCD47-SIRPα系のがん治療への応用

  栁田 匡彦, Murata Yoji, 田中 大介, Kotani Takenori, Saito Yasuyuki, Komori Takahide, Matozaki Takashi

  なし, Jul. 2015, Japanese, なし, 箱根, Domestic conference

  Oral presentation


• 異種間移植におけるCD47-SIRPα系の役割とその応用

  Saito Yasuyuki, Matozaki Takashi

  なし, Jul. 2015, Japanese, なし, 箱根, Domestic conference

  Oral presentation


• Analysis of cell-cell interaction signal that regulates microglial homeostasis

  Miho Sato-Hashimoto, Tomomi Nozu, Eriko Urano, Saito Yasuyuki, Kotani Takenori, Murata Yoji, Matozaki Takashi, Hiroshi Ohnishi

  The 38th Annual Meeting of the Japan Neuroscience Society, Jul. 2015, English, The Japan Neuroscience Society, 神戸, Domestic conference

  Poster presentation


• Roles of Protein Tyrosine Phosphatases in Homeostasis of Intestinal Epithelium

  Matozaki Takashi

  Joint Symposium of Université de Liège and Kobe University, May 2015, English, Center for Collaborative Research and Technology Development & Graduate School of Medicine, Kobe University, 神戸, International conference

  Oral presentation


• Role of the protein tyrosine phosphatase Shp2 in homeostasis of the intestinal epithelium

  Kotani Takenori, Hironari Yamashita, Jung-ha Park, Murata Yoji, Hideki Okazawa, Hiroshi Ohnishi, Ku Yonson, Matozaki Takashi

  The 5th International Symposium on Carcinogenic SpiralInfection, Immunity, and Cancer, Feb. 2015, English, Carcinogenic Spiral, 神戸, International conference

  Poster presentation


• Essential role og SIRPα on dendritic dells in organization and homeostasis of the spleen

  Ken Washio, Kotani Takenori, Datu Respatika, Murata Yoji, Saito Yasuyuki, Hideki Okazawa, Hiroshi Ohnishi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  The 43rd Annual Meeting of The Japanese Society for Immunology, Dec. 2014, English, Japanese Society for Immunology, 京都, Domestic conference

  Oral presentation


• Essential role of SIRP on dendritic cells in organization and homeostasis of the spleen

  Ken Washio, Kotani Takenori, Respatika Datu, Murata Yoji, Saito Yasuyuki, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  第43回日本免疫学会学術集会, Dec. 2014, English, 日本免疫学会, 大阪, Domestic conference

  Oral presentation


• Essential role of SIRP? on dendritic cells in organization and homeostasis of the spleen

  Ken Washio, Kotani Takenori, Respatika Datu, Murata Yoji, Saito Yasuyuki, Yoriaki Kaneko, Hideki Okazawa, Hiroshi Ohnishi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  第43回日本免疫学会学術集会, Dec. 2014, English, 日本免疫学会, 大阪, Domestic conference

  Oral presentation


• Regulation by CD-SIRPα signaling of hematopoietic and immune systems

  Kotani Takenori, 鷲尾 健, ダトゥ レスパティカ, Murata Yoji, Saito Yasuyuki, Matozaki Takashi

  The 37th Annual Meeting of the Molecular Biology Society of Japan, Nov. 2014, Japanese, The Molecular Biology Society of Japan, 横浜, Domestic conference

  Public symposium


• Shear stress-induced redistribution of VE-PTP in endothelial cell and its role in cell elongation

  Murata Yoji, Isnainiasih Mantilidewi Kemala, Kotani Takenori, Hiroshi Ohnishi, Matozaki Takashi

  11th International Conference on Protein PhosphataseProtein Phosphatases in Health and Diseases, Nov. 2014, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Oral presentation


• Roles of protein throsine phosphatases in homeostasis of intestinal epithelium

  Matozaki Takashi, Murata Yoji, Kotani Takenori, Saito Yasuyuki

  11th International Conference on Protein PhosphataseProtein Phosphatases in Health and Diseases, Nov. 2014, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Oral presentation


• Regulation by the intestinal microflora of Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20 expression in intestinal epithelial cells

  Yasuaki Kitamura, Murata Yoji, Jung-ha Park, Kotani Takenori, Azuma Takeshi, Matozaki Takashi

  11th International Conference on Protein PhosphataseProtein Phosphatases in Health and Diseases, Nov. 2014, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Poster presentation


• Regulation by microbiota of intestinal epithelium turnover

  Jung-ha Park, Kotani Takenori, Yasuaki Kitamura, Murata Yoji, Matozaki Takashi

  The 37th Annual Meeting of the Molecular Biology Society of Japan, Nov. 2014, English, The Molecular Biology Society of Japan, 横浜, Domestic conference

  Poster presentation


• Functinal analysis of protein tyrosine phosphatase Shp2 in post-mitotic neurons

  Shinya Kusakari, Fumihito Saitow, Miho Hashimoato, Yasunori Matsuzaki, Kotani Takenori, Murata Yoji, Hirokazu Hirai, Hidenori Suzuki, Matozaki Takashi, Hiroshi Ohnishi

  11th International Conference on Protein PhosphataseProtein Phosphatases in Health and Diseases, Nov. 2014, English, Japanese Association for Protein Phosphatase Research, 仙台, International conference

  Oral presentation


• Roles of the protein tyrosine phosphatase Shp2 in maintaining homeostasis of the intestinal epithelium

  Kotani Takenori, 山下 博成, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  The 87th Annual Meeting of the Japanese Biochemical Society, Oct. 2014, Japanese, The Japanese Biochemical Society, 京都, Domestic conference

  Oral presentation


• Expression of CEACAM20 in intestine epithelial cells and regulation of its expression by intestinal microflora

  北村 泰明, Murata Yoji, Bak Jeongha, 今田 慎也, Kotani Takenori, 岡澤 秀樹, Azuma Takeshi, Matozaki Takashi

  The 87th Annual Meeting of the Japanese Biochemical Society, Oct. 2014, Japanese, The Japanese Biochemical Society, 京都, Domestic conference

  Oral presentation


• Expression of CEACAM20 in intestinal epithelial cells and regulation of its expression by intestinal microflora

  Yasuaki Kitamura, Murata Yoji, Jung-ha Park, Shinya Imada, Kotani Takenori, Hideki Okazawa, Azuma Takeshi, Matozaki Takashi

  第87回 日本生化学会大会, Oct. 2014, Japanese, 日本生化学会, 京都, Domestic conference

  Poster presentation


• Roles of the protein tyrosine phosphatase VE-PTP in endothelial Cells of tumor vessels and normal their counterparts

  Murata Yoji, Isnainiasih Mantilidewi Kemala, Munemasa Mori, Kotani Takenori, Shinya Kusakari, Hiroshi Ohnishi, Matozaki Takashi

  The 73rd Annual Meeting of the Japanese Cancer Association, Sep. 2014, English, The Japanese Cancer Association, 横浜, Domestic conference

  Oral presentation


• Shp2ホスファターゼはRas活性化を介して腸上皮の恒常性と腸炎発症を制御する

  Matozaki Takashi, 山下 博成, Kotani Takenori, Bak Jeongha, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson

  第73回日本癌学会学術総会, Sep. 2014, English, がん研究会, 神奈川, Domestic conference

  Oral presentation


• Regulation of microglial homeostasis through cell-cell interaction signal

  Miho Sato-Hashimoto, Yuriko Hayashi, Shinya Kusakari, Kotani Takenori, Murata Yoji, Matozaki Takashi, Hiroshi Ohnishi

  Neuroscience 2014The 37th Annual Meeting of the Japan Neuroscience Society, Sep. 2014, English, The Japan Neuroscience Society, 横浜, Domestic conference

  Poster presentation


• Functional Analysis of protein tyrosine phosphatase Shp2 in the adult forebrain neurons

  Hiroshi Ohnishi, Shinya Kusakari, Fumihito Saitow, Miho Hashimoto, Yasunori Matsuzaki, Kotani Takenori, Murata Yoji, Hirokazu Hirai, Hidenori Suzuki, Matozaki Takashi

  Neuroscience 2014The 37th Annual Meeting of the Japan Neuroscience Society, Sep. 2014, English, The Japan Neuroscience Society, 横浜, Domestic conference

  Oral presentation


• 腸管におけるCDACAM20の発現と腸内細菌叢を介した発現制御

  北村 泰明, Murata Yoji, Bak Jeongha, Kotani Takenori, 岡澤 秀樹, Azuma Takeshi, Matozaki Takashi

  なし, Jul. 2014, Japanese, なし, 岐阜, Domestic conference

  Oral presentation


• 樹状細胞及び二次リンパ組織の恒常維持におけるSIRPαの役割

  鷲尾 健, Kotani Takenori, ダトゥ レスパティカ, Murata Yoji, Saito Yasuyuki, 金子 和光, 岡澤 秀樹, 大西 浩史, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  なし, Jul. 2014, Japanese, なし, 岐阜, Domestic conference

  Oral presentation


• Roles of the protein tyrosine phosphatase Shp2 in maintaining homeostasis of the intestinal epithelium

  Kotani Takenori, 山下 博成, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  The 66th Annual Meeting of the Japan Society for Cell Biology, Jun. 2014, Japanese, The Japan Society for Cell Biology, 奈良, Domestic conference

  Oral presentation


• Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation.

  Murata Yoji, ケマラ イスナイニアシ, マンティリデヴィ, 森 宗昌, Kotani Takenori, 大坪 千裕, 草苅 伸也, 大西 浩史, Matozaki Takashi

  The 66th Annual Meeting of the Japan Society for Cell Biology, Jun. 2014, Japanese, The Japan Society for Cell Biology, 奈良, Domestic conference

  Oral presentation


• 樹状細胞とSLE：樹状細胞特異的SHP-1欠損マウスの解析

  廣村 桂樹, 渡辺 光治, 大石 裕子, 金子 和光, 斎藤 泰之, 金子 哲也, 高岸 憲二, 大西 浩史, Matozaki Takashi, 野島 美久

  The 58th Annual General Assembly and Scientific Meeting ofthe Japan College of Rheumatology, Apr. 2014, Japanese, Japan College of Rheumatology, 東京, Domestic conference

  [Invited]

  Nominated symposium


• Shear Stress-induced Redistribution of Vascular Endothelial-Protein-tyrosine Phosphatase (VE-PTP) in Endothelial Cells and Its Role in Cell Elongation.

  Isnainiasih Mantilidewi Kemala, Murata Yoji, Munemasa Mori, Kotani Takenori, Shinya Kusakari, Hideki Okazawa, Hiroshi Ohnishi, Matozaki Takashi

  The 18th International Vascular Biology Meeting（IVBM2014）, Apr. 2014, English, International Vascular Biology Meeting, 京都, International conference

  Poster presentation


• SIRPα-CD47 system regulates the homeostasis of dendritic cells in lymphoid tissues

  Ken Washio, Kotani Takenori, Datu Respatika, Murata Yoji, Hideki Okazawa, Hiroshi Ohnishi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  University of Washington-Kobe University Symposium on Membrane biology, Mar. 2014, English, University of Washington-Kobe University, Seattle, USA, International conference

  Poster presentation


• SIRPα-CD47 system regulates the homeostasisof dendritic cells in lymphoid tissues

  Ken Washio, Kotani Takenori, Datu Respatika, Murata Yoji, Hideki Okazawa, Hiroshi Ohnishi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  The 2nd University of Washington-Kobe University Joint Symposium on Membrane Biology, Mar. 2014, English, University of Washington, Seattle, USA, International conference

  Poster presentation


• Roles of protein tyrosine phosphatases in homeostasis of intestinal epithelium

  Matozaki Takashi

  University of Washington-Kobe University Symposium on Membrane biology, Mar. 2014, English, University of Washington-Kobe University, Seattle, USA, International conference

  [Invited]

  Invited oral presentation


• Role of VE-PTP in shear stress responses of endothelial cells

  Isnainiasih Mantilidewi Kemala, Murata Yoji, Munemasa Mori, Kotani Takenori, Shinya Kusakari, Hideki Okazawa, Hiroshi Ohnishi, Matozaki Takashi

  University of Washington-Kobe University Symposium on Membrane biology, Mar. 2014, English, University of Washington-Kobe University, Seattle, USA, International conference

  Poster presentation


• 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割

  Kotani Takenori, 山下 博成, 朴 貞河, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  The 6th Annual Meeting of Japanese Association for Protein Phosphatase Research, Feb. 2014, Japanese, Japanese Association for Protein Phosphatase Research, 三重, Domestic conference

  Oral presentation


• 樹状細胞及び二次リンパ組織の恒常性維持におけるSIRPαの役割

  鷲尾 健, Kotani Takenori, レスパティカ ダトゥ, Murata Yoji, 岡澤 秀樹, 大西 浩史, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  The 6th Annual Meeting of Japanese Association for Protein Phosphatase Research, Feb. 2014, Japanese, Japanese Association for Protein Phosphatase Research, 三重, Domestic conference

  Oral presentation


• 細胞質型チロシンホスファターゼShp2による脳機能制御

  草苅 伸也, 齋藤 文仁, 橋本 美穂, 柴崎 貢志, 吾郷 由紀夫, Kotani Takenori, Murata Yoji, 松田 敏夫, Benjamin G. Neel, Matozaki Takashi, 大西 浩史

  The 6th Annual Meeting of Japanese Association for Protein Phosphatase Research, Feb. 2014, Japanese, Japanese Association for Protein Phosphatase Research, 三重, Domestic conference

  Oral presentation


• SIRPα-CD47 system regulates the homeostasis of dendritic cells in lymphoid tissues

  WASHIO Ken, Kotani Takenori, RESPATIKA Datu, Murata Yoji, OKAZAWA Hideki, OHNISHI Hiroshi, Fukunaga Atsushi, Nishigori Chikako, Matozaki Takashi

  Annual Meeting of the Japanese Society for Immunology, 2013, Dec. 2013, English, Japanese Society for Immunology, 千葉, Domestic conference

  Poster presentation


• R3 受容体型チロシンホスファターゼの発現、局在と生理機能

  Matozaki Takashi, Murata Yoji, Kotani Takenori, Yana Supriatna, 森 宗昌, 岡澤 秀樹, 大西 浩史

  The 36th Annual Meeting of the Molecular Biology Society of Japan, Dec. 2013, Japanese, The Molecular Biology Society of Japan, 兵庫, Domestic conference

  [Invited]

  Nominated symposium


• Expression, localization, and biological function of the R3 subtype of receptor-type protein tyrosine phosphatases

  Matozaki Takashi

  The 2nd Taiwan-Japan Bilateral Conference on Protein Phosphatases, Nov. 2013, English, Japanese Association for Protein Phosphatase Research, Hsinchu, Taiwan, International conference

  [Invited]

  Invited oral presentation


• Roles of the protein tyrosine phosphatase Shp2 in maintaining 213 homeostasis of the intestinal epithelium

  山下 博成, Kotani Takenori, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  The 72rd Annual Meeting of the Japanese Cancer Association, Oct. 2013, Japanese, The Japanese Cancer Association, 神奈川, Domestic conference

  Oral presentation


• Regulation of intestinal immunity by the protein tyrosine phosphatase SAP-1

  Murata Yoji, Kotani Takenori, Supriatna Yana, 森 宗昌, 草苅 伸也, 岡澤 秀樹, 大西 浩史, Matozaki Takashi

  The 72rd Annual Meeting of the Japanese Cancer Association, Oct. 2013, Japanese, The Japanese Cancer Association, 神奈川, Domestic conference

  Oral presentation


• Roles of the protein tyrosine phosphatase Shp2 in maintaining homeostasis of the intestinal epithelium

  Kotani Takenori, 山下 博成, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  The 86th Annual Meeting of the Japanese Biochemical Society, Sep. 2013, Japanese, The Japanese Biochemical Society, 神奈川, Domestic conference

  Oral presentation


• Molecular basis for regulation of the life span of intestinal epithelial cell

  Matozaki Takashi, Kotani Takenori, Murata Yoji

  The 86th Annual Meeting of the Japanese Biochemical Society, Sep. 2013, Japanese, The Japanese Biochemical Society, 神奈川, Domestic conference

  [Invited]

  Nominated symposium


• 細胞質型チロシンホスファターゼShp2の成熟脳における機能解析

  草苅 伸也, 橋本 美穂, 柴崎 貢志, 吾郷 由希夫, 松田 敏夫, Benjamin G. Neel, Kotani Takenori, Murata Yoji, Matozaki Takashi, 大西 浩史

  The 60th Annual Meeting of KITAKANTO Medical Society, Sep. 2013, Japanese, KITAKANTO Medical Society, 群馬, Domestic conference

  Poster presentation


• Role of VE-PTP in shear stress responses of endothelial cells

  Isnainiasih Mantilidewi Kemala, Murata Yoji, Munemasa Mori, Kotani Takenori, Shinya Kusakari, Hideki Okazawa, Hiroshi Ohnishi, Matozaki Takashi

  The 86th Annual Meeting of the Japanese Biochemical Society, Sep. 2013, English, The Japanese Biochemical Society, 神奈川, Domestic conference

  Oral presentation


• SIRPαによる脾臓T細胞の恒常性の調節

  橋本 美穂, 齊藤 泰之, 金子 哲也, 大西 浩史, 草苅 伸也, Kotani Takenori, Murata Yoji, 岡澤 秀樹, Matozaki Takashi

  The 60th Annual Meeting of KITAKANTO Medical Society, Sep. 2013, Japanese, KITAKANTO Medical Society, 群馬, Domestic conference

  Poster presentation


• Roles of the protein tyrosine phosphatase Shp2 in homeostasis of the intestinal epithelium

  Kotani Takenori, 山下 博成, Murata Yoji, 岡澤 秀樹, 大西 浩史, Matozaki Takashi

  2013 FASEB Science Research Conferences, Aug. 2013, English, FASEB, SteambatSprings（Colorad）, USA, International conference

  Poster presentation


• Microbiota modulates the turnover of intestinal epithelial cells

  Jung-ha Park, Kotani Takenori, Murata Yoji, Matozaki Takashi

  2013 FASEB Science Research Conferences, Aug. 2013, English, FASEB, SteambatSprings（Colorad）, USA, International conference

  Poster presentation


• 腸上皮の恒常性維持におけるチロシンホスファターゼShp2の役割

  Kotani Takenori, 山下 博成, Murata Yoji, 岡澤 秀樹, 大西 浩史, Ku Yonson, Matozaki Takashi

  第12回生体機能研究会, Jul. 2013, Japanese, 生体機能研究会, 群馬, Domestic conference

  Oral presentation


• 成熟腸上皮細胞の寿命決定の分子基盤

  Matozaki Takashi, 朴 貞河, Kotani Takenori

  第12回生体機能研究会, Jul. 2013, Japanese, 生体機能研究会, 群馬, Domestic conference

  Oral presentation


• Ｈｙｐｔｈｅｒｍｉａ−ｄｅｐｅｎｄｅｎｔ ａｎｄ −ｉｎｄｅｐｅｎｄｅｎｔ effects of forced swim on the phosphorylation satates of signaling molecules in mouse hippocampus

  橋本(佐藤) 美穂, 林 由里子, 草苅 伸也, 浦野 江里子, 滋野 雅大, 関島 恒夫, Kotani Takenori, Murata Yoji, 村上 博和, Matozaki Takashi, 大西 浩史

  The 36th annual Meeting of the Japan Neuroscience SocietyThe 56th Annual Meeting of Japanese Society for NeurochemistryThe 23rd Annual Conference of Japanese Neural Network Society, Jun. 2013, English, The Japan Neuroscience Society, 京都, Domestic conference

  Poster presentation


• Ｈｙｐｔｈｅｒｍｉａ?ｄｅｐｅｎｄｅｎｔ ａｎｄ ?ｉｎｄｅｐｅｎｄｅｎｔ effects of forced swim on the phosphorylation satates of signaling molecules in mouse hippocampus

  橋本(佐藤) 美穂, 林 由里子, 草苅 伸也, 浦野 江里子, 滋野 雅大, 関島 恒夫, Kotani Takenori, Murata Yoji, 村上 博和, Matozaki Takashi, 大西 浩史

  The 36th annual Meeting of the Japan Neuroscience SocietyThe 56th Annual Meeting of Japanese Society for NeurochemistryThe 23rd Annual Conference of Japanese Neural Network Society, Jun. 2013, English, The Japan Neuroscience Society, 京都, Domestic conference

  [Invited]

  Poster presentation


• Functional Analysis of A non-receptor type protein tyrosine phosphatase Shp2 in the adult brain

  草苅 伸也, 齋藤 文仁, 橋本(佐藤) 美穂, 柴崎 貢志, 吾郷 由希夫, 松田 敏夫, Neel BG, Kotani Takenori, Murata Yoji, Matozaki Takashi, 大西 浩史

  The 36th annual Meeting of the Japan Neuroscience SocietyThe 56th Annual Meeting of Japanese Society for NeurochemistryThe 23rd Annual Conference of Japanese Neural Network Society, Jun. 2013, English, The Japan Neuroscience Society, 京都, Domestic conference

  Poster presentation


• Tyrosine phosphorylation of CEACAM20 and its functional roles

  エドウィン ウィジャント, ダニウィジャヤ, Murata Yoji, Kotani Takenori, 大西 浩史, Matozaki Takashi

  10th International Conference on Protein Phosphatase Protein Phosphatases and Diseases, Feb. 2013, English, Japanese Association for Protein Phosphatase Research, 東京, CEACAM20 is an immunoglobulin-superfamily transmembrane protein that contains the ITAM-like motif in its cytoplasmic region. We have recently found that CEACAM20 is a putative substrate of SAP-1, a receptor type tyrosine phosphatase, in mouse intestinal epithelial cells. However, tyrosine phosphorylation of CEACAM20 and its physiological significance remain largely unknown. Her, International conference

  Poster presentation


• Hypothermia-induced tyrosine phosphorylation of SIRPα in the brain

  草苅 伸也, 丸山 登士, 橋本 美穂, 林 由里子, 浦野 江里子, 草苅 百合子, Kotani Takenori, Murata Yoji, 岡澤 秀樹, Per-Arne Oldenborg, Matozaki Takashi, 大西浩史

  10th International Conference on Protein Phosphatase Protein Phosphatases and Diseases, Feb. 2013, English, Japanese Association for Protein Phosphatase Research, 東京, Protein tyrosine phosphatase Shp2 expresses ubiquitously, and promotes the activation of the Ras-MAPK cascade by growth factor and cytokine stimulation. Shp2 regulates proliferation and differentiation via Ras/MAPK cascade, and Shp2 deficient mice were embryonic lethal. Shp2 also is abundantly expressed in the adult brain, and Shp2 activity promotes differentiation of neuronal, International conference

  Poster presentation


• Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell diffierentiation and induces autoimmunity

  Kotani Takenori, 金子 哲也, 齋藤 泰之, 橋本 美穂, 草苅 伸也, 金子 和光, Murata Yoji, 大西 浩史, 高岸 憲二, Matozaki Takashi

  10th International Conference on Protein Phosphatase Protein Phosphatases and Diseases, Feb. 2013, English, Japanese Association for Protein Phosphatase Research, 東京, Dendritic cells (DCs) promote immune responses to foreign antigens (Ags) and immune tolerance to self-Ags. Deregulation of DCs is implicated in autoimmunity, but the molecules that regulate DCs to protect against autoimmunity have remained unknown. In this study, we show that mice lacking the protein tyrosine phosphatase Shp1 specifically in DCs develop splenomegaly associated, International conference

  Poster presentation


• Signal regulatory protein alpha regulates the homeostasis of T lymphocytes in the spleen.

  橋本(佐藤) 美穂, 齊藤 泰之, 金子 哲也, 大西 浩史, 草苅 伸也, Kotani Takenori, Murata Yoji, 岡澤 秀樹, Matozaki Takashi

  The 85th Annual Meeting of the Japanese Biochemical Society, Dec. 2012, Japanese, The Japanese Biochemical Society, 福岡, SIRPα（Signal regulatory proteinα）は、樹状細胞やマクロファージに発現する膜タンパク質であり、その細胞外領域のリガンドである膜タンパク質CD47と相互作用し、細胞間相互作用シグナルCD47-SIRPα系を構成する。今回我々は、SIRPαノックアウト（KO）マウスの脾臓において、白脾髄の縮小と、CD4陽性T細胞数の減少を見出した。また、脾臓Ｔ細胞領域のストローマ細胞が産生するケモカインであるCCL19およびCCL21、サイトカインであるIL-7の遺伝子発現量の減少も見出した。同様のフェノタイプは、SIRPαのリガンドであるCD47のKOマウスでも認められた。これらの結果から、CD47-SIRPα系が、T細胞の恒常性維持に関与する可能性が考えられた。さらに、SIRPα KOと野生型マウスの間で作製した骨髄キメラマウスを解析, Domestic conference

  Poster presentation


• Protein tyrosine phosphatases and the CD47-SIRPα System that mediates cell-to-cell communication

  Matozaki Takashi

  The First Taiwan Phosphatase Conference, Nov. 2012, English, Academia Sinica, National Cheng Kung University, 台湾, 台南市, SIRPα, also known as SHPS-1/SIRPα, is a transmembrane protein that binds to the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is predominantly expressed in macrophages, dendritic cells and neurons. CD47, a widely expressed transmembrane protein, is a ligand for SIRPα, with the two proteins constituting a cell-to-cell communication system. The, International conference

  [Invited]

  Invited oral presentation


• Hypothermia-induced tyrosine phosphorylation of SIRPa in the brain

  草苅 伸也, 丸山 登士, 橋本 美穂, 林 由里子, 草苅 百合子, Kotani Takenori, Murata Yoji, 岡澤 秀樹, 岸 章治, Matozaki Takashi, 大西浩史

  11th biennial meeting of APSN/55th Meeting of JSN, Oct. 2012, Japanese, The Japanese Society for Neurochemistry, The Asian Pacific Society of Nephrology, 兵庫, Signal regulatory protein a (SIRPa also known as SHPS-1, BIT, or P84) is a neuronal membrane protein that has three immunoglobulin-like domains in its extracellular region and tyrosine phosphorylation sites in the cytoplasmic region. Tyrosine phosphorylated SIRPa binds and activates protein tyrosine phosphatase Shp2. Previously, we found that SIRP a undergoes tyrosine phosphory, International conference

  Oral presentation


• 低温ストレスによる受容体型分子SIRPαのチロシンリン酸化誘導

  草苅 伸也, 橋本 美穂, 丸山 登士, 林 由里子, 草苅 百合子, Matozaki Takashi, 大西 浩史

  The 30th JES Summer Seminar on Endocrinology & Metabolism, Jul. 2012, Japanese, the Japan Endocrine Society, 群馬, 樹状細胞、神経細胞、膵β細胞などに特異的に発現する膜蛋白質SIRPαは、細胞内にチロシンリン酸化モチーフをもつ。SIRPα KOマウスは、免疫機能異常、行動異常、糖代謝異常を示すことから、SIRPαはチロシンリン酸化を介して免疫系、神経系、内分泌系の制御に重要な役割を果たすと考えられるが、SIRPαリン酸化誘導の詳細なメカニズムは明らかではない。今回我々は、低温ストレスによりSIRPαのチロシンリン酸化が誘導されることを新たに見いだしたので報告する。, Domestic conference

  Poster presentation


• Importance of The Protein Tyrosine Phosphatase Shp1 In Dendritic Cells for Prevention of Th1 Cell Differentiation And Autoimmunity: A Potential Target for the Therapy

  金子 哲也, 齋藤 泰之, Kotani Takenori, 大西 浩史, Murata Yoji, 米本 由木夫, 岡邨 興一, Matozaki Takashi, 高岸 憲二

  欧州リウマチ学会議2012, Jun. 2012, English, The European League Against Rheumatism, Berlin, Germany, Background: Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating immune response to pathogens as well as for maintaining immune tolerance to self-antigens. Dysregulation of the function of DCs is thought to cause abnormal immune responses to self-antigens, which in turn cause autoimmunity. Src homology 2 domaincontaining protein tyrosine phosph, International conference

  Oral presentation


• Dendritic cell-specific depletion of protein-tyrosine phosphatase Shp1 causes autoimmunity

  金子 哲也, 岡邨 興一, 米本 由木夫, Matozaki Takashi, 高岸 憲二

  The 56th AnnualGeneralAssembly and Scientific Meeting of the Japan College of Rheumatology Symposium, Apr. 2012, Japanese, Japan College of Rheumatology, 東京, [Objectives]Dendritic cells (DCs) promote immune responses to foreign antigens and immune tolerance to self-antigens. Dysregulation of the function of DCs is through to cause abnormal immune responses, which in turn cause autoimmunity. Spontaneous mutatio, Domestic conference

  Oral presentation


• チロシンホスファターゼの機能と病態

  Matozaki Takashi

  群馬大学・秋田大学連携グローバルCOEプログラム「生体調節シグナルの統合的研究」最終シンポジウム, Feb. 2012, Japanese, GCOEプログラム, 前橋市, Domestic conference

  Invited oral presentation


• 腸微絨毛特異的な発現を示す受容体型チロシンホスファターゼSAP-1による腸管免疫制御

  Kotani Takenori, Murata Yoji, ヤナ スプリアトゥナ, 岡澤 秀樹, 大西 浩史, エドウィン ダニヴィジャヤ, 草苅 伸也, 定方 久延, 大川 克也, Matozaki Takashi

  第5回プロテインホスファターゼ研究会 学術集会 大阪, Jan. 2012, Japanese, 日本プロテインホスファターゼ研究会, 吹田市, Domestic conference

  Oral presentation


• 成熟脳におけるShp2の生理機能解析

  草苅 伸也, Kotani Takenori, 橋本 美穂, Murata Yoji, 岡澤 秀樹, 吾郷 由紀夫, 松田 敏夫, ベンジャミン G ニール, Matozaki Takashi, 大西 浩史

  第5回プロテインホスファターゼ研究会 学術集会 大阪, Jan. 2012, Japanese, 日本プロテインホスファターゼ研究会, 吹田市, Domestic conference

  Oral presentation


• 蛋白質チロシンホスファターゼShp2の成熟脳における機能解析

  草苅 伸也, Kotani Takenori, 橋本 美穂, 林 由里子, 草苅 百合子, Murata Yoji, 岡澤 秀樹, Matozaki Takashi, 大西 浩史

  第2回国際放射線神経生物学会大会, Dec. 2011, Japanese, International Society of Radiation Neurobiology, 前橋市, International conference

  Poster presentation


• The R3 subtype of receptor-type protein tyrosine phosphatases: Expression, localization, and biological function

  Matozaki Takashi

  The First Japan-Taiwan Bilateral Conference on Protein Phosphatases, Dec. 2011, English, 日本プロテインホスファターゼ研究会, 岡崎市, International conference

  Invited oral presentation


• Dendritic cell-specific depletion of protein tyrosine phosphatase Shp1 promotes Th1 differentiation causes autoimmunity

  金子 哲也, 齊藤 泰之, 大西 浩史, 橋本 美穂, Kotani Takenori, Murata Yoji, 岡澤 秀樹, 高岸 憲二, Matozaki Takashi

  第40回日本免疫学会学術集会, Nov. 2011, English, 日本免疫学会, 千葉市（幕張）, Domestic conference

  Poster presentation


• A new phosphotyrosine signaling pathway related to autoimmune diseases and cancers

  Matozaki Takashi

  2nd International Joint Symposium Frontier In Biomedical Sciences:From Genes to Applications, Nov. 2011, English, ガチャマダ大学, ジョグジャカルタ, インドネシア, International conference

  Invited oral presentation


• 樹状細胞のチロシンホスファターゼSHP-1は自己免疫疾患発症に関与する

  金子 哲也, 齊藤 泰之, 大西 浩史, 岡邨 興一, 米本 由木夫, 篠崎 哲也, Matozaki Takashi, 高岸 憲二

  第26回日本整形外科学会 基礎技術集会, Oct. 2011, Japanese, 日本整形外科学会, 前橋市, Domestic conference

  Poster presentation


• Regulation by protein tyrosine phosphorylation of depression-like behavior

  大西 浩史, Matozaki Takashi

  第34回日本神経科学大会, Sep. 2011, English, 日本神経科学学会, 横浜市, International conference

  Oral presentation


• 血管内皮細胞のシェアストレス刺激応答におけるVE-PTPの機能解析

  Murata Yoji, 森 宗昌, ケマラ マンティリデヴィ, 岡澤 秀樹, 大西 浩史, Matozaki Takashi

  群馬大学・秋田大学連携グローバルCOEプログラム「生体調節シグナルの統合的研究」第5回グローバルCOE若手研究者シンポジウム, Aug. 2011, Japanese, GCOEプログラム, 秋田市, Domestic conference

  Oral presentation


• Stress-evoked tyrosine phosphorylation of SIRPα regulates depression-like behavior

  大西 浩史, Matozaki Takashi

  ISN-ESN-2011 23rd Biennial Meeting of the International Society for Neurochemistryjointly with the European Society for Neurochemistry, Aug. 2011, English, International Society for Neurochemistry,European Society for Neurochemistry, アテネ, ギリシャ, International conference

  Oral presentation


• チロシンホスファターゼの機能と病態

  Matozaki Takashi

  日本生化学会東北支部 第77回 例会・シンポジウム, Jul. 2011, Japanese, 日本生化学会東北支部, 仙台市, Domestic conference

  Invited oral presentation


• チロシンホスファターゼSAP-1の機能と病態

  岡澤 秀樹, Murata Yoji, エドウィン ダニヴィジャヤ, Matozaki Takashi

  第10回生体機能研究会, Jul. 2011, Japanese, 生体機能研究会, 美馬市穴吹町, Domestic conference

  Invited oral presentation


• Shear stress regulates cellular localization of vascular endothelial-protein tyrosine phosphatase (VE-PTP)

  森 宗昌, Murata Yoji, Kemala Isnainiasih Mantilidewi, 大西 浩史, Matozaki Takashi

  発がんスパイラル第1回国際シンポジウム第11回プロテインホスファターゼ国際カンファレンス, Feb. 2011, English, 東京, International conference

  Oral presentation


• Regulation of Intestinal Immunity by SAP-1, a Microvillus-Specific Receptor-Type Protein Tyrosine Phosphatase

  Matozaki Takashi

  発がんスパイラル第1回国際シンポジウム第9回プロテインホスファターゼ国際カンファレンス, Feb. 2011, English, 東京, International conference

  Invited oral presentation


• Hypothermia-induced tyrosine phosphorylation of SIRPα in the brain

  丸山 登士, 大西 浩史, 草苅 伸也, 林 由里子, Murata Yoji, 齊藤 泰之, Per-Arne Oldenborg, 岸 章治, Matozaki Takashi

  発がんスパイラル第1回国際シンポジウム第10回プロテインホスファターゼ国際カンファレンス, Feb. 2011, English, 東京, International conference

  Poster presentation


• 神経細胞間相互作用シグナルCD47-SIRPα系による脳のストレス応答制御機構

  大西 浩史, 草苅 伸也, 村田 考啓, 林 由里子, 丸山 登士, 大川 克也, Per-Arne Oldenborg, Murata Yoji, 宮川 剛, Matozaki Takashi

  第1回放射線神経生物学研究集会, Jan. 2011, Japanese, 群馬, Domestic conference

  Poster presentation


• 低温ストレスによるSIRPαチロシンリン酸化の誘導

  丸山 登士, 大西 浩史, 草苅 伸也, 林 由里子, 草苅 百合子, Murata Yoji, 齊藤 泰之, 岸 章治, Matozaki Takashi

  BMB2010第33回日本分子生物学会年会第83回日本生化学会大会合同年会, Dec. 2010, Japanese, 日本分子生物学会・日本生化学会, 神戸, 日本, Domestic conference

  Poster presentation


• 腸微絨毛特異的な発現を示す受容体型チロシンキナーゼSAP-1とIL-10による炎症性腸疾患の制御

  Kotani Takenori, Murata Yoji, Yana Supriatna, 岡澤 秀樹, 大西 浩史, Edwin Daniwijaya, 定方 久延, 草苅 伸也, 齊藤 泰之, 大川 克也, Matozaki Takashi

  BMB2010第33回日本分子生物学会年会第85回日本生化学会大会合同年会, Dec. 2010, Japanese, 日本分子生物学会・日本生化学会, 神戸, 日本, Domestic conference

  Poster presentation


• 血管内皮細胞のシェアストレス刺激応答におけるVE-PTPの機能解析

  Murata Yoji, 森 宗昌, Kotani Takenori, 草苅 伸也, 岡澤 秀樹, 齊藤 泰之, 大西 浩史, Matozaki Takashi

  BMB2010第33回日本分子生物学会年会第84回日本生化学会大会合同年会, Dec. 2010, Japanese, 日本分子生物学会・日本生化学会, 神戸, 日本, Domestic conference

  Oral presentation


• チロシンリン酸化シグナルによる脳のストレス応答制御機構

  草苅 伸也, 大西 浩史, 村田 考啓, 林 由里子, 丸山 登士, 高雄 啓三, 香田 健, 吾郷 由希夫, 大川 克也, Pre-Arne Oldenborg, Murata Yoji, 松田 敏夫, 宮川 剛, Matozaki Takashi

  BMB2010第33回日本分子生物学会年会第85回日本生化学会大会合同年会, Dec. 2010, Japanese, 日本分子生物学会・日本生化学会, 神戸, 日本, Domestic conference

  Oral presentation


• Rho kinase pathway regulates contact hypersensitivity response by regulating DC migration through SHPS-1.

  Ogura Kanako, Fukunaga Atsushi, Shuntaro Oniki, Nagai Hiroshi, Hideki Okazawa, Matozaki Takashi, Nishigori Chikako, Tatsuya Horikawa

  日本研究皮膚科学会第37回年次学術大会・総会, Dec. 2010, English, 日本研究皮膚科学会, 和歌山, Domestic conference

  Poster presentation


• チロシンリン酸化シグナルによる脳のストレス応答制御機構

  草苅 伸也, 大西 浩史, Murata Yoji, 齊藤 泰之, 岡澤 秀樹, Matozaki Takashi

  群馬大学・秋田大学連携グローバルCOEプログラム「生体調節シグナルの統合的研究」第4回グローバルCOE若手研究者シンポジウム, Nov. 2010, Japanese, 秋田, Domestic conference

  Oral presentation


• Stress-evoked tyrosine phosphorylation of SIRPα mediates an antidepressant effect

  大西 浩史, 草苅 伸也, 村田 考啓, 林 由里子, 丸山 登士, 岡澤 秀樹, Murata Yoji, 高雄 啓三, 宮川 剛, Per-Arne Oldenborg, Matozaki Takashi

  40th Annual Meeting of Society for Neuroscience,Neuroscience 2010, Nov. 2010, English, Society for Neuroscience, サンディエゴ, アメリカ, International conference

  Poster presentation


• 脳におけるSIRPαチロシンリン酸化の解析

  丸山 登士, 大西 浩史, 草苅 伸也, 林 由里子, Murata Yoji, 齊藤 泰之, 岸 章治, Matozaki Takashi

  第57回北関東医学会総会, Oct. 2010, Japanese, 北関東医学会, 群馬, Domestic conference

  Poster presentation


• CD47-SIRPα系の機能とヒト遺伝子多型

  大西 浩史, 草苅 伸也, 大井 一高, 橋本 亮太, 村田 考啓, 丸山 登士, 林 由里子, 高雄 啓三, 宮川 剛, 大川 克也, 齊藤 泰之, Murata Yoji, 武田 雅俊, Matozaki Takashi

  第一回脳表現型の分子メカニズム研究会, Oct. 2010, Japanese, 大阪, Domestic conference

  Oral presentation


• チロシンリン酸化シグナルによる脳のストレス応答制御

  大西 浩史, 草苅 伸也, 村田 考啓, 丸山 登士, 林 由里子, 高雄 啓三, 宮川 剛, 吾郷 由希夫, 香田 健, 松田 敏夫, 大川 克也, 齊藤 泰之, Murata Yoji, Matozaki Takashi

  Neuro 2010（第33回日本神経科学大会、第53回日本神経化学会大会、第20回日本神経回路学会大会、合同大会）, Sep. 2010, Japanese, 日本神経回路学会、日本神経化学会、日本神経科学会, 神戸, International conference

  Oral presentation


• Regulation by SIRPα of dendritic cell homeostasis in lymphoid tissues.

  齊藤 泰之, 岩村 紘子, 金子 哲也, 大西 浩史, Murata Yoji, 岡澤 秀樹, 金澤 義丈, 橋本 美穂, 小林 久江, Per-Arne Oldenborg, 金子 和光, Matozaki Takashi

  11th International Symposium on Dendritic Cells in Fundamental and Clinical Immunology, Sep. 2010, English, Institute for Research in Biomedicine, ルガーノ, スイス, International conference

  Poster presentation


• Roles of SIRPα in the homeostatic regulation of mucosal immunity in the intestine.

  金澤 義丈, 齊藤 泰之, 岩村 紘子, 橋本 美穂, Murata Yoji, 岡澤 秀樹, Yana Supriatna, 大西 浩史, 木内 喜孝, 下瀬川 徹, Matozaki Takashi

  15th International Congress of Immunology, Aug. 2010, English, 日本免疫学会・国際免疫学会連合, 神戸, International conference

  Poster presentation


• Regulation by SIRPα of homeostasis of lymphoid tissue dendritic cells.

  齊藤 泰之, 岩村 紘子, 金子 哲也, 金澤 義丈, 橋本 美穂, Murata Yoji, 大西 浩史, 金子 和光, 野島 美久, Matozaki Takashi

  14th International Congress of Immunology, Aug. 2010, English, 日本免疫学会・国際免疫学会連合, 神戸, International conference

  Poster presentation


• 細胞間相互作用シグナルCD47-SIRPα系による脳のストレス応答制御

  大西 浩史, 草苅 伸也, 丸山 登士, 林 由里子, 齊藤 泰之, Murata Yoji, Matozaki Takashi

  第9回生体機能研究会, Jul. 2010, Japanese, 第9回生体機能研究会, 神奈川（箱根）, Domestic conference

  Oral presentation


• Stress-evoked tyrosine phosphorylation of SIRPα mediates an antidepressant effect

  Matozaki Takashi, 大西 浩史, 草苅 伸也, 村田 考啓, 林 由里子, 岡澤 秀樹, Murata Yoji, 宮川 剛, Per-Arne Oldenborg

  FASEB Summer Research Conferences"Protein Phosphatases", Jul. 2010, English, 米国連邦実験生物学会, コロラド, アメリカ, International conference

  Poster presentation


• Promotion of cell spreading and migration by vascular endothelial-protein tyrosine phosphatase (VE-PTP) in cooperation with integrin

  森 宗昌, Murata Yoji, Kotani Takenori, 草苅 伸也, 大西 浩史, 齊藤 泰之, 岡澤 秀樹, 森 昌朋, Matozaki Takashi

  FASEB Summer Research Conferences"Protein Phosphatases", Jul. 2010, English, 米国連邦実験生物学会, コロラド, アメリカ, International conference

  Poster presentation


• Expression of PTPRO in the interneurons of adult mouse olfactory bulb

  Kotani Takenori, Murata Yoji, 大西 浩史, 森 宗昌, 草苅 伸也, 齊藤 泰之, 岡澤 秀樹, John L. Bixby, Matozaki Takashi

  FASEB Summer Research Conferences"Protein Phosphatases", Jul. 2010, English, 米国連邦実験生物学会, コロラド, アメリカ, International conference

  Poster presentation


• Essential roles of the CD47-SIRPα signaling system for dndritic cell homeostasis in lymphoid tissues

  齊藤 泰之, 岩村 紘子, 金子 哲也, 大西 浩史, Murata Yoji, 橋本 美穂, Per-Arne Oldenborg, 内藤 誠, 野島 美久, Matozaki Takashi

  JSH (日本血液学会）International Symposium 2010, Jul. 2010, English, 日本血液学会, 秋田, International conference

  Poster presentation


• 神経系における細胞間相互作用シグナルCD47-SHPS-1系の機能

  MATOZAKI TAKASHI

  第143回日本獣医学会学術集会, 2007, Japanese, Domestic conference

  Nominated symposium


• 細胞間シグナル伝達システムCD47-SHPS-1系による神経突起形成の制御機構

  MATOZAKI TAKASHI

  日本プロテインホスファターゼ研究会 第 ３ 回 国 内 集 会 “プロテインホスファターゼとシグナル分子 - 基礎と臨床 - ”, 2007, Japanese, Domestic conference

  Oral presentation


• SHPチロシンホスファターゼ結合分子SHPS-1とAutoimmunity

  MATOZAKI TAKASHI

  日本プロテインホスファターゼ研究会 第 ３ 回 国 内 集 会 “プロテインホスファターゼとシグナル分子 - 基礎と臨床 -”, 2007, Japanese, Domestic conference

  Oral presentation


• Roles of SHPS-1 and its family protein SIRPb in regulation of macrophage phagocytosis

  MATOZAKI TAKASHI

  第59回日本細胞生物学会大会 第40回日本発生生物学会大会 合同大会, 2007, Japanese, Domestic conference

  Poster presentation


• Regulation by CD47-SHPS-1 system of neurite development and its molecular mechanism

  MATOZAKI TAKASHI

  第59回日本細胞生物学会大会 第40回日本発生生物学会大会 合同大会, 2007, Japanese, Domestic conference

  Public symposium


• Regulation by CD47-SHPS-1system of neurite development and its molecular mechanism

  MATOZAKI TAKASHI

  Korea-Japan joint meeting on Cell signaling and Molecular imaging, 2007, English, International conference

  Public symposium


• Regulation by CD47 of epithelial cell spreading and migration and its signal transduction

  MATOZAKI TAKASHI

  第59回日本細胞生物学会大会 第40回日本発生生物学会大会 合同大会, 2007, Japanese, Domestic conference

  Poster presentation


• EAEにおける CD47-SHPS-1シグナル系の解析

  MATOZAKI TAKASHI

  第48回日本神経学会総会, 2007, Japanese, Domestic conference

  Poster presentation


• An essential role of SHPS-1 in development of Th17-mediated inflammatory autoimmune diseases

  MATOZAKI TAKASHI

  EuroPhosphatases 2007 "Protein Phosphatases in Health and Disease", 2007, English, International conference

  Poster presentation


• 神経系におけるCD47-SHPS-1系の機能解析

  MATOZAKI TAKASHI

  第５回生体機能研究会, 2006, Japanese, Domestic conference

  Oral presentation


• SHPS-1によるマクロファージ貪食抑制の分子機構：変異型SHPS-1を用いた検討

  MATOZAKI TAKASHI

  第６５回日本癌学会学術総会, 2006, Japanese, Domestic conference

  Poster presentation


• SHPS-1-mediated transendocytosis of CD47 and its molecular mechanism.

  MATOZAKI TAKASHI

  COE国際シンポジウム「細胞内小胞輸送 －分子機構から疾患まで－」Molecular Physiology and Pathology of Membrane Traffic, 2006, English, International conference

  Poster presentation


• NKT細胞の活性化と癌転移抑制におけるSHPS-1の役割

  MATOZAKI TAKASHI

  第６５回日本癌学会学術総会, 2006, Japanese, Domestic conference

  Oral presentation


• CD47のトランスエンドサイトーシス制御機構

  MATOZAKI TAKASHI

  第５回生体機能研究会, 2006, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系の生理機能とその分子機構

  MATOZAKI TAKASHI

  群馬大学・秋田大学合同シンポジウム「生体情報伝達研究のカティングエッジ」, 2006, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系による神経突起形成の制御機構

  MATOZAKI TAKASHI

  平成18年度 生理学研究所シナプス研究会 「シナプス形成と可塑性機構獲得の統合的理解へ向けた学際的アプローチ」, 2006, Japanese, Domestic conference

  Poster presentation


• CD47 promotes neuronal development through Src-and FRG/Vav2-mediated activation of Rac and Cdc42

  MATOZAKI TAKASHI

  20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress, 2006, English, International conference

  Poster presentation


• 上皮細胞におけるCD47による細胞の接着と運動の制御

  MATOZAKI TAKASHI

  第64回日本癌学会学術総会, 2005, Japanese, Domestic conference

  Public symposium


• 細胞間シグナル伝達システムCD47-SHPS-1系の神経系における機能解析

  MATOZAKI TAKASHI

  第２回日本プロテインホスファターゼ研究会, 2005, Japanese, Domestic conference

  Oral presentation


• 細胞間シグナル伝達システムCD47-SHPS-1系とがんの浸潤・転移の制御

  MATOZAKI TAKASHI

  第64回日本癌学会学術総会, 2005, Japanese, Domestic conference

  Public symposium


• 極性をもった細胞間相互作用システムCD47-SHPS-1系による神経突起形成制御

  MATOZAKI TAKASHI

  第２８回日本分子生物学会年会, 2005, Japanese, Domestic conference

  Poster presentation


• マクロファージ貪食制御におけるSHPS-1とそのファミリー分子SIRPβの役割

  MATOZAKI TAKASHI

  第７８回日本生化学会大会, 2005, Japanese, Domestic conference

  Public symposium


• SHPS-1を介したCD47のトランスエンドサイトーシスとその分子メカニズム

  MATOZAKI TAKASHI

  第７８回日本生化学会大会, 2005, Japanese, Domestic conference

  Public symposium


• SHPS-1のEctodomain Sheddingとその細胞運動制御における役割

  MATOZAKI TAKASHI

  第64回日本癌学会学術総会, 2005, Japanese, Domestic conference

  Public symposium


• CD47による上皮細胞の接着と運動の制御

  MATOZAKI TAKASHI

  第７８回日本生化学会大会, 2005, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系の生理機能：CD47の機能を中心に

  MATOZAKI TAKASHI

  第４回生体機能研究会, 2005, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系による細胞運動と接着の制御機構

  MATOZAKI TAKASHI

  第28回 日本分子生物学会年会, 2005, Japanese, Domestic conference

  Public symposium


• CD47-SHPS-1系によるマクロファージ貪食の負の制御

  MATOZAKI TAKASHI

  第２回日本プロテインホスファターゼ研究会, 2005, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系によるマクロファージ貪食の制御

  MATOZAKI TAKASHI

  第64回日本癌学会学術総会, 2005, Japanese, Domestic conference

  Public symposium


• A Novel Intercellular Communication System, The CD47-SHPS-1 System, in Neuronal Network

  MATOZAKI TAKASHI

  ISN-ESN: 20th Biennial Meeting International Society for Neurochemistry jointly with the European Society for Neurochemistry, 2005, English, International conference

  Nominated symposium


• 新規細胞間シグナルシステムCD47-SHPS-1系の神経系における機能

  MATOZAKI TAKASHI

  第２７回日本神経科学大会・第４７回日本神経化学会大会 合同大会 (Neuro2004), 2004, Japanese, Domestic conference

  Oral presentation


• 上皮細胞におけるCD47の局在とその機能

  MATOZAKI TAKASHI

  第７７回 日本生化学会大会, 2004, Japanese, Domestic conference

  Poster presentation


• 細胞間シグナルシステムCD47-SHPS-1系の神経系における機能解析

  MATOZAKI TAKASHI

  第７７回 日本生化学会大会, 2004, Japanese, Domestic conference

  Oral presentation


• ポスターセッション「受容体型チロシンホスファターゼSAP-1とチロシンキナーゼLckの相互作用：そのT細胞機能への役割」

  MATOZAKI TAKASHI

  第42回日本癌治療学会総会, 2004, Japanese, Domestic conference

  Poster presentation


• チロシンホスファターゼSHP-2 を介して作用する新たな細胞間シグナル伝達機構とその神経系における機能

  MATOZAKI TAKASHI

  第７７回 日本薬理学会年会, 2004, Japanese, Domestic conference

  Public symposium


• The role of SHPS-1 in the negative regulation of macrophage phagocytosis

  MATOZAKI TAKASHI

  Gordon Research Conference on Signaling by Adhesion Receptors, 2004, English, International conference

  Oral presentation


• The CD47-SHPS-1 system: a novel cell-cell communication system for regulation of cell migration, macrophage phagocytosis, and neurite extension through cytoskeletal reorganization

  MATOZAKI TAKASHI

  Gordon Research Conference on Signaling by Adhesion Receptors, 2004, English, International conference

  Oral presentation


• SHPS-1を介したマクロファージ貪食制御の分子機構

  MATOZAKI TAKASHI

  第５１回北関東医学会総会, 2004, Japanese, Domestic conference

  Oral presentation


• Roles of SHPS-1 and its family protein SIRPβ in regulation of macrophage phagocytosis

  MATOZAKI TAKASHI

  第３４回日本免疫学会総会・学術集会, 2004, Japanese, Domestic conference

  Public symposium


• Roles of CD47 in regulation of cell-cell adhesion and cell migration inepithelial cells

  MATOZAKI TAKASHI

  第五回 文部科学省特定領域研究「がん」６領域 若手研究者ワークショップ, 2004, Japanese, Domestic conference

  Oral presentation


• Role of the CD47-SHPS-1 system in regulation of cell migration and macrophage phagocytosis

  MATOZAKI TAKASHI

  6th International Conference on Protein Phosphatases & International Symposium on Nano-Biotechnology, 2004, English, International conference

  Nominated symposium


• Positive regulation of phagocytosis by SIRPbeta and Its signaling mechanism in macrophage

  MATOZAKI TAKASHI

  Gordon Research Conference on Signaling by Adhesion Receptors, 2004, English, International conference

  Oral presentation


• CD47-SHPS-1系によるマクロファージ貪食制御

  MATOZAKI TAKASHI

  第７７回 日本生化学会大会, 2004, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1系によるマクロファージ貪食制御

  MATOZAKI TAKASHI

  第３回生体機能研究会, 2004, Japanese, Domestic conference

  Oral presentation


• CD47-SHPS-1シグナル系の赤血球代謝に関する機能解析

  MATOZAKI TAKASHI

  第３４回日本免疫学会総会・学術集会, 2004, Japanese, Domestic conference

  Oral presentation


• 免疫性溶血性貧血の病態形成におけるSHPS-1/CD47シグナル系の機能解析

  MATOZAKI TAKASHI

  第３３回 日本免疫学会・学術集会, 2003, Japanese, Domestic conference

  Oral presentation


• 脳における新しい細胞間シグナリングシステムCD47-SHPS-1系の機能

  MATOZAKI TAKASHI

  平成１５年生理学研究所研究会「神経可塑性の分子的基盤」, 2003, Japanese, Domestic conference

  Oral presentation


• 中枢神経系における新しいシグナリングシステムCD47-SHPS-1系の機能

  MATOZAKI TAKASHI

  第２回 生体機能研究会, 2003, Japanese, Domestic conference

  Oral presentation


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系による細胞運動の制御

  MATOZAKI TAKASHI

  日本癌学会第62回総会, 2003, Japanese, Domestic conference

  Public symposium


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系による細胞運動の制御

  MATOZAKI TAKASHI

  第１回 日本プロテインホスファターゼ研究会学術集会, 2003, Japanese, Domestic conference

  Oral presentation


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系によるがん細胞浸潤の制御

  MATOZAKI TAKASHI

  日本癌学会第62回総会, 2003, Japanese, Domestic conference

  Poster presentation


• 受容体型チロシンホスファターゼSAP-1とLckの相互作用：そのT細胞機能への役割

  MATOZAKI TAKASHI

  日本癌学会第62回総会, 2003, Japanese, Domestic conference

  Oral presentation


• 受容体型チロシンホスファターゼSAP-1とLckの相互作用：そのT細胞機能への役割

  MATOZAKI TAKASHI

  第1回プロテインホスファターゼ研究会学術集会, 2003, Japanese, Domestic conference

  Oral presentation


• The Molecular Mechanism for Negative Regulation by SHPS-1 of Phagocytosis by Macrophages

  MATOZAKI TAKASHI

  第４回 文部科学省特定領域「がん」6領域若手研究者ワークショップ, 2003, Japanese, Domestic conference

  Poster presentation


• SIRPβによるマクロファージの貪食制御とそのシグナル伝達経路

  MATOZAKI TAKASHI

  第２６回 日本分子生物学会年会, 2003, Japanese, Domestic conference

  Oral presentation


• SHPS-1によるマクロファージ機能のCD47依存的および非依存的制御

  MATOZAKI TAKASHI

  日本癌学会第62回総会, 2003, Japanese, Domestic conference

  Oral presentation


• SHPS-1によるマクロファージ機能のCD47依存的および非依存的制御

  MATOZAKI TAKASHI

  第１回 日本プロテインホスファターゼ研究会学術集会, 2003, Japanese, Domestic conference

  Oral presentation


• Role of the CD47-SHPS-1 System in Regulation of Cell Migration

  MATOZAKI TAKASHI

  The American Society for Cell Biology 43rd Annual Meeting, 2003, English, International conference

  Poster presentation


• Regulation of the binding ability of SHPS-1 to its ligand CD47 by the cytoplasmic tail of SHPS-1

  MATOZAKI TAKASHI

  第７６回 日本生化学会大会, 2003, Japanese, Domestic conference

  Poster presentation


• Positive regulation by SIRPbeta of macrophage phagocytosis and its signal transduction

  MATOZAKI TAKASHI

  群馬大学 国際シンポジウム Molecular Mechanisms of Vesicle Trafficking and Membrane Fusion, 2003, Japanese, International conference

  Poster presentation


• Polarized localization of SHPS-1 and its ligand in hippocampal neurons

  MATOZAKI TAKASHI

  第７６回 日本生化学会大会, 2003, Japanese, Domestic conference

  Poster presentation


• Polarized localization of SHPS-1 and its ligand CD47 in hippocampal neurons

  MATOZAKI TAKASHI

  第４６回 日本神経化学会大会, 2003, Japanese, Domestic conference

  Poster presentation


• Polarized localization of SHPS-1 and its ligand CD47 in hippocampal neurons

  MATOZAKI TAKASHI

  群馬大学 国際シンポジウム Molecular Mechanisms of Vesicle Trafficking and Membrane Fusion, 2003, English, International conference

  Poster presentation


• Physiological roles of the CD47-SHPS-1 system

  MATOZAKI TAKASHI

  第７６回 日本生化学会大会, 2003, Japanese, Domestic conference

  Public symposium


• Ectodomain shedding of SHPS-1 and its functional roles.

  MATOZAKI TAKASHI

  第７６回 日本生化学会大会, 2003, Japanese, Domestic conference

  Poster presentation


• CD47 promote neurite extension and filopodium formation through activation of Rac and Cdc42

  MATOZAKI TAKASHI

  群馬大学 国際シンポジウム Molecular Mechanisms of Vesicle Trafficking and Membrane Fusion, 2003, English, International conference

  Poster presentation


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系の生理機能

  MATOZAKI TAKASHI

  第１回 生体機能研究会, 2002, Japanese, Domestic conference

  Oral presentation


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系の機能

  MATOZAKI TAKASHI

  平成１４年度がん特定領域研究「がん生物」・「先端がん」領域合同シンポジウム, 2002, Japanese, Domestic conference

  Public symposium


• 新しい細胞間シグナル伝達システムCD47-SHPS-1系と細胞機能

  MATOZAKI TAKASHI

  生体調節研究所シンポジウム”脂質メディエーターの動態と生体機能”, 2002, Japanese, Domestic conference

  Public symposium


• 細胞の増殖と接着の制御に関与する新規シグナル分子の網羅的探索と創薬

  MATOZAKI TAKASHI

  第４９回北関東医学会総会, 2002, Japanese, Domestic conference

  Public symposium


• Role of the CD47-SHPS-1 System in Regulation of Cell Migration

  MATOZAKI TAKASHI

  第１回 文部科学省特定領域「がん」6領域若手研究者ワークショップ, 2002, Japanese, Domestic conference

  Poster presentation


• Regulation of Ras and Rho small G proteins by protein tyrosine phosphatases in growth factor signaling

  MATOZAKI TAKASHI

  2nd International Symposium“Frontiers in Pancreatic Research: From Basics to Clinics”and “Exocrine Glands, Japan-Korea”99th Annual Meeting, the Japanese Society of Internal Medicine (2002), 2002, English, International conference

  Public symposium


• Physiological roles of the CD47-SHPS-1 system

  MATOZAKI TAKASHI

  2002 SYMPOSIUM ON EXOCRINE PANCREAS: Secretory Mechanism and Signaling in Cell Death & Survival, 2002, English, International conference

  Public symposium


• Physiological roles of SHPS-1

  MATOZAKI TAKASHI

  5 th International Conference on Phosphatases and Cellular Regulation (2002), 2002, English, International conference

  Public symposium

• 日本プロテインホスファターゼ研究会


• 日本神経化学会


• Japan Society for Cell Biology


• The Japanese Biochemical Society


• 日本内科学会


• 米国生化学・分子生物学会


• 日本免疫学会


• The Japanese Cancer Association


• 日本分子生物学会


• 米国癌学会


• 米国細胞生物学会


• 北米神経科学会

• 自然免疫系細胞によるがん免疫監視機構に関する研究

  的崎 尚, ODUORI SYLVANUS OKECHI

  日本学術振興会, 科学研究費助成事業, 特別研究員奨励費, 神戸大学, 22 Apr. 2022 - 31 Mar. 2024


• 自然免疫制御によるがん細胞の生存・維持の分子基盤の解明

  的崎 尚

  日本学術振興会, 科学研究費助成事業, 基盤研究(A), 神戸大学, 05 Apr. 2021 - 31 Mar. 2024


• Molecular mechanisms of cancer cell survival and maintenance

  Matozaki Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A), Kobe University, 01 Apr. 2018 - 31 Mar. 2021, Principal investigator

  Tumor cells create a favorable environment for their own survival and maintenance by controlling the "tumor microenvironment" that consists of surrounding immune cells. The CD47-SIRPα signaling pathway has been considered as a key molecular signal in the regulation of the tumor microenvironment, which protects cancer cells from innate immune cells such as dendritic cells and macrophages. In the present study, we clarified new regulatory mechanisms of tumor immuity by innate immune cells, which is regulated by the CD47-SIRPα system and other SIRP faminily molecules.

  Competitive research funding


• Novel regulatory mechanisms of the intestinal immunity via the microvilli of intestinal epithelial cells

  Matozaki Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research, Grant-in-Aid for Challenging Exploratory Research, Kobe University, 01 Apr. 2016 - 31 Mar. 2018, Principal investigator

  SAP-1, a receptor-type protein tyrosine phosphatase that is specifically expressed in intestinal epithelial cells, likely participates in the regulation of intestinal immunity by controlling the tyrosine phosphorylation level of its ligand CEACAM20. In this study, the regulatory mechanisms of SAP-1/CEACAM20-function and -expression were analyzed in vitro and in vivo. I showed a part of regulatory mechanisms of SAP-1/CEACAM20-mediated intestinal immunity.

  Competitive research funding


• Molecular basis of the CD47-SIRP alpha signaling system in the regulation of physiological function

  Matozaki Takashi, OHNISHI Hiroshi, MURATA Yoji, SAITO Yasuyuki, KOTANI Takenori

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2014 - 31 Mar. 2017, Principal investigator

  We have here investigated the molecular basis of the CD47-SIRPα signaling system in the regulation of physiological function in the central nervous system (CNS) as well as in the immune system. In the CNS, we have shown that the protein tyrosine phosphatase Shp-2, which is a downstream molecule of SIRPα, regulates synaptic functions and thereby modulates learning and locomotor activity. In the immune system, we have shown that SIRPα is essential for the maintenance of dendritic cell homeostasis in the secondary lymphoid organs and skin. Furthermore, we have found that anti-SIRPα antibodies appear to be a potential new tool for cancer immunotherapy.

  Competitive research funding


• （AMED）貪食細胞-がん細胞相互作用を制御する新たながん免疫療法の開発

  的崎 尚

  国立研究開発法人日本医療研究開発機構, 次世代がん医療創生研究事業, 2017, Principal investigator

  Competitive research funding


• （AMED）多機能幹細胞を用いた自然免疫再構築による新規肝炎／肝癌治療法の開発/CD34+肝細胞由来顆粒球・マクロファージ前駆細胞系の抗腫瘍機構の解明

  的崎 尚

  国立大学法人広島大学, 感染症実用化研究事業 肝炎等克服実用化研究事業 肝炎等克服緊急対策研究事業, 2017, Principal investigator

  Competitive research funding


• Molecular mechanisms of regulation of intestinal immunity by intestinal epithelial cells

  Matozaki Takasi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research, Grant-in-Aid for Challenging Exploratory Research, Kobe University, 01 Apr. 2014 - 31 Mar. 2016, Principal investigator

  SAP-1 is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in intestinal epithelial cells. I previously found that SAP-1 ablation results in exacerbation of spontaneous colitis in Il10 knockout mice. In this study, I showed that tyrosine phosphorylation of CEACAM, a dephosphorylation substrate for SAP-1, promotes the activation of downstream molecules, thereby inducing production of chemokines such as IL-8. In addition, I found that SAP-1 specifically interacts with CEACAM and that this interaction is mediated via the ectodomains of both proteins. Thus, SAP-1 in intestinal epithelial cells is likely to regulate the intestinal immunity by controlling the tyrosine phosphorylation level of CEACAM.

  Competitive research funding


• （AMED）貪食細胞-がん細胞相互作用を制御する新たながん免疫療法の開発

  的崎 尚

  国立研究開発法人日本医療研究開発機構, 次世代がん医療創生研究事業（P-CREATE）, 2016, Principal investigator

  Competitive research funding


• （AMED）多機能幹細胞を用いた自然免疫再構築による新規肝炎／肝癌治療法の開発(D34＋肝細胞由来顆粒球・マクロファージ前駆細胞系の抗腫瘍機構の解明)

  的崎 尚

  肝炎等克服実用化研究事業, 2016, Principal investigator

  Competitive research funding


• 血管内皮細胞特異的に発現するチロシンホスファターゼによる腫瘍血管新生制御

  的崎 尚

  日本学術振興会, 科学研究費助成事業 新学術領域研究(研究領域提案型), 新学術領域研究(研究領域提案型), 神戸大学, 01 Apr. 2013 - 31 Mar. 2015, Principal investigator

  研究代表者は、受容体型チロシンホスファターゼVE-PTPが血管内皮細胞に特異的に発現し、血流により生じる力学的な刺激であるシェアストレス(SS)により、VE-PTPの局在が制御されると共に、シェアストレスによる血管内皮細胞の多様な機能制御に関与する可能性を見出している。本研究では、VE-PTPの生理機能とその作用機構の解析を行うことにより、腫瘍血管新生の新たな制御メカニズムを明らかにすると共に、VE-PTPを利用した新規のがん治療法の開発を目的とする。 VE-PTPがSSの下流方向へ移動・局在化する分子機序につき、培養血管内皮細胞を用いさらに検討を行なった。その結果、VE-PTPのSSの下流方向への移動・局在化には、細胞外基質としてインテグリンとVE-PTPの細胞外領域が重要であること、また低分子量G蛋白質であるCdc42やRab５以外に、Arf6の関与が示唆された。VE-PTPはエンドサイトーシを受けSSにより下流に局在するが、これにもCdc42やインテグリンが関与することを明らかにした。血管内皮細胞・時期特異的VE-PTP KOマウスを準備できたので、今後、これを用い、SS下でのVE-PTPの生理機能を明らかにしようと試みる。メラノーマ細胞を移植したB6マウスに抗VE-PTP抗体を投与することで、一定の腫瘍抑制効果を観察しているので、さらに、詳細な検討を進めている。

  Competitive research funding


• がん微小環境を標的とした革新的治療法の実現（貪食細胞－がん細胞相互作用を制御する新たながん治療法の開発）

  的崎 尚

  日本医療研究開発機構, 次世代がん研究シーズ戦略的育成プログラム 革新的がん医療シーズ育成領域, 2015, Principal investigator

  Competitive research funding


• A-STEP「膜型分子SIRPαを標的とした新たな自己免疫疾患治療薬の開発」

  的崎 尚

  科学技術振興機構, 研究成果最適展開支援プログラム フィージビリティスタディステージ 探索タイプ, 2015, Principal investigator

  Competitive research funding


• The integrative research for regulation by protein tyrosine phosphatases of biological functions and its molecular mechanism

  MATOZAKI Takashi, OHNISHI Hiroshi, MURATA Yoji

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2011 - 31 Mar. 2014, Principal investigator

  We have here performed the integrative research for the biological functions and molecular mechanisms for the protein tyrosine phosphatases SHP-2 as well as the related signaling pathway CD47-SIRPalpha, and R3-receptor type PTPs. We have shown that SHP-2 in the post-mitotic neurons is important for regulation of the neuronal activity. The CD47-SIRPalpha is important for regulation of dendritic cells as well as organization of lymphoid tissues. In addition, VE-PTP is implicated in regulation of endothelial cell functions by shear stress.

  Competitive research funding


• がん微小環境を標的とした革新的治療法の実現（貪食細胞－がん細胞相互作用を制御する新たながん治療法の開発）

  的崎 尚

  次世代がん研究シーズ戦略的育成プログラム, 2014, Principal investigator

  Competitive research funding


• A-STEP「膜型分子SIRPαを標的とした新たな自己免疫疾患治療薬の開発」

  的崎 尚

  研究成果最適展開支援プログラム フィージビリティスタディステージ 探索タイプ, 2014, Principal investigator

  Competitive research funding


• 血管内皮細胞特異的に発現する受容体型チロシンホスファターゼによる腫瘍血管新生制御

  的崎 尚

  日本学術振興会, 科学研究費助成事業 新学術領域研究(研究領域提案型), 新学術領域研究(研究領域提案型), 神戸大学, 01 Apr. 2011 - 31 Mar. 2013, Principal investigator

  研究代表者は、受容体型チロシンホスファターゼVE-PTPが血管内皮細胞に特異的に発現し、血流により生じる力学的な刺激であるシェアストレス(SS)により、VE-PTPの局在が制御されると共に、SSによる血管内皮細胞の多様な機能制御に関与する可能性を見出している。本研究では、VE-PTPの生理機能とその作用機構の解析を行うことにより、腫瘍血管新生の新たな制御メカニズムを明らかにすると共に、VE-PTPを利用した新規のがん治療法の開発を目的とした。 前年度に引き続き、VE-PTPがSSにより、血管内皮細胞の下流に移動・局在する機構につき解析を行い、低分子量G蛋白質であるRacやRabの関与が示唆された。また、細胞外領域が、SSによるVE-PTPの細胞内移動に重要であることを見出した。VE-PTPノックダウンの系を確立し、VE-PTPがSSの下流に局在する分子のチロシンリン酸化レベルを制御する可能性を見出した。VE-PTP-floxマウスを作製し血管内皮細胞特異的にCre-ERT2リコンビナーゼを発現するマウスとの交配をすすめていたが、得られた後者のマウスではタモキシフェン誘導によるCreの発現が上手く機能しないため、この実験に関しては新たに別のCre-ERT2リコンビナーゼを発現するマウスを入手し研究を進めることとした。

  Competitive research funding


• 細胞寿命を決定する分子基盤に関する研究

  的崎 尚, PARK Jung-Ha

  日本学術振興会, 科学研究費助成事業 特別研究員奨励費, 特別研究員奨励費, 神戸大学, 2012 - 2013, Principal investigator

  ヒトにおいては皮膚ケラチフサイトで約1ヶ月、赤血球で約3ケ月、骨細胞で約10年、脳神経細胞で数10年の寿命があると言われているが、最終分化後の個々の細胞の寿命がどのようにして決定されるかについては明らかとなっていない。本研究では、細胞寿命を決定する分子基盤の解明を目指し、特に、生体内でのターンオーバーが早く、この解析の糸口となり得ると考えられるマウス腸上皮細胞を研究対象として解析を進めている。平成24年度までの解析では・マウス回腸の腸上皮細胞はクリプトと呼ばれる領域で分裂した後に腸絨毛の先端まで移動し、分裂後約3-4日で消失していくことを確認すると同時に、これらの過程は腸内細菌によって制御される可能性を見出していた。 そこで平成25年度は無菌マウスに腸内細菌を経口投与し、腸内細菌が腸上皮細胞のターンオーバーに与える影響について観察を行った。その結果、腸内細菌を投与したマウスでは無菌マウスと比べて腸上皮細胞の分裂数が増え、移動が速くなることが確認できた。また腸上皮細胞の三次元培養(オルガノイド培養)を行い、腸内細菌の構成成分や代謝物が腸上皮細胞にどのような影響を与えるかについて解析を行ったところ、腸内細菌の代謝物が腸上皮細胞の分裂に寄与している可能性を見出した。現在、どのような分子メカニズムで腸内細菌の代謝物が腸上皮細胞の分裂を制御しているのかについても解析を進めるとともに、マウスに腸内細菌の代謝物を与えた場合に腸上皮細胞のターンオーバーにどのような影響が出るかについても解析を進めている。

  Competitive research funding


• がん微小環境を標的とした革新的治療法の実現（貪食細胞－がん細胞相互作用を制御する新たながん治療法の開発）

  的崎 尚

  次世代がん研究シーズ戦略的育成プログラム, 2013, Principal investigator

  Competitive research funding


• A-STEP「膜型分子SIRPαを標的とした新規がん治療薬の開発」

  的崎 尚

  研究成果最適展開支援プログラム シーズ顕在化タイプ, 2013, Principal investigator

  Competitive research funding


• Molecular basis for regulation of the cellular life span

  MATOZAKI Takashi, OHNISHI Hiroshi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research, Grant-in-Aid for Challenging Exploratory Research, Kobe University, 2011 - 2012, Principal investigator

  Cells constituting organs in the mammals have cell-type-specific life span after their terminal differentiation. The differences in cellular life span are though to be dependent on cell characteristics and functions. However, the molecular basis underlying the regulation of the life span of terminally differentiated cells is not fully elucidated. Moreover, the biological significance of cell-type-specific life span still remains unclear. To clarify the mechanism of the regulation of cellular life span, we performed approaches using mouse intestinal epithelial cells as a model.

  Competitive research funding


• がん微小環境を標的とした革新的治療法の実現（貪食細胞－がん細胞相互作用を制御する新たながん治療法の開発）

  的崎 尚

  次世代がん研究シーズ戦略的育成プログラム, 2012, Principal investigator

  Competitive research funding


• A-STEP「膜型分子SIRPαを標的とした新規がん治療薬の開発」

  的崎 尚

  研究成果最適展開支援プログラム シーズ顕在化タイプ, 2012, Principal investigator

  Competitive research funding


• がん微小環境を標的とした革新的治療法の実現（貪食細胞－がん細胞相互作用を制御する新たながん治療法の開発）

  的崎 尚

  次世代がん研究シーズ戦略的育成プログラム, 2011, Principal investigator

  Competitive research funding


• A-STEP「抗SIRPαモノクローナル抗体を利用した新たながん治療法の開発」

  的崎 尚

  研究成果最適展開支援プログラム フィージビリティスタディステージ 探索タイプ 一般型, 2011, Principal investigator

  Competitive research funding


• Physiological and pathological roles of CD47-SHPS-1 system

  MATOZAKI Takashi, OHNISHI Hiroshi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Gunma University, 2008 - 2010

  SHPS-1 and CD47 are transmembrane proteins and they constitute a cell-cell communication system by interacting their ectodomains. In this research project, we have shown that CD47-SHPS-1 system participates in regulation of brain stress response and depression-like behavior as well as induction of IL-17-producing helper T cells and autoimmune diseases. In addition, it also plays an important role in regulation of insulin secretion from pancreatic βcells.


• Protein tyrosine phosphatases and regulation of cancer cell adhesion/migration

  MATOZAKI Takashi, OHNISHI Hiroshi, OKAZAWA Hideki, MURATA Yoji

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Priority Areas, Grant-in-Aid for Scientific Research on Priority Areas, Gunma University, 2005 - 2009

  In this grant project, we have investigated the physiological role of protein tyrosine phosphorylation as well as its relation to oncogenesis and metastasis. We have clarified that a novel cell-cell communication system “CD47-SHPS-1 system" or SAP-1, a receptor-type protein tyrosine phosphatase, is important for regulation of cancer metastasis and of inflammation that is directly related to development of cancers.


• 受容体型チロシンホスファターゼSAP-1の消化管における生理的、病態的意義

  的崎 尚, SUPRIATNA Yana, SUPRIATNA Y

  日本学術振興会, 科学研究費助成事業 特別研究員奨励費, 特別研究員奨励費, 群馬大学, 2007 - 2008

  本研究では、消化管に高度に発現する新規受容体型チロシンホスファターゼSAP-1の生理的、病態的意義を明らかにするために、SAP-1遺伝子破壊(KO)マウスを用いたin vitroおよびin vivoでの解析を試みた。前年度の解析をさらに進め、SAP-1が消化管上皮細胞特異的な発現様式を示すこと、また、腸管腫瘍自然発症マウスモデルであるApe minマウスとSAP-1 KOマウスとの交配実験から、SAP-1が消化管における腫瘍形成の制御に関与することを明らかにした。さらに、腸管における主要な疾患の一つである腸炎へのSAP-1の関与につき解析を試みた。腸炎のマウスモデルの作製に広く使用される硫酸デキストラン(DSS)を用いSAP-1 KOマウスおよび野生型マウスに腸炎を誘導したところ、その発症と重症度がSAP-1 KOマウスにおいて抑制される傾向が認められた。一方、炎症性腸疾患のマウスモデルとして知られているIL-10 KOマウスとSAP-1 KOマウスとの交配を行い、IL-10、SAP-1二重遺伝子破壊(DKO)マウスを作製し解析を行ったところ、IL-10 KOマウスに比べIL-10、SAP-1 DKOマウスにおいて腸炎の発症度と重要度が強まることを見出した。これらの実験結果から、SAP-1は腸炎の発症やその病態の制御に関与し、腸炎の発症機序の違いにより相反する作用を示すことが示唆された。現在、SAP-1によるこれら腸炎発症制御の分子機構の解析を進めている。


• Physiological roles of CD47-SHPS-1 system, an intercellular signaling, in regulation of various cellular functions

  MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Gunma University, 2006 - 2007

  SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47, a ligand for SHPS-1. The cytoplasmic region of SHPS-1 binds the protein tyrosine phosphatases SHIP-1 or SHP-2. CD47 is a penta-transmembrane protein, which was originally identified as a binding partner of integrin. We have recently elucidated that CD47 and SHIPS-1 constitute an intercellular communication system (the CD47-SHPS-1 system), that plays important roles in the following cell functions. In this study, we investigated the physiological roles of CD47-SHPS-1 system. The results obtained are follows: (1) Interaction of CD47 with SHIPS-1 cooperatively regulates neurite development and eventually it contributes to formtion of neuronal networks. (2) The cytoplasmic region as well as tyrosine phosphorylation sites in this region of SHIPS-1 appear indispensable for this inhibitory action of SHIPS-1 for macrophage phagocytosis. SHIPS-1 may regulate the attachment of phagocytosed target cells to macrophages. (3) Trans-interaction of CD47 and SHPS-1 that occurred on contact of CD47-expressing cells and SHIPS-1-expressing cells results in endocytosis of the ligand-receptor complex into either cell type (trans-endocytosis). Such endocytosis is regulated by clathrin or dynamin as well as Rae and Cdc42. (4) SHPS-1 expressed on dendritic cells is important for induction of Th17 or Th1 cells as well as activation of NKT cells.


• Research for physiological roles of the CD47-SHPS-1 system.

  MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Gunma University, 2004 - 2005

  SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47 and whose cytoplasmic region binds the protein tyrosine phosphatases SHP-1 or SHP-2. CD47 is a penta-transmembrane protein, which was originally identified as a binding partner of integrin. We have recently elucidated that CD47 and SHPS-1 constitute an intercellular communication system (the CD47-SHPS-1 system), that plays important roles in the following cell functions. In this study, we investigated the physiological roles of CD47-SHPS-1 system. The results obtained are follows : (1) By using mice bearing mutant SHPS-1 lacking most of the cytoplasmic region, we have shown that engagement of SHPS-1 (on macrophages) by CD47 (on RBCs) negatively regulates the phagocytosis of RBCs, thereby determining both the life span of individual RBCs and the number of circulating erythrocytes. (2) Engagement of SIRPβ, a family member of SHPS-1, promotes phagocytosis in macrophages by inducing the tyrosine phosphorylation of DAP 12, Syk, and SLP-76 and the subsequent activation of a MEK-MAPK-MLCK cascade. (3) In N1E-115 neuroblastoma cells, forced expression of CD47 induced neurite extension and filopodium formation, those were further enhanced by CD47-Fc fusion protein. Such regulation involves the activation of Rac and Cdc42, and integrins containing the β3 subunit. CD47-deficient hippocampal neurons manifested markedly impaired development of dendrites and axons. Such regulation involved, at least in part, activation of Cdc42 and Rac mediated by Src. (4) The ectodomain of SHPS-1 has now been shown to be shed from cells in a reaction likely mediated by LPA as well as other stimuli. The shedding of the ectodomain of SHPS-1 plays an important role in regulation of cell migration and spreading by this protein.


• New approach to internal radiotherapy combined with somatostatin receptor binding technique

  TANADA Shuji, IRIE Toshiaki, ENDO Keigo, MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), National Institute of Radiological Sciences, 2004 - 2005

  As octreotide, an analogue of somatostatin, binds specifically to the somatostatin receptor in the living body, it has a potential for specific targeting therapy against cancer if it could be labeled with cytotoxic radioisotope (RI). The present research was undertaken to study the feasibility to develop internal radiotherapy combined with somatostatin receptor binding technique, using gene engineering technique with the expression of somatostatin receptor on cancer cell membrane in cancer-bearing mice. It was also undertaken to possibly develop a quantitative visualizing method of somatostatin receptors on cancer cell membrane using gamma-emitting RI with which octreotide could be labeled. The most important part was to obtain optimal gene-recombinant adenovirus which could have the ability to express somatostatin receptor on cancer cell membrane after the infection of the virus to the experimental mice. We introduced Gene-recombinant Adenovirus (AxCA-SSTR2) and tried to produce adenovirus vector, namely Adex-HAhSStr2 which was transfected with HA-human somatostatin receptor gene type 2, and to obtain the somatostatin-receptor expressing cancer cells with very high efficiencies. Regrettably, we have not reached the satisfactory goal of this step yet and are thinking further research. We have been scrutinizing the technique to label octreotide with beta or gamma emitting RI with high efficiencies, and have encountered some difficulty to achieve the stable result for labeling octreotide with the specific activity sufficient to perform basic animal experiments. We expect to continue further study for the goal. Imaging technology is essential for precise visualization of cancer lesions and is very important to evaluate the effect of RI internal radiotherapy. Positron emission tomography has been one the most useful imaging technology for the evaluation of therapy effects and predicting patient prognosis. We have studied the optimal imaging technique for this purpose. We also examined the behavior of beta emitting RI in the body for the preparation of future RI internal radiotherapy.


• 細胞の増殖シグナルと接着シグナルのクロストーク制御機構とヒトがんにおける異常

  的崎 尚, 大西 浩史, 岡澤 秀樹

  日本学術振興会, 科学研究費助成事業 特定領域研究, 特定領域研究, 群馬大学, 2002 - 2004

  生理的な細胞増殖と細胞接着のシグナル伝達機構の解明は、がんの生物学的特性である無制限な増殖能や浸潤・転移能を分子レベルで理解する上で必須であると考えられる。このような観点から、私共は細胞の増殖と接着の制御機構における蛋白質チロシンリン酸化シグナルの生理的役割とがん化や転移の病態との関連につき研究を行っており、本年度は、新しい細胞間シグナル伝達系であるCD47-SHPS-1系に関連する分子の生理的機能と作用機構を中心に研究を行い、以下の結果を得た。 (1)糖鎖認識型ユビキチンリガーゼであるNFB42はSHPS-1の細胞外領域に結合し、SHPS-1を基質としてユビキンチン化し、SHPS-1の細胞表面への発現を制御することを明らかにした。 (2)赤血球上のCD47はマクロファージ上のSHPS-1と相互作用して、赤血球貪食を負に制御する。一方、SHPS-1の類縁分子であるSIRPβはMAPキナーゼ系を介してマクロファージ貪食能を正に制御していることを明らかにした。 (3)神経芽腫由来細胞において、CD47の強制発現により突起伸長が刺激された。CD47の強制発現による突起伸長にはRacが、SHPS-1-Fcによるfilopodia形成にはCdc42が関与すること、また前者の効果にはintegrinの関与が示唆された。 上記の如く、当初の研究目的を充分に達成することが出来た。


• 細胞増殖のシグナリング機構

  高井 義美, 入江 賢児, 匂坂 敏朗, 池田 わたる, 扇田 久和, 清水 一也, 中西 宏之, 萬代 研二, 三好 淳, 的崎 尚, 佐々木 卓也

  日本学術振興会, 科学研究費助成事業 特定領域研究, 特定領域研究, 大阪大学, 2000 - 2004

  細胞の運動・増殖・接着のそれぞれのシグナル伝達系の間には密接なクロストークが存在し、細胞の接触阻害の破綻ががんの増殖や浸潤・転移の機構へとつながる。私共は、接着分子ネクチンが、上皮細胞のアドヘレンスジャンクション(AJ)とタイトジャンクション(TJ)の形成を制御すること、低分子量Gタンパク質Cdc42とRacを活性化することを明らかにしている。一方、ネクチン様分子Necl-5が細胞の運動および増殖を制御していることも明らかにしている。本年度の研究では、ネクチンとネクチン様分子を介した細胞の運動・増殖・接着のシグナル系のクロストークに焦点をあてて解析し、以下の成果を得た。 (1)接着分子ネクチンは、アファディンとアクチン細胞骨格を介して、AJとTJの構成因子を接着部位にリクルートしてAJとTJを形成した。また、ネクチンによるCdc42とRacの活性化には、c-Src、低分子量Gタンパク質Rap1、GDP/GTP交換因子FRG、Vav2が関与していた。ネクチンによって活性化されたCdc42とRacはそれぞれフィロポディアとラメリポディアの形成を促進し、細胞間接着の形成の速度を促進した。 (2)ネクチン様分子Necl-5はインテグリンおよび増殖因子受容体と協調的に作用して細胞の運動・増殖を促進した。細胞膜表面のNecl-5は、細胞が接触して他の細胞のネクチンと結合するとダウンレギュレーションされ、その結果細胞の運動・増殖は低下した。細胞ががん化するとNecl-5はアップレギュレーションされ、細胞が接触しても細胞膜表面のNecl-5は減少せず、細胞の運動・増殖は低下しなかった。 以上の結果から、ネクチンとネクチン様分子は、細胞の運動・増殖の接触阻害やがん化によるその破壊の分子機構に関与していることが示唆された。このように、本年度の研究は予想以上に進展し、当初の目的を達成することができた。


• Research for physiological roles of the CD47-SHPS-1 system.

  MATOZAKI Takashi, OHE Yoshihide, KANEKO Yoriaki, OKAZAWA Hideki, KOBAYASHI Hisae

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), Gunma University, 2002 - 2003

  SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47 and whose cytoplasmic region binds the protein tyrosine phosphatases SHP-1 or SHP-2. CD47 is a penta-transmembrane protein, which was originally identified as a binding partner of integrin. We have recently elucidated that CD47 and SHPS-1 constitute an intercellular communication system (the CD47-SHPS-1 system), that plays important roles in the following cell functions. In this study, we investigated the physiological roles of CD47-SHPS-1 system. The results obtained are follows : (1)The SHPS-1-SHP-2 complex positively regulated the migration of melanoma cells and other cultured cells, however engagement of SHPS-1 by CD47 prevented such regulation. Engagement of SHPS-1 by CD47 also induced the dephosphorylation of SHPS-1 and enhanced Rho activity accompanied by formation of stress fibers and adoption of a less polarized morphology. Thus, the CD47-SHPS-1 system might thus contribute to the inhibition of cell migration by cell-cell contact. (2)The phagocytosis of opsonoized red blood cells (RBCs) by peritoneal macrophages (PEMs) from mice bearing mutant SHPS-1 lacking most of cytoplasmic regions (SHPS-1-Δcyto) was markedly increased, compared wild-type PEMs. In contrast, the difference between WT and the mutant was not observed when CD47-null RBC was used as a phagocytotic target or in the presence of blocking antibodies of SHPS-1. Thus, the engagement of SHPS-1 (on macrophages) by CD47 (on RBCs) negatively regulates the phagocytosis of opsonized RBCs through a manner dependent of SHP-1. (3)In primary cultured hippocampal neurons, SHPS-1 and CD47 were localized in a different manner ; the former predominantly on axons and the latter on dendrites, respectively. Exogenous expression of SHPS-1 and CD47 in cultured neurons also confirmed this observation. (4)In N1E-115 neuroblastoma cells, forced expression of CD47 induced neurite extension and filopodium formation, those were further enhanced by CD47-Fc fusion protein. Such regulation involved the activation of Rac and Cdc42, and integrins containing the β3 subunit.


• MAPキナーゼ特異的ホスファターゼが膵β細胞の高次機能を発現・維持する機構

  竹内 利行, 的崎 尚

  日本学術振興会, 科学研究費助成事業 萌芽研究, 萌芽研究, 群馬大学, 2002 - 2002

  PTHrPはcAMP経路を介してインスリン含量とそのmRNA発現を増加させる。この効果はラット膵島や継代数の少ないMIN6細胞で顕著に見られる。我々は、PTHrP/cAMP経路がMAPキナーゼ特異的ホスファターゼ(MKP)群を高発現させることと、MKPがインスリン発現を増加させ、β細胞を長期生存させることを見出した。MKPは現在9種類知られており、各MKP特異的プライマーによるPCRで、膵β細胞では少なくとも5種類のMKPが発現していた。このうちMKP-1のみがPTHrPで誘導されることをノザンブロットで確認した。β細胞でMKPのターゲットとなるMAPキナゼをそのインヒビターで調べた。ERK1/2に特異的なPD98059はインスリン発現に影響を与えなかった。しかしP38とJNKに特異的なSB203585はインスリン発現を上昇させ、そのdoseとp38及びJNKのリン酸化型の解析からSB203585の効果はJNKの阻害によると推測された。そこでJNKを特異的に阻害するSP600125をMIN6に作用させるとインスリン量とインスリンmRNAが用量依存的に増加した。MKP-1をアデノウィルスベクターでβ細胞に導入すると、β細胞は長期生存するのみならずインスリン発現が増加した。ところでMKP-1の阻害剤Ro-31-8220はMKP-依存的インスリン発現を完全に抑制した。従ってMKP-1が成熟β細胞のインスリン発現を制御していることが明らかとなった。


• 細胞の増殖と接着の制御機構

  的崎 尚, 岡澤 秀樹, 大西 浩史

  日本学術振興会, 科学研究費助成事業 特定領域研究(C), 特定領域研究(C), 群馬大学, 2001 - 2001

  生理的な細胞増殖と細胞接着のシグナル伝達機構の解明は、がんの生物学的特性である無制限な増殖能や浸潤・転移能を分子レベルで理解する上で必須であると考えられる。このような観点から、私共は細胞の増殖と接着の制御機構における蛋白質チロシンリン酸化シグナルの生理的役割とがん化や転移の病態との関連につき研究を行っており、本年度も、チロシンホスファターゼの生理的機能と作用機構を中心に研究を行い、以下の結果を得た。 (1)チロシンホスファターゼSHP-2は、上皮系細胞であるMDCK細胞において低分子量G蛋白質RasとRhoの活性制御に関与し、細胞接着と細胞運動を制御することを明らかにした。 (2)上皮系細胞では、カドヘリン依存性の細胞間接着により、ドッキング蛋白質Gab-1がSrcファミリーチロシンキナーゼの作用を介してチロシンリン酸化をうけ、下流シグナルであるRas/MAPキナーゼあるいはPI3-キナーゼ/Aktの活性化に重要であることを示した。 (3)SHP-2の脱リン酸化基質であり結合蛋白質であるSHPS-1は、その細胞外領域のリガンド分子であるCD47と相互作用して、マクロファージ機能ならびに神経シナプス機能の制御に重要な役割を果たす可能性を示した。 (4)受容体型チロシンホスファターゼSAP-1が、細胞-基質間接着依存性に活性化され、細胞-基質間接着部位に局在するp130CasやFAKチロシンキナーゼなどのチロシンリン酸化蛋白質を基質として作用し、細胞増殖に抑制的に働くことを明らかにした。 今後、さらにSHP-2によるRas系制御の分子メカニズムにつき検討すると共に、新たな細胞間シグナル伝達系であるCD47-SHPS-1系の生理機能とその作用機構、さらにがんにおける異常について解析する予定である。また、SAP-1は長らく明らかにされていないコンタクトインヒビションの分子機構に密接に関与する可能性が想定され、今後、SAP-1の細胞増殖抑制の分子機構をさらに明らかにすると共に、がんにおける異常と転移との関連につき検討する予定である。


• 増殖因子受容体の細胞接着部位特異的な局在化の分子機構

  的崎 尚, 久保原 禅

  日本学術振興会, 科学研究費助成事業 萌芽的研究, 萌芽的研究, 群馬大学, 2001 - 2001

  増殖因子やホルモンがその受容体に結合して下流へ効率よくシグナルを伝達するためには、これらの受容体がクラスタリングする必要がある。私共は、すでに、肝細胞増殖因子(HGF)受容体や上皮細胞増殖因子(EGF)受容体が上皮細胞などの極性をもつ細胞において細胞間接着部位に局在化することを明らかにしているが、この局在化の分子機構は未だ十分明らかでない。そこで、本研究では、この増殖因子受容体の細胞接着部位への局在化の分子機構をはじめて明らかにしようと試みた。その結果、私共は、HGF受容体チロシンキナーゼの基質蛋白質であるGab-1が、接着分子カドヘリンを介した細胞間接着によってチロシンリン酸化を受けることを見い出した。Gab-1は、HGF受容体に直接結合しチロシンリン酸化を受け、これに会合するシグナル分子を介して下流にHGFのシグナルを伝えるいわゆるドッキング蛋白質である。しかし、カドヘリンを介した細胞間接着によるGab-1のチロシンリン酸化には、細胞質型のチロシンキナーゼSrcが重要であることを明らかにした。Gab-1は、Pleckstrin-homology(PH)ドメインを持ちこのドメインを介して細胞膜リン脂質に結合し細胞膜近傍に局在化すると考えられている。すなわち、本研究結果からHGF受容体はGab-1と複合体を形成し、さらに何らかの未知の分子機構によりカドヘリン系と連関することが予想される。この未知の機構こそが、HGF受容体の細胞間接着部位への局在化に寄与する可能性が高いと考えている。Gab-1はHGF受容体のみならず、EGF、FGF、IGF-I、インスリンなどの増殖因子の受容体チロシンキナーゼの基質でもあることが知られており、Gab-1がこれらの増殖因子受容体の細胞接着部位への局在化に普遍的に関与している可能性が想定される。また今後、Gab-1とカドヘリン系との連関に関与する分子機構を詳細に検討する予定である。


• Research for physiological roles of protein tyrosine phosphatases for cell adhesion.

  MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), 1999 - 2000

  It has been suggested that tyrosine phosphorylation or dephosphorylation of proteins localized at cell-cell junctions plays an important role in the regulation of cell adhesion functions. We have been studying physiological roles of protein tyrosine phosphatases (PTPases) and discovered novel PTPases, such as SAP-1, SHP-2, and PTPH1. SAP-1 is a receptor-like PTPase, while SHP-2 is a non-transmembrane-type PTPase containing two SH2 domains. PTPH1 is also a non-transmembrane-type PTPase that contains an Ezrin-like structure and a PDZ domain in its N-terminal region. Thus, all these PTPases could be involved in the regulation of cell adhesion. In this study, we investigated the physiological roles of these three PTPases. The results obtained are follows : (1) Integrin-based cell adhesion directly regulates the catalytic activity of SAP-1. Expression of SAP-1 inhibits cell proliferation presumably through dephosphorylation of p130cas and other proteins localized at integrin-based cell adhesion sites. This inhibitory effect of SAP-1 may be related to "contact inhibition". (2) SHP-2 physiologically suppresses the activity of Rho and it thereby positively regulates the HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway. We have generated knockout mice of SHPS-1, an SHP-2 substrate, and have shown that SHPS-1 is essential for the regulation of Ras and Rho. (3) We have tried to identify the proteins bound to the Ezrin domain or the PDZ domain of PTPH1 by the yeast two-hybrid system. We will analyze the function of these binding partners of PTPH1.


• Analysis of expressional changes of liver enriched transcription factors during occurrence and development of hepatocellular carcinoma, its application to pathological diagnosis and gene therapy

  YOSHITAKE Hayashi, MATOZAKI Takashi, SANO Kimihiko

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)., Grant-in-Aid for Scientific Research (B)., Kobe University, 1998 - 2000

  Several liver enriched transcription factors were identified and the regulation of their expressions has been well known. We showed that HNF-1a expression decreased, although HNF-1β remained unchanged, during dedifferentiation from well differentiated hepatocellular carcinoma (HCC) to poorly differentiated HCC.We also characterized an undifferentiated HCC cell-line, referred to as ETK-1, which has the potency of bilateral differentiation, like liver stem cell, into both hepatocyte, referred to as MEK, and biliary epithelial cell, referred to as NEC.ETK-1 cell expressed neither HNF-1α nor HNF-4. MEK cell showed expression of both HNF-1α and HNF-4. NEC expressed only HNF-4, but not HNF-1α. ETK-1 and NEC had no expression of liver specific genes, such as transthyretin and albumin, AFP and so on, although MEK expressed all sets of liver specific genes. Our study focused on the mechanism how NEC has no expression of liver specific genes or HNF-1α in spite of its expression of HNF-4. Fluorescent microscopic observations of NEC cell demonstrated that the HNF-4 located in the cytoplasm, not in the nucleus. The lack of transference of HNF-4 from cytoplasm into nucleus seemed to induce its functional defect as a transcription regulator. Such abnormal distribution of nuclear transcription factors might be an important process in dedifferentiation of HCC.We also analysed the signal transduction molecules inplicated in liver enriched transcription regulation during dedifferentiation of HCC.Immunohistochemical and western- and northern-blot analysis of surgically hepatectomized HCC tissues showed that overexpression of SAP-1, a human transmembrane-type protein tyrosine phosphatase in well differentiated HCC and its expression decreased during dedifferentiation of HCC.Induction of overexpression of SAP-1 in poorly differentiated HCC cell-line by transgene caused redifferentiation of HCC, and suppressed cellular proliferation and invasion. SAP-1 may be a molecule implicated in evolution and metastasis of HCC through hepatocytic differentiation.


• チロシンホスファターゼSHP-2の生理機能に関する研究

  的崎 尚

  日本学術振興会, 科学研究費助成事業 特定領域研究(A), 特定領域研究(A), 大阪大学, 1999 - 1999

  私共は、SH2ドメインを有しているPTPase、SHP-2を発見し、SHP-2が、様々な増殖因子によるRasの活性化に重要な役割を果たしていることを見い出した。さらに、最近、私共は、SHP-2の脱チロシンリン酸化基質蛋白質、SHPS-1の遺伝子クローニングに成功した。SHPS-1は、免疫グロブリンスーパーファミリーに属する受容体型蛋白質である。また、SHPS-1は、インスリン等の増殖因子刺激のみならず、インテグリンを介した細胞接着やリゾホスファチジン酸刺激依存性にチロシンリン酸化を受ける。一方、SHPS-1が細胞接着によってもチロシンリン酸化を受けることから、最近、SHP-2が細胞の接着や運動にも関与している可能性も出てきた。そこで、本研究計画においては、さらにSHP-2の生理機能の解析を、細胞接着と細胞運動を中心に行い、以下の結果を得た。 (1)SHP-2は、上皮系細胞であるMDCK細胞において低分子量G蛋白質Rhoの活性制御に関与し、増殖因子による細胞運動を制御することを明らかにした。また、この作用にはGDP/GTP交換促進蛋白質であるVav2が関わることを示した。 (2)SHP-2は、培養繊維芽細胞においても、増殖因子による細胞運動を制御し、複数の蛋白質のチロシンリン酸化を制御している可能性を示した。 (3)SHP-2は、増殖因子によるJunキナーゼの活性化にも関与している可能性を示した。 このように、私共は、本年度の研究予定をほぼ達成することができた。


• Modes of activation and action of Small G proteins

  TAKAI Yoshimi, SASAKI Takuya, SHIRATAKI Hiromichi, TANAKA Kazuma

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)., Grant-in-Aid for Scientific Research (B)., Osaka University, 1998 - 1999

  Small G proteins exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than one hundred members. This superfamily is structurally classified into at least five families : the Ras, Rho, Rab, Sarl/Arf, and Ran families. They regulate a wide variety of cell functions : The Ras family regulates gene expression; the Rho family regulates reorganization of cytoskeleton and gene expression; the Rab and Sarl/Arf families regulate vesicle trafficking; and the Ran family regulates nucleocytoplasmic transport. Many upstream regulators and downstream effectors of small G proteins have been isolated. In the present research project, we have studied the modes of activation and action of small G proteins, especially the Rab and Rho families. 1. The regulatory mechanism of the Rab family : Rab3A is a member of the Rab family which is particularly implicated in neurotransmitter release from the nerve terminal. We had isolated its regulatory proteins, named Rab GDI, Rab3 GEP, and Rab3 GAP. In this research project, we have shown that these proteins modulate the neurotransmitter release process through regulation of Rab3A. 2. The downstream pathway of the Rab family : We had isolated an effector of Rab3A, named Rabphilin-3A. In this research project, we have shown that Rabphilin-3A actually plays a crucial role in neurotransmitter release using the squid giant axon system. Moreover, we have identified an effector of Rab11, named Rabphilin-11, and found that the Rab11-Rabphilin-11 system is involved in cell migration through regulation of the vesicle recycling. 3. The regulatory mechanism of the Rho family : We have discovered a novel GDP/GTP exchange protein of Cdc42, named Frabin, and shown that the Frabin-Cdc42 pathway functions as the most upstream regulator for cell migration. 4. The downstream pathway of the Rho family : In S. cerevisiae, we have isolated two downstream effectors of Rho, BNI1 and BNR1, and demonstrated that Rho regulates actin cytoskeleton and microtubules through these targets, leading to budding or cytokinesis. In mammalian cells, ROCK, a serine/threonine protein kinase, and mDia, a mammalian counterpart of BNI1, cooperatively regulate reorganization of the actin cytoskeleton. We have also shown that Rac and Cdc42 regulate cadherin-based cell-cell adhesion.


• チロシンホスファターゼSHP-2の標的基質蛋白質に関する研究

  的崎 尚

  日本学術振興会, 科学研究費助成事業 特定領域研究(A), 特定領域研究(A), 神戸大学, 1998 - 1998

  研究代表者は、src-ホモロジー2領域(SH2ドメイン)を有しているPTPase、SHP-2を発見し以後一貫してこのPTPaseの細胞増殖機構における生理的役割につき研究を継続している。SHP-2は、様々な増殖因子刺激によるRas/MAPキナーゼの活性化に重要な役割を果たしている。SHP-2の生理機能を明らかにする上で、最近、私達は、SHP-2の結合基質蛋白質SHPS-1(SHP Substrate-1)の遺伝子クローニングに成功している。SHPS-1は、分子量120kDaの受容体型の糖化膜蛋白質で、4個のYXXL/V/Iチロシンリン酸化モチーフを細胞内部分に有している。増殖因子刺激や細胞接着刺激等によりSHP-2はSHPS-1と複合体を形成することにより活性化され、Ras/MAPキナーゼカスケードを活性化する可能性が想定される。しかしながら、SHPS-1/SHP-2複合体による、Ras/MAPキナーゼ活性化の詳細な機序は未だ不明である。そこで、本研究計画においては、以下の研究を行った。 [1]SHPS-1の細胞内、外ドメインに対する結合分子の同定免疫グロブリンFc領域との融合蛋白とした可溶性SHPS-1細胞外ドメインを大量に精製し、これを探子として、SHPS-1リガンド候補蛋白質の解析を行った。肝臓、及び脳にSHPS-1リガンドの存在を示唆する結果を得ている。現在、Cos細胞を用いた発現クローニングを行っている。一方、SHPS-1の細胞内ドメインに結合する蛋白質を酵母LexA-Two-Hybrid Systcmを用いスクリーニングしたが、有望なクローンは得られなかった。 [2]SHS-1遺伝破壊マウスの作製と解析SHPS-1遺伝子破壊マウスを作製した。 [3]新規SHP-2結合基質蛋白質の同定SHP-2結合基質蛋白質は、PTPase活性を喪失した変異型SHP-2を強制発現させた際には、高度にチロシンリン酸化され且つSHP-2と安定な複合体を形成する分子量100K蛋白質を精製した。


• Research for a protein tyrosine phosphatase for cell adhesion and its mutations in gastrointestinal cancers.

  MATOZAKI Takashi, AOYAMA Nobuo

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Grant-in-Aid for Scientific Research (C), Kobe University, 1997 - 1998

  Since the level of tyrosine phosphorylation is determined by the balance between the actions of both protein tyrosine kinases and protein tyrosine phosphatases (PTPases), not only the unregulated activation of PTKs but also the inactivation of PTPases may be involved in the malignant transformation of gastrointestinal cells. PTPH1 is a human non-transmembrane-type PTPase that has recently been molecularly cloned. This enzyme contains an Ezrin-like structure and a PDZ domain in its N-terminal region. Since Ezrin-like structures are suggested to be involved in cell adhesion, PTPH1 may locate at the cell adhesion sites and regulate cell adhesion through the control of tyrosine phosphorylation of proteins at cell adhesion sites. In this study, we investigated the physiological roles of PTPH1 and clinical applications of PTPH1. (1) PTPH1 located at cell adhesion sites. (2) Transfection of PTPH1 mutants into cultured cells did not show any changes in terms of cell adhesion. We will further examine the effect of microinjection of antibody to PTPH1 into cultured cells. (3) With the use of RT-P CR, we have examined the mutations of PTPH1 gene in various gastrointestinal cancers. We have found several mutations in PTPH1 gene in gastrointestinal cancer sample. We will further investigate whether the mutations found in gastrointestinal cancers results in oncogenesis of these cancers. In addition, we will try to identify the proteins bound to the Ezrin domain or the PDZ domain of PTPH1 by the yeast two-hybrid system.


• チロシンホスファターゼSHP-2の結合基質蛋白質SHPS-1に関する研究

  的崎 尚

  日本学術振興会, 科学研究費助成事業 重点領域研究, 重点領域研究, 神戸大学, 1997 - 1997

  私達は、昨年度、チロシンホスファターゼSHP-2の脱チロシンリン酸化基質蛋白質、SHPS-1の遺伝子クローニングに成功した。SHPS-1は、分子量120kDaの受容体型の糖化膜蛋白質で、複数の免疫グロブリン様構造を細胞外部分に、4個のYXXL/V/Iチロシンリン酸化モチーフを細胞内部分に有している。そこで、本研究計画においては、さらにSHPS-1の生理作用を明らかにしようと試みた。野性型および、チロシンリン酸化部位を欠損させた様々な変異型SHPS-1cDNAを、CHO-IR細胞に発見させ、インスリン刺激によるSHPS-1のチロシンリン酸化とSHP-2の結合を検討した。その結果、SHPS-1のTyr449とTyr473がチロシンリン酸化部位であることが明らかとなった。さらに、野性型SHPS-1の過剰発現により、インスリンによるMAPキナーゼの活性化が、SHPS-1SHP-2複合体の形成の増加に伴い、有意に増強された。インテグリンを介したSHPS-1のチロシンリン酸化は、FAKやSRCキナーゼを欠損する細胞においてはほとんど認められなかった。LPAによるSHPS-1のチロシンリン酸化は、ボツリヌスC3酵素の処理で、ほぼ完全に抑制されRhoの関与が示唆された。免疫グロブリンFc領域との融合蛋白質としてSHPS-1の細胞外ドメインを大量に発現、精製した。これを探子として用いたところ、ラット大脳皮質神経細胞に特異的な結合を認め、現在発現cDNAライブラリーよりSHPS-1のリガンド遺伝子をクローニング中である。本研究により、インスリン、LPA、インテグリンを介した細胞接着刺激によりSHPS-1がチロシンリン酸化を受け、SHPS-1SHP-2複合体が形成され、Rsa-MAPキナーゼの活性化に関与している可能性が示唆された。インスリン受容体キナーゼによって、SHPS-1は直接チロシンリン酸化されるが、イテグリンによるSHPS-1のチロシンリン酸化には、FAK、SRCキナーゼが、重要であり、また、LPAによるSHPS-1のチロシンリン酸化には、Rhoが関与するようで、リガンド刺激によりSHPS-1のチロシンリン酸化の機序も異なるようである。今後さらに、SHPS-1SHP-2複合体によるRas活性化機序の詳細に関し研究を行う予定である。SHPS-1の細胞外ドメインに対する結合分子の遺伝子クローニングについても来年度可能になると考えている。


• Basic research and clinical application of SAP-1, a protein tyrosine phosphatase expressed in gastrointestinal cancers.

  MATOZAKI Takashi, NAKAJIMA Motoo, KITAGAWA Motoji, TAKEYAMA Yoshifumi, HAYASHI Yoshitaka, AOYAMA Nobuo

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A), Grant-in-Aid for Scientific Research (A), Kobe University, 1996 - 1997

  Since the level of tyrosine phosphorylation is determined by the balance between the actions of both protein tyrosine kinases and protein tyrosine phosphatases (PTPases), not only the unregulated activation of PTKs but also the inactivation of PTPases may be involved in the malignant transformation of gastrointestinal cells. SAP-1 is a human transmembrane-type PTPase that has recently been molecularly cloned. This enzyme contains a single PTPase domain in the cytoplasmic region and eight fibronectin type III-like domains with multiple potential N-glycosylation sites in the extracellular region. SAP-1 is abundant in human colorectal cancer cell lines and pancreatic cancer cell lines but not in the corresponding normal tissues. In this study, we investigated the physiological roles of SAP-1 and clinical applications of SAP-1. (1) Overexpression of SAP-1 inhibited growth of cultured cells. SAP-1 binds to EGF receptors. (2) Genomic DNA of SAP-1 promoter region was cloned and several transcription factor binding elements were observed. (3) With the use of immunohistochemistry, we have now examined the expression of SAP-1 in surgically or endoscopically excised colorectal cancers, adenoma and normal colon mucosa. Normal colon tissue or adenomas with mild dysplasia showed no detectable expression of SAP-1. In contrast, 19 of 48 (40%) adenocarcinomas expressed SAP-1. Sequencing of the K-RAS gene revealed that 10 of 15 (67%) SAP-1-positive cancers contained a mutation in codon 12. These results suggest that SAP-1 is frequently overexpressed in human colorectal cancers and that such overexpression may occur relatively late in the adenoma-carcinoma sequence. We will further investigate the existance of soluble form of SAP-1 in serm of patients with cob-rectal or pancreatic cancers.


• Analysis of how liver-specific transcriptional regulation factors are implicated in hepatocytic differentiation and oncogenesis ; their application for histo- and clinicopathological diagnosis

  HAYASHI Yoshitake, SAIJOH Kiyofumi, ITOH Hiroshi, SANO Kimihiko, HANIOKA Keisuke, MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (B), KOBE UNIVERSITY, 1995 - 1997

  Hepatic nuclear factor 1 (HNF-1), as a transcription regulator, binds the promoters or enhancers of genes expressed almost exclusively in liver. We have previously reported that the ratio of HNF-1alpha and HNF-1beta mRNA is related to histological differentiation of hepatocellular carcinoma (HCC) (Ninomiya T et al., J Hepatol, 25 : 445-453,1996). Furthermore, to investigate the expression pattern in HCCs, we relatively quantitatively compared the expression of HNF-1alpha and HNF-1beta proteins in various histologically differentiated cancerous as well as surrounding noncancerous tissues and their binding activity for B element in alpha-fetoprotein enhaner. The polyclonal antibodies for human HNF-1alpha and HNF-1beta were generated by Glutathione S-transferase fussion protein. Nuclear extracts were prepared from the tested tissues. The expression of HNF-1alpha and HNF-1beta proteins in isolated nuclei were measured by western blotting and their binding activity examined by gel mobility assay. Immunohistochemistry were performed in frozen and parafin embedded sections. Western blottings demonstrated that HNF-1alpha protein was overexpressed in well differentiated HCC tissues but decreased from well differentiated to poorly differentiated HCCs compared with surrounding non-HCC tissues. The HNF-1beta expression did not after from well differentiated to poorly differentiated HCCs athough it is more abundant in cancerous tissues than the surrounding noncancerous portions. In gel mobility assay, the decreasing tendency was shown in the assay of HNF-1alpha binding activity. These findings provide an evidence involved in effect of HNF-1alpha alteration on the differentiations of HCC that the histological differentiation of HCC turns poor when HNF-1alpha expression decreases and HNF-1beta competes to bind the elements formerly occupied by HNF-1alpha (Wang W et al., J Pathol in press).


• Ras活性化機構におけるチロシンホスファターゼの機能に関する研究

  的崎 尚, 青山 伸郎

  日本学術振興会, 科学研究費助成事業 重点領域研究, 重点領域研究, 神戸大学, 1996 - 1996

  私達は、src-homology2領域(SH2 domain)を有するPTPaseであるSAP-2が、インスリン刺激によるRasの活性化に決定的な役割を果たしていることを見い出し、SAP-2が増殖因子刺激による細胞増殖反応のポジティブな細胞内メディエーターとして作用していることを明らかにした。しかしながら、SAP-2の脱チロシンリン酸化基質蛋白質や、Ras活性化の詳細なメカニズムに関しては未だ不明のままである。そこで、本研究において、私達は、SAP-2の標的基質蛋白質の同定、遺伝子クローニングを計画した。さらに、消化器癌におけるSAP-2癌性変異の同定を計画した。 1.v-Srcによりトランスフォームされたfibroblastよりアフィニティー精製により、SAP-2の標的基質蛋白質であるpp120の精製、全長cDNAのクローニングに成功した。pp120は、SAP-2の脱チロシンリン酸化基質蛋白質考えられたため、SHPS-1(SHP Substrate-1)と命名した。SHPS-1は、分子量120kDaの受容体型の糖化膜蛋白質で、複数の免疫グロブリン様構造を細胞外部分に、4個のYXXL/V/Iチロシンリン酸化モチーフを細胞内部分に有している。さらにSHPS-1が、インスリン等の増殖因子刺激のみならず、細胞接着刺激依存性にチロシンリン酸化され、SAP-2がそのSH2ドメインを介してSHPS-1に結合することを見い出した。 2.各種大腸癌、膵癌、胃癌細胞株より、PT-PCR法により、SAP-2遺伝子を増幅し、SAP-2遺伝子異常を検出しようと試みた。しかしながら、現在までのところ、癌細胞に特異的なSAP-2の遺伝子異常は検出されていない。 3.SHPS-1のSAP-2による、脱チロシンリン酸化の生理的意義や、SHPS-1のSAP-2によるRas活性化機序における役割の詳細は未だ明らかでない。さらに、SAP-2の細胞癌化機構への関連も不明である。今後、さらにこれらの点に留意しつつ研究を進めることにより、SAP-2のより詳細な作用機構が解明されるものと思われる。


• 大腸癌に高発現するチロシンホスファターゼSAP-1の生理機能に関する研究

  的崎 尚, 青山 伸郎

  日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 1996 - 1996

  私達が、最近、遺伝子クローニングした、新しいタイプの受容体型PTPase,SAP-1は、正常大腸粘膜には、ほとんど認めなかったが、大腸癌に特異的に高発現を認めている。SAP-1の消化器癌における過剰発現が、発癌機序に関与している可能性を想定している。しかしながら、SAP-1の機能における生理的役割に関しては、全く不明のままである。そこで、本研究においては、SAP-1の生理機能の一端を明らかにする目的で、SAP-1のPTPase基質蛋白の同定、及びSAP-1の外側ドメインに対するリガンドの同定を計画した。 1.SAP-1の脱リン酸化基質蛋白質の同定 (1)src familyキナーゼが、SAP-1の標的基質蛋白であるか否かを検討した。しかしながら、src familyキナーゼ活性は、SAP-1の強発現細胞において変化しておらず、標的基質蛋白である可能性は少ないと考えられた。 (2)src familyキナーゼ以外にも、未知のSAP-1の標的基質蛋白質は想定される為、ウェストーウェスタン法によるSAP-1ターゲットの同定を行った。現在、複数のSAP-1の標的基質蛋白質と考えられるクローンを得ておりこれらを解析中である。 2.SAP-1のリガンドの同定 SAP-1の外側ドメインに結合する特異的リガンドも種々の受容体型接着因子蛋白とのアナロジーから、細胞表面に発現される膜蛋白質である可能性を考えている。そこで、IgのFcドメイン領域との融合蛋白として、SAP-1の外側ドメイン部分を過剰に分泌する細胞株を樹立し、この接着上清よりProtein Aアフィニティーカラムを用い大量にSAP-1外側ドメインを精製した。これをプローブとして用い、現在数種のSAP-1リガンドの候補蛋白を同定しており、これらを解析中である。


• Study of signal transduction via an SH2 which recognizes phosphotyrosine residues of proteins

  YAMAMURA Hirohei, OKADA Masato, NOZAWA Yoshinori, YAMAMOTO Tadashi, ONO Yoshitaka, MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A), Grant-in-Aid for Scientific Research (A), KOBE UNIVERSITY, 1995 - 1996

  SH2 (src homology region 2) is a region which specifically recognized the phosphotyrosine residues in various proteins and is believed to be an important structure in signal transduction. A non-receptor type protein-kinase Syk is expressed in almost all the hematopoietic cells. We tried to found out the importance of 2 SH2 of Syk in signal transduction. Both SH2 domains were required for BCR-mediated Syk and phospholipase C_2 phosphorylation, inositol 1,4,5-triphosphate release and calcium mobilization. A possible explanation for this requirement was provided by findings that recruitment of Syk to tyrosine-phosphorylated immuno-globulin a and reqiures both Syk SH2 domains. Protein tyrosine phosphatase, such as SHP-1 AND SHP-2, that contain SH2 domains play important roles in growth factor and cytokine signal transduction pathways. A protein of -115 kD that interacts with SHP-1 and SHP-2 was purified from v-src-transformed rat fibroblasts and the corresponding cDNA was cloned (SHPS-1). It has four YXX (L/V/I) motifs, potential tyrosine phosphorylation and SH2-domain binding sites, in its cytoplasmic region. SHP-1 may be a potential substrate for SHP-2 and may function in both growth factor-and cell adhesion-induced cell signaling. Interaction of Fyn and Zap-70 in T cells was studied. Deletion of both the SH2 and SH3 domains of Fyn resulted in the decrease of the assciation with Zap-70. Consistently, Fyn-SH2 and SH3 fused to glutathione S-transferase were able to bind to Zap-70. Thus multiple sites of Fyn and Zap-70 are involved in the association. We propose that Fyn phosphorylates and activates Zap-70 and that both kinases cooperate in TCR signaling. Tyrosine phosphorylation of paxillin was induced by nerve growth factor and epidermal growth factor and KCI.Various evidence suggested that tyrosine phosphorylation of paxillin may be involved in calcium-dependent events in neuronal and neuroendocrine cells. We have succeeded in making a CD45-deficient DT-40 cells. Using this cell lines we have found that the dephosphorylation of tyrosine residues at both autophosphorylation and negative regulatory sites is mediated by CD45 in vivo and that dephosphorylation of C-terminal tyrosine is a prerequisite for participation of Lyn in B cell receptor signaling. We have been searching the family of Syk/Zap-70 in brain and other tissues. We found novel kinases in brain and liver cells. Now we are purifying these kinases and cloning the cDNAs of these kinases.


• 消化器癌におけるチロシンホスファターゼの異常に関する研究

  的崎 尚, 林 祥剛

  日本学術振興会, 科学研究費助成事業 一般研究(C), 一般研究(C), 神戸大学, 1995 - 1995

  A.研究目的 リン酸化チロシンを脱リン酸化するチロシンホスファターゼ(PTPase)は、生理的な細胞増殖や、発癌過程の関与している可能性が想定される。私達は、最近、ヒト胃癌細胞より、全く新しいタイプの受容体型PTPase, SAP-1の遺伝子クローニングに成功した。SAP-1は、正常大腸癌粘膜には、ほとんど認めなかったが、多くの大腸癌細胞株に過剰発現を認めている。そこで、本研究においてはヒト大腸腺種及び大腸癌組織におけるSAP-1の発現を検討することを計画した。また、患者血中のSAP-1活性を検索することを計画した。さらに、CL-100と呼ばれるPTPaseの消化器癌における異常をも検索しようと試みた。 B.方法と結果 1.内視鏡検査や、手術時に得られた大腸腺種及び大腸癌組織におけるSAP-1の発現を、免疫組織化学的に抗SAP-1モノクローナル抗体を用いて検討した。46例の大腸癌組織中20例にSAP-1の高発現を観察した。14例の大腸腺種中では、2例のみに、SAP-1の高発現を観察し、この2例とも腺種内癌を伴った症例であった。 2.CL-100の遺伝子発現を、胃癌細胞8株、大腸癌細胞3株につき検討した。正常胃および大腸における発現に比し、胃癌細胞や大腸癌細胞においては、CL-100の遺伝子発現の低下を認めた。CL-100の遺伝子変異についても検討を行ったが、明らかな変異の存在は、確認されていない。 C.考察 本研究により、SAP-1がヒト大腸癌組織においても、高頻度に高発現していることが明らかになった。以前より、大腸癌組織や、大腸癌細胞株において、c-srcのC末端の脱チロシンリン酸化が認められ、c-src活性の上昇が報告されている。従って、SAP-1の消化器癌における過剰発現が、c-srcのC末端の脱チロシンリン酸化を介して、c-srcを活性化させ、発癌機序に関与している可能性が想定される。SAP-1のモノクローナル抗体を早急に作成し、患者末梢血中の、SAP-1を測定し、SAP-1を新しい腫瘍マーカーとして臨床的に応用しようと考えている。また、CL-100の発現低下に関しても今後、ヒト胃癌、大腸癌組織における検索を行う予定である。


• Mechanism of insulin action and its disorder

  KASUGA Masato, MATOZAKI Takashi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (A), Grant-in-Aid for General Scientific Research (A), Kobe University, 1994 - 1995

  Non-insulin-dependent diabetes mellitus (NIDDM) is common disorder of glucose homeostasis affecting -5% of the general population. NIDDM is characterized by defects in the insulin secretion from pancreatic beta-cells and/or the insulin action in peripheral tissues. Insulin treatment of various intact cells causes rapid tyrosine phosphorylation of a high molecular weight protein (Mr=16,000-185,000) designated pp185. A cDNA encoding pp185 was isolated and the predicted protein was named insulin receptor substrate-1 (IRS-1). Tyrosinphosphorylated IRS-1 binds several signaling molecules, including the 85kDa subunit of phosphoinositide (PI) 3-kinase, Grb2・Sos complex and SH PTP-2 via their Src homology 2 (SH2) domain. To identify new candidate genes for NIDDM,we overexpressed the dominant negative type of 85kDa subunit of PI 3-kinase, Grb2・Sos complex and SH PTP-2 in Chinese hamster ovary cells overexpressing the insulin receptor. Overexpression of dominant negative type of these signaling molecules revealed that PI 3-kinase involves in insulin-stimulated glucose uptake and translocation of glucose transporters, but not in Ras activation. On the other hand, Grb2 and SH PTP-2 involves in insulin-stimulated Ras activation, but not in insulin-stimulated glucose uptake and translocation of glucose transporters. These data suggest that PI 3-kinase is a new candidate gene for NIDDM.


• 増殖因子シグナル伝達系におけるチロシンホスファターゼの機能に関する研究

  的崎 尚, 春日 雅人

  日本学術振興会, 科学研究費助成事業 重点領域研究, 重点領域研究, 神戸大学, 1994 - 1994

  A.研究目的 チロシンホスファターゼは、チロシンキナーゼ系を介した正常な細胞増殖や発癌過程に重要な調節的役割をはたしているものと考えられるが、未だその詳細は明らかでない。私達は、最近、src-homology2領域(SH2 domain)を有するPTPaseであるSAP-2のcDNAクローニングに成功しているが、SAP-2はSH2 domainを介してチロシンキナーゼ型受容体やその気質蛋白に結合し、作用することが想定される。本研究では、チロシンキナーゼ型増殖因子受容体の細胞内シグナル伝達機構における、SAP-2の生理機能を明らかにしようと計画した。 B.方法と結果 1.SAP-2のPTPase活性を消失させた変異型SAP-2cDNAを、インスリン受容体を過剰発現するCHO細胞にトランスフェクトした。PTPase活性-の細胞においては、インスリン刺激によるRasの活性化、およびMAPキナーゼの活性化が著名に抑制されていた。一方、インスリン刺激によるPI3キナーゼの活性化は、有意に変化していなかった。さらに、変異型SAP-2を過剰発現する細胞において、変異型SAP-2とのみ複合体を形成する分子量12OKのチロシンリン酸化蛋白を同定した。 2.SAP-2遺伝子欠損マウスの作成に関しては、SAP-2ゲノムDNAを単離した後、これをneo耐性遺伝子、ジフテリア毒素遺伝子を含むターゲッテイング用ベクターに組み込み、現在、homologous recombinationを生じたクローンをサザン法にて選択中である。 C.考察 本研究により、SAP-2がインスリンのRas活性化に決定的な役割を果たしていることが明らかとなった。おそらく、インスリン以外の他の増殖因子のシグナル伝達においても、Ras活性化に働き、細胞増殖に対して促進的に作用するものと考えられる。次に、どのようなメカニズムを介してSAP-2がRasの活性化を刺激するかが興味深いが、私達は、変異型SAP-2とのみ複合体を形成する分子量120Kのチロシンリン酸化蛋白が、SAP-2の気質蛋白ではないかと想定している。即ち、変異型SAP-2はPTPase活性を有しない為、そのターゲット蛋白である120Kは強度にチロシンリン酸化され、且つ変異型SAP-2と複合体を形成するものと考えられる。120K蛋白の精製、およびcDNAクローニングにより、SAP-2のより詳細な作用機構が解明されるものと思われる。


• 胃粘液上皮細胞増殖因子に関する分子細胞生物学的検討

  坂本 長逸, 的崎 尚

  日本学術振興会, 科学研究費助成事業 一般研究(C), 一般研究(C), 神戸大学, 1994 - 1994

  1.モルモット胃粘液上皮細胞培養液の生物活性の検討- CHO細胞にヒトEGF受容体cDNAをトランスフェクトしたCHO・ER細胞を用い、〔^3H〕チミジンの取り込み、及びEGF受容体チロシンリン酸化能を検討したところ、コンデションメディウム(CM)にはチミジンの取り込み促進作用、EGF受容体チロシンリン酸化能を認めた。 そこでCMをヘパリンセファロースカラムにて、ヘパリン縮合物質と、そうでない増殖因子とに分離し、CHO・ER細胞でチミジンの取り込みを検討したところ、カラムを通過したヘパリン非縮合溶出液中にCHO・ER刺激活性を認めた。この活性はTGFα中和抗体で中和され、濃縮後、TGFα抗体を用いたウェスタンブロット法によってTGFαがCM中に存在することを確認した。ヘパリンに縮合した溶出液中にもBT3fibroblastに対する増殖促進活性を認め、このCM中にはTGFαとそれ以外の増殖因子も分泌されることが確認された。 胃粘液上皮細胞におけるEGF,TGFα,AR及びHBEGFmRNA発現量のノーザンブロット法による解析-報告された遺伝子配列を基にマウス唾液腺、ヒト大腸癌細胞株及びヒト単球より逆転写酵素を用いたpolymerase chane reaction(RT-PCR)法によりそれぞれの増殖因子cDNAを得た。モルモット胃粘液上皮細胞には、TGFαmRNAの発現を認め、他の増殖因子については現在ノーザンブロットにて解析中である。


• 消化器癌におけるチロシンホスファターゼの癌性変異に関する研究

  的崎 尚, 林 祥剛, 青山 伸郎

  日本学術振興会, 科学研究費助成事業 一般研究(C), 一般研究(C), 神戸大学, 1994 - 1994

  私達が、独自にcDNAクローニングした受容体型チロシンオスファターゼ、SAP-1の過剰発現が、直接消化器癌の発癌に関与しているか否か、又、ヒト消化器癌組織においてSAP-1が過剰発現しているか否かを検討した。 (1)SAP-1のN末端、C末端に対する特異的抗体を作製した。両抗体は、培養細胞ライセ-トよりのSAP-1受渡沈降、ウエスタンブロッティング、及びヒト大腸癌組織のパラフィン切片を用いた免疫染色に用いる事が可能であった。 (2)SAP-1cDNAをNIH3T3細胞に、一過性に過剰発現させ、細胞のトランスフォーメーション能を検討した。しかしながら、SAP-1cDNA単独のトランスフェクションにては、明らかな細胞のトランスフォーメーションは認められなかった。さらに正常YMT、変異型p53遺伝子cDNAとの同時、トランスフェクション法にて、SAP-1の細胞癌化への関与を検討中である。 (3)ヒト大腸癌組織を、抗SAP-1C末抗体を用いて、免疫組織化学的に検討するとCEA陽性例の大部分の症例で、SAP-1の過剰発現が認められた。SAP-1の過剰発現の有無と大腸癌組織型との関連は、現在迄のところ、有意な相関は認められないが、今後、症例数を増し、検討する予定である。 (4)大腸癌患者・血清中のSAP-1免疫活性を測定する目的で、そのアッセイ系を開発中である。上記(1)で、述べたN末抗体を用いた検討では、明らかにSAP-1免疫活性の上昇を認める症例を確認しているが、さらに、鋭敏な測定系を開発する為に、SAP-1に対するモノクローナル抗体を作製し、これを用いた測定系を確定しつつある。


• 受容体型チロシンキナーゼを介する情報伝達機構

  春日 雅人, 的崎 尚, 岡林 克典

  日本学術振興会, 科学研究費助成事業 がん特別研究, がん特別研究, 神戸大学, 1993 - 1993

  phosphoinositide(PI)3-キナーゼはcatalytic subunitである110K蛋白(p110)とadaptor subunitである85K蛋白(85K)よりなる。インスリンがインスリン受容体に結合すると受容体に内在するチロシンキナーゼ活性が活性化され、IRS-1と呼ばれる蛋白がチロシン燐酸化される。この部位をp85のSH2ドメインが特異的に認識し結合して、IRS-1とPI3-キナーゼの複合体ができる。この複合体がインスリン作用の中でどのような情報を伝達しているか明らかにするために、P110と結合しえない変異p85を細胞内に大量に発現することを試みた。IRS-1上のp85結合部位をこの変異p85が占拠すれば、PI3-キナーゼがどのようなインスリン作用を伝達しているか明らかになると思われる。実際にこの変異p85を大量にCHO-IR細胞(Chinese hamster ovary細胞にインスリン受容体を発現させた細胞)に発現すると、IRS-1に結合しているPI3-キナーゼ活性は高度に低下した。さらにインスリンによるPI(3,4,5)3燐酸の上昇も低下していた。この細胞におけるインスリン作用を検討すると、インスリンによるrasの活性化は認められるが、糖輸送の活性化、膜ラッフリングの形成は認められなかった。すなわち、IRS-1に結合したPI3-キナーゼは、インスリンの作用の中で糖輸送の活性化、膜ラッフル形成を担っていると推定された。インスリンの糖輸送の活性化は糖輸送担体が細胞内から細胞表面へtranslocationすることによるが、変異p85を発現した細胞ではインスリンによる糖輸送担体のtranslocationが低下していることが確認された。従って、PI3-キナーゼは、細胞内のvesicleのtranslocationなどに関与していることが推定された。


• 胃粘膜上皮細胞type2シクロオキシゲナーゼの発現調節に関する分子生物学的検討

  坂本 長逸, 的崎 尚

  日本学術振興会, 科学研究費助成事業 一般研究(C), 一般研究(C), 神戸大学, 1993 - 1993

  (1)マウスtype2シクロオキシゲナーゼに対する特異抗体の作製-type2シクロオキシゲナーゼのC端アミノ酸フラグメントを合成し、ラビットに免疫してポリクローナル抗体を作製した。ELISAでの検討では1万倍希釈にてペプチドフラグメントを認識しうる特異抗体であり、現在、ウエスタンブロット、免疫染色が可能か否か検討中である。 (2)マウス胃粘膜粘液上皮細胞の単層培養系の確立-プライマリーカルチャー系の確立はきわめて困難であり、現在、温度感受性SU40LT抗原を用いた、トランスジェニックマウスから、上皮細胞の培養系を得るべく努力している。 (3)マウスにおける実験潰瘍モデルの作成と、シクロオキシゲナーゼ発現の検討-マウス胃漿膜下に20%酢酸を注入し実験胃潰瘍を作製した。組織学的には潰瘍作製後2日〜5日目が活動期であり、10日〜20日目が治療期で30〜40日で瘢痕化した。実験潰瘍発症直後より40日目までtype1シクロオキシゲナーゼ遺伝子発現はノーザン分析でまったく変化を認めなかった。一方、ノーザン分析ではtype2シクロオキシゲナーゼの発現も認めないがpolymerase chaine reaction法を用いてmRNAの半定量も行うと、type2シクロオキシゲナーゼ遺伝子は、潰瘍の急性期に一致してその発現量が増加した。現在シクロオキシゲナーゼ活性及び特異抗体を用いたtypeシクロオキシゲナーゼ蛋白の発現について、解析中である。


• EGFのプロスタグランジンを介した胃粘膜上皮増殖刺激作用に関する研究

  坂本 長逸, 的崎 尚

  日本学術振興会, 科学研究費助成事業 一般研究(C), 一般研究(C), 神戸大学, 1992 - 1992

  I.モルモット胃粘膜粘液上皮細胞の単層培養系を確立した。10%血清存在下で増殖した細胞を15時間無血清下で培養ののち、EGFを添加するとEGFの濃度に依存した〔^3H〕チミジンの取り込み増加が観察された。インスリンも又胃粘膜上皮細胞のDNA合成を用量依存性に促進し、10^<-7>MインスリンはEGF刺激のDNA合成促進作用を増強した。bFGFも用量依存性に胃粘膜上皮のDNA合成を促進し、EGF+インスリンの作用を増強した。 II.EGFはDNA合成を促進する濃度範囲で、10%血清あるいはアラキドン酸存在下に胃粘膜上皮における各種プロスタグランジン(PG)の産生を刺激した。EGF刺激PGE_2の放出はインドメタシンにより用量依存性に、ほぼ完全に抑制された。EGFは胃粘膜上皮のホスホリパーゼA_2活性には影響を与えなかったが、胃粘膜上皮ミクロソーム画分のシクロオキシゲナーゼ活性を刺激した。EGF刺激シクロオキシゲナーゼ活性はインドメタシンで抑制された。EGFはまた、濃度及び時間依存性にウエスタンブロット法で同定されるシクロオキシゲナーゼ蛋白の発現を刺激した。EGF刺激PGE_2分泌とシクロオキシゲナーゼ活性はシクロヘキサミド及びアクチノマイシンDにより抑制され、シクロオキシゲナーゼ蛋白の発現調節は遺伝子の転写及び翻訳によって調節されることが示唆された。 III.マウスシクロオキシゲナーゼI及びIIcDNAを用いて、モルモット胃粘膜上皮シクロオキシゲナーゼ遺伝子の発現をノーザンブロット法にて解析した。EGFはtypeIIシクロオキシゲナーゼ遺伝子の発現を刺激し、typeI遺伝子の発現は観察されなかった。


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