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MINAMI Yasuhiro
Graduate School of Medicine / Faculty of Medical Sciences
Professor

Researcher basic information

■ Research news
■ Research Areas
  • Life sciences / Tumor biology
  • Life sciences / Molecular biology
  • Life sciences / Cell biology
  • Life sciences / Pathobiochemistry

Research activity information

■ Paper
  • Takeshi Saji, Mitsuharu Endo, Yasushi Okada, Yasuhiro Minami, Michiru Nishita
    Lysosomes, crucial cellular organelles, undergo bidirectional transport along microtubules, mediated by motor proteins such as cytoplasmic dynein-1 (dynein) and various kinesins. While the kinesin-3 family member KIF1C is established in mediating anterograde vesicle transport, its role in lysosomal transport remains unclear. Our study reveals that KIF1C unexpectedly supports the retrograde transport of lysosomes, driven by dynein, and contributes to their perinuclear localization. Notably, while KIF1C facilitates this perinuclear positioning, its motor activity is not required and, instead, exerts an inhibitory effect on this process. Mechanistically, KIF1C facilitates this process by interacting with the dynein-activating adaptor Hook3, which associates with the lysosome-anchored protein RUFY3. This regulatory mechanism is critical for the efficient degradation of cargo in autophagic and endocytic pathways. Our findings identify an unconventional, non-motor role for KIF1C in activating dynein-driven lysosomal transport, expanding our understanding of its functional diversity in cellular trafficking.
    Oct. 2024, Communications biology, 7(1) (1), 1305 - 1305, English, International magazine
    Scientific journal

  • Koki Kamizaki, Yasuhiro Minami, Michiru Nishita
    Ror-family receptors, Ror1 and Ror2, are type I transmembrane proteins that possess an extracellular cysteine-rich domain, which is conserved throughout the Frizzled-family receptors and is a binding site for Wnt ligands. Both Ror1 and Ror2 function primarily as receptors or co-receptors for Wnt5a to activate the β-catenin-independent, non-canonical Wnt signaling, thereby regulating cell polarity, migration, proliferation, and differentiation depending on the context. Ror1 and Ror2 are expressed highly in many tissues during embryogenesis but minimally or scarcely in adult tissues, with some exceptions. In contrast, Ror1 and Ror2 are expressed in many types of cancers, and their high expression often contributes to the progression of the disease. Therefore, Ror1 and Ror2 have been proposed as potential targets for the treatment of the malignancies. In this review, we provide an overview of the regulatory mechanisms of Ror1/Ror2 expression and discuss how Wnt5a-Ror1/Ror2 signaling is mediated and regulated by their interacting proteins.
    May 2024, In vitro cellular & developmental biology. Animal, 60(5) (5), 489 - 501, English, International magazine
    Scientific journal

  • Natsuko Yamauchi, Mako Otsuka, Tomohiro Ishikawa, Yoshihiro Kakeji, Akira Kikuchi, Atsuhiro Masuda, Yuzo Kodama, Yasuhiro Minami, Koki Kamizaki
    Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either Ror1 or Wnt5b in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.
    Mar. 2024, Genes to cells : devoted to molecular & cellular mechanisms, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Hiroshi Nishida, Antonio Bolea Albero, Kenta Onoue, Yuko Ikegawa, Shivakshi Sulekh, Ugurcan Sakizli, Yasuhiro Minami, Shigenobu Yonemura, Yu-Chiun Wang, Sa Kan Yoo
    Historically, necrosis has been considered a passive process, which is induced by extreme stress or damage. However, recent findings of necroptosis, a programmed form of necrosis, shed a new light to necrosis. It has been challenging to detect necrosis reliably in vivo, partly due to the lack of genetically encoded sensors to detect necrosis. This is in stark contrast with the availability of many genetically encoded biosensors for apoptosis. Here we developed Necrosensor, a genetically encoded fluorescent sensor that detects necrosis in Drosophila, by utilizing HMGB1, which is released from the nucleus as a damage-associated molecular pattern (DAMP). We demonstrate that Necrosensor is able to detect necrosis induced by various stresses in multiple tissues in both live and fixed conditions. Necrosensor also detects physiological necrosis that occurs during spermatogenesis in the testis. Using Necrosensor, we discovered previously unidentified, physiological necrosis of hemocyte progenitors in the hematopoietic lymph gland of developing larvae. This work provides a new transgenic system that enables in vivo detection of necrosis in real time without any intervention.
    The Company of Biologists, Dec. 2023, Biology Open
    Scientific journal

  • Mitsuharu Endo, Yuki Tanaka, Mayo Fukuoka, Hayata Suzuki, Yasuhiro Minami
    Abstract Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.
    Wiley, Oct. 2023, Glia, English
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Michiru Nishita, Koki Kamizaki, Kyoka Hoshi, Kana Aruga, Ikumi Nishikaku, Hiroshi Shibuya, Kunio Matsumoto, Yasuhiro Minami
    Elsevier BV, Sep. 2023, Journal of Biological Chemistry, 299(10) (10), 105248 - 105248, English
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Ryosuke Takahashi, Koki Kamizaki, Keitaro Yamanaka, Yoshito Terai, Yasuhiro Minami
    Ovarian cancer (OC) is a refractory cancer that shows recurrence due to the acquisition of resistance to anticancer drugs, including cisplatin. However, the molecular mechanism underlying the acquisition of cisplatin resistance by cancer cells remains largely unknown. In the present study, two sets of ovarian endometrioid carcinoma cell lines were used: The parental A2780 cell line, the OVK18 cell line, and their derived cisplatin‑resistant cells. It was found that cisplatin could induce ferroptosis in these parental cells by enhancing mitochondrial membrane potential and lipid peroxidation as assessed by flow cytometric analysis, and that expression of Ferredoxin1 (Fdx1), an iron‑sulfur protein localized to the mitochondria, could be upregulated in cisplatin‑resistant cells in the absence of cisplatin. Intriguingly, it was shown that the siRNA‑mediated depletion of Fdx1 in cisplatin‑resistant cells resulted in enhanced ferroptosis by increasing the mitochondrial membrane potential and lipid peroxidation induced by cisplatin. By examining Fdx1 expression with immunohistochemical analysis in clinical specimens from patients with OC, higher expression of Fdx1 was detected in cisplatin‑resistant specimens than in cisplatin‑sensitive specimens. Collectively, these results indicated that Fdx1 may be a novel and suitable diagnostic/prognostic marker and therapeutic molecular target for the treatment of cisplatin‑resistant OC.
    Jun. 2023, Oncology reports, 49(6) (6), English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yuki Tanaka, Yasuhiro Minami, Mitsuharu Endo
    Abstract Ror1 signaling regulates cell polarity, migration, proliferation, and differentiation during developmental morphogenesis, and plays an important role in regulating neurogenesis in the embryonic neocortices. However, the role of Ror1 signaling in the brains after birth remains largely unknown. Here, we found that expression levels of Ror1 in the mouse neocortices increase during the postnatal period, when astrocytes mature and start expressing GFAP. Indeed, Ror1 is highly expressed in cultured postmitotic mature astrocytes. RNA‐Seq analysis revealed that Ror1 expressed in cultured astrocytes mediates upregulated expression of genes related to fatty acid (FA) metabolism, including the gene encoding carnitine palmitoyl‐transferase 1a (Cpt1a), the rate‐limiting enzyme of mitochondrial fatty acid β‐oxidation (FAO). We also found that Ror1 promotes the degradation of lipid droplets (LDs) accumulated in the cytoplasm of cultured astrocytes after oleic acid loading, and that suppressed expression of Ror1 decreases the amount of FAs localized at mitochondria, intracellular ATP levels, and expression levels of peroxisome proliferator‐activated receptor α (PPARα) target genes, including Cpt1a. Collectively, these findings indicate that Ror1 signaling promotes PPARα‐mediated transcription of FA metabolism‐related genes, thereby facilitating the availability of FAs derived from LDs for mitochondrial FAO in the mature astrocytes.
    Wiley, Feb. 2023, Genes to Cells, 28(4) (4), 307 - 318
    Scientific journal

  • Akira Kikuchi, Junichi Takagi, Shinji Takada, Tohru Ishitani, Yasuhiro Minami
    Wnt2022 was held on November 15th-19th, 2022, in Awaji Yumebutai International Conference Center, Hyogo Prefecture, Japan, as an in-person meeting for the first time in last 3 years. Wnt signaling is a highly conserved pathway among various species. Since Wnt1 was discovered in 1982, a number of studies using many model animals and human samples have revealed that Wnt signaling plays crucial roles in embryonic development, tissue morphogenesis, and regeneration, as well as many other physiological and pathological processes. Since the year 2022 marks the 40th anniversary of Wnt research, we aimed to look back at our research progress and discuss the future direction of this field. The scientific program consisted of plenary lectures, invited talks, short talks selected from abstracts, and poster sessions. Whereas several different Wnt meetings have been held almost every year in Europe and the United States, this was the first Wnt meeting convened in Asia. Therefore, Wnt2022 was highly anticipated to bring together leaders and young scientists from Europe, the United States, and especially Asia and Oceania. In fact, 148 researchers from 21 countries attended this meeting. Although there were travel and administrative restrictions due to COVID-19, the meeting was highly successful in enabling face-to-face discussions.
    Feb. 2023, Genes to cells : devoted to molecular & cellular mechanisms, English, International magazine
    Scientific journal

  • Tomohiro Ishikawa, Yasuka Ogura, Kazuhiro Tanaka, Hiroaki Nagashima, Takashi Sasayama, Mitsuharu Endo, Yasuhiro Minami
    Abstract Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem‐like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid‐forming glioblastoma stem‐like cells (GSCs), and Ror1 expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of Ror1 in the cells. Consistently, we show that both NICD and hypoxia‐inducible factor 1 alpha bind to upstream regions within the Ror1 gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid‐forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a–Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell‐like property.
    Wiley, Nov. 2022, Cancer Science, 114(2) (2), 561 - 573
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • グリオブラストーマ細胞におけるRor1の発現制御とRor1による幹細胞性維持機構の解析(Molecular mechanism regulating expression of Ror1 in GSCs and the role of Ror1 in maintaining their stemness)
    石川 智弘, 遠藤 光晴, 田中 一寛, 長嶋 宏明, 篠山 隆司, 南 康博
    (一社)日本癌学会, Sep. 2022, 日本癌学会総会記事, 81回, P - 2118, English

  • グリオーマの悪性化におけるRor2-Nrf2シグナル伝達系の重要な役割(Critical role of Ror2-Nrf2 signaling axis in regulating malignant progression of gliomas)
    遠藤 光晴, 長嶋 宏明, 田中 一寛, 篠山 隆司, 南 康博
    (一社)日本癌学会, Sep. 2022, 日本癌学会総会記事, 81回, P - 2047, English

  • Ror2による骨格筋間葉系前駆細胞の機能制御機構
    紙崎 孝基, 勝川 美都子, 上住 聡芳, 深田 宗一朗, 遠藤 光晴, 南 康博
    (一社)日本筋学会, Aug. 2022, 日本筋学会学術集会プログラム・抄録集, 8回, 86 - 86, Japanese

  • Takeshi Saji, Michiru Nishita, Kazuho Ikeda, Mitsuharu Endo, Yasushi Okada, Yasuhiro Minami
    Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices and driving cell migration in complex 3D environments. Previous studies have indicated that microtubules (MTs) play a crucial role in elongation of invadopodia, but not their formation, probably by regulating delivery of membrane and secretory proteins within invadopodia. However, the identity of the responsible MT-based molecular motors and their regulation has been elusive. Here, we show that KIF1C, a member of kinesin-3 family, is localized to the tips of invadopodia and is required for their elongation and the invasion of cancer cells. We also found that c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, thereby enhancing its association with tyrosine phosphatase PTPD1, that in turn activates MT-binding ability of KIF1C, probably by relieving the autoinhibitory interaction between its motor and stalk domains. These findings shed new insights into how c-Src signaling is coupled to the MT-dependent dynamic nature of invadopodia and also advance our understanding of the mechanism of KIF1C activation through release of its autoinhibition.
    Elsevier BV, May 2022, Journal of Biological Chemistry, 298(7) (7), 102090 - 102090, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Daiki Okamoto, Natsuko Yamauchi, Gosuke Takiguchi, Michiru Nishita, Yoshihiro Kakeji, Yasuhiro Minami, Koki Kamizaki
    Accumulating evidence demonstrates that bone marrow (BM)-derived mesenchymal stem cells (MSCs) play critical roles in regulating progression of various types of cancer. We have previously shown that Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, and that CXCL16 secreted from MSCs then binds to its cognate receptor CXCR6 on the surface of an undifferentiated gastric cancer cell line MKN45 cells, eventually leading to proliferation and migration of MKN45 cells. However, it remains unclear about a possible involvement of another (other) cytokine(s) in regulating progression of gastric cancer. Here, we show that CXCL16-CXCR6 signaling is also activated in MSCs through cell-autonomous machinery, leading to upregulated expression of CCL5. We further show that CCR1 and CCR3, receptors of CCL5, are expressed on the surface of MKN45 cells, and that CCL5 secreted from MSCs promotes migration of MKN45 cells presumably via its binding to CCR1/CCR3. These data indicate that cell-autonomous CXCL16-CXCR6 signaling activated in MSCs upregulates expression of CCL5, and that subsequent activation of CCL5-CCR1/3 signaling in MKN45 cells through intercellular machinery can promote migration of MKN45 cells. Collectively, these findings postulate the presence of orchestrated chemokine signaling emanated from MSCs to regulate progression of undifferentiated gastric cancer cells.
    Corresponding, Wiley, May 2022, Genes to Cells, 27(5) (5), 368 - 375, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Mitsuharu Endo, Koki Kamizaki, Yasuhiro Minami
    Last, Apr. 2022, Frontiers in Cell and Developmental Biology, 10(1) (1), 27 - 38, English
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Naoya Murao, Norihide Yokoi, Harumi Takahashi, Tomohide Hayami, Yasuhiro Minami, Susumu Seino
    Elsevier BV, Jan. 2022, Molecular Metabolism, 55, 101414 - 101414, English
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Dai Sonoda, Koki Kamizaki, Yukiko Matsuo, Kana Aruga, Masashi Mikubo, Keishi Yamashita, Michiru Nishita, Yasuhiro Minami, Yukitoshi Satoh
    Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring‑like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU‑Lu‑MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU‑Lu‑MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription‑quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU‑Lu‑MPPt3 CS and AD cells, respectively. Following KU‑Lu‑MPPt3 CS cell plating onto collagen‑coated culture dishes, some cells exhibited a transformation of their morphology into KU‑Lu‑MPPt3 AD‑like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU‑Lu‑MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU‑Lu‑MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU‑Lu‑MPPt3 cells.
    Spandidos Publications, Nov. 2021, Oncology Reports, 47(1) (1), English, International magazine
    [Refereed]
    Scientific journal

  • グリア細胞の機能制御と神経炎症病態 bFGFによる反応性アストロサイトの機能変換機構と神経炎症制御における役割
    遠藤 光晴, 田中 祐紀, 鈴木 逸太, 南 康博
    (公社)日本生化学会, Nov. 2021, 日本生化学会大会プログラム・講演要旨集, 94回, [3S10a - 05], Japanese

  • グリオブラストーマ幹細胞におけるRor1受容体の発現・機能制御機構の解析
    石川 智弘, 小倉 安加, 篠山 隆司, 遠藤 光晴, 南 康博
    (公社)日本生化学会, Nov. 2021, 日本生化学会大会プログラム・講演要旨集, 94回, [P - 755], Japanese

  • Mellissa C. Alcantara, Kentaro Suzuki, Alvin R. Acebedo, Yuki Sakamoto, Michiru Nishita, Yasuhiro Minami, Akira Kikuchi, Gen Yamada
    External genitalia development in mice involves multiple developmental processes under the regulation of various signaling pathways. Wnt5a, one of the major Wnt ligands, is a crucial developmental regulator of outgrowing organs such as the limb, the mandible, and the external genitalia. Defects in Wnt5a signaling have been linked to Robinow syndrome, a genetic disorder in which male patients manifest a micropenis and defective urethral tube formation. Whereas Wnt5a is required for cell proliferation during embryonic external genitalia outgrowth, its role for urethral tube formation has yet to be understood. Here, we show that Wnt5a contributes to urethral tube formation as well as external genitalia outgrowth. Wnt5a is expressed in the embryonic external genitalia mesenchyme, and mesenchymal-specific conditional Wnt5a knockout mice resulted in hypospadias-like urethral defects. Early deletion of Wnt5a at E10.5 showed severe defects in both external genitalia outgrowth and urethral tube formation, along with reduced cell proliferation. The severe urethral tube defect persisted during later timing deletion of Wnt5a (E13.5). Further analyses revealed that loss of Wnt5a disrupted cell polarity and led to a reduction of the phosphorylated myosin light chain and the focal adhesion protein, vinculin. Altogether, these results suggest that Wnt5a coordinates cell proliferation and directed cell migration in a stage-dependent manner during male external genitalia development. Furthermore, Wnt5a may regulate cell polarity, focal adhesion formation, and cell contractility, leading to directed cell migration during male-type urethral formation in a manner that has not been reported in other organ fusion events.
    Wiley, Nov. 2021, Congenital Anomalies, 61(6) (6), 212 - 219, English, International magazine
    [Refereed]
    Scientific journal

  • Mehmet Ozgur Avincsal, Koki Kamizaki, Naoe Jimbo, Hirotaka Shinomiya, Ken-Ichi Nibu, Michiru Nishita, Yasuhiro Minami
    Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV‑negative and HPV‑positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV‑negative and HPV‑positive OPSCC tissues. We then confirmed that HPV‑positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV‑negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G1/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV‑positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV‑related cancers.
    Jul. 2021, Oncology reports, 46(1) (1), English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Hiroshi Nishida, Morihiro Okada, Lynna Yang, Tomomi Takano, Sho Tabata, Tomoyoshi Soga, Diana M Ho, Jongkyeong Chung, Yasuhiro Minami, Sa Kan Yoo
    Oncogenes often promote cell death as well as proliferation. How oncogenes drive these diametrically opposed phenomena remains to be solved. A key question is whether cell death occurs as a response to aberrant proliferation signals or through a proliferation-independent mechanism. Here, we reveal that Src, the first identified oncogene, simultaneously drives cell proliferation and death in an obligatorily coupled manner through parallel MAPK pathways. The two MAPK pathways diverge from a lynchpin protein Slpr. A MAPK p38 drives proliferation whereas another MAPK JNK drives apoptosis independently of proliferation signals. Src-p38-induced proliferation is regulated by methionine-mediated Tor signaling. Reduction of dietary methionine uncouples the obligatory coupling of cell proliferation and death, suppressing tumorigenesis and tumor-induced lethality. Our findings provide an insight into how cells evolved to have a fail-safe mechanism that thwarts tumorigenesis by the oncogene Src. We also exemplify a diet-based approach to circumvent oncogenesis by exploiting the fail-safe mechanism.
    eLife Sciences Publications, Ltd, Apr. 2021, eLife, 10, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Koki Kamizaki, Mitsuharu Endo, Yasuhiro Minami, Yasuhiro Kobayashi
    The Ror-family receptor tyrosine kinases (RTKs), consisting of Ror1 and Ror2, play crucial roles in morphogenesis and formation of various tissues/organs, including the bones and skeletal muscles, the so-called musculoskeletal system, during embryonic development, by acting as receptors or coreceptors for a noncanonical Wnt protein Wnt5a. Furthermore, several lines of evidence have indicated that Ror1 and/or Ror2 play critical roles in the regeneration and maintenance of the musculoskeletal system in adults. Considering the anatomical and functional relationship between the skeleton and skeletal muscles, their structural and functional association might be tightly regulated during their embryonic development, development after birth, and their regeneration after injury in adults. Importantly, in addition to their congenital anomalies, much attention has been paid onto the age-related disorders of the musculoskeletal system, including osteopenia and sarcopenia, which affect severely the quality of life. In this article, we overview recent advances in our understanding of the roles of Ror1- and/or Ror2-mediated signaling in the embryonic development, regeneration in adults, and congenital and age-related disorders of the musculoskeletal system and discuss possible therapeutic approaches to locomotive syndromes by modulating Ror1- and/or Ror2-mediated signaling.
    Corresponding, Jan. 2021, Developmental dynamics : an official publication of the American Association of Anatomists, 250(1) (1), 27 - 38, English, International magazine
    [Refereed]
    Scientific journal

  • Okechi S Oduori, Naoya Murao, Kenju Shimomura, Harumi Takahashi, Quan Zhang, Haiqiang Dou, Shihomi Sakai, Kohtaro Minami, Belen Chanclon, Claudia Guida, Lakshmi Kothegala, Johan Tolö, Yuko Maejima, Norihide Yokoi, Yasuhiro Minami, Takashi Miki, Patrik Rorsman, Susumu Seino
    By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (KATP) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell-specific Kcnj11-/- mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.
    Dec. 2020, The Journal of clinical investigation, 130(12) (12), 6639 - 6655, English, International magazine, Co-authored internationally
    Scientific journal

  • Misuzu Hashimoto, Ayako Kumabe, Jun-Dal Kim, Kazuya Murata, Sowmya Sekizar, Anna Williams, Weizhe Lu, Junji Ishida, Tsutomu Nakagawa, Mitsuharu Endo, Yasuhiro Minami, Akiyoshi Fukamizu
    PRMT1, a major arginine methyltransferase, plays critical roles in transcription, DNA damage response, and cell proliferation. Although we have previously discovered the crucial roles of PRMT1 for oligodendrocyte lineage progression in the central nervous system of neural stem cell-specific PRMT1 conditional knockout (PRMT1-CKO) mice, the context of other glial cell states that may cause the hypomyelination phenotype in PRMT1-CKO mice has not been explored so far. Here, we performed RNA-seq of the neonatal cortices of PRMT1-CKO mice to reveal overall gene expression changes and show the up-regulation of inflammatory signaling which is generally mediated by astrocytes and microglia in advance of the myelination defects. In particular, qRT-PCR analyses revealed Interleukin-6 (Il-6), a major central nervous system cytokine, was dramatically increased in the PRMT1-CKO brains. The gene expression changes led to augmentation of glial fibrillary acidic protein and Vimentin protein levels in PRMT1-CKO mice, showing severe reactive astrogliosis after birth. We further show that IBA1-positive and CD68-positive activated microglia were increased in PRMT1-CKO mice, in spite of intact Prmt1 gene expression in purified microglia from the mutant mice. Our results indicate that PRMT1 loss in the neural stem cell lineage causes disruptive changes in all glial types perturbing postnatal brain development and myelination.
    Aug. 2020, Journal of neurochemistry, English, International magazine, Co-authored internationally
    Scientific journal

  • Tomoaki Nagai, Tomohiro Ishikawa, Yasuhiro Minami, Michiru Nishita
    Much attention has been paid on the mechanism of cancer invasion from the viewpoint of the behaviour of individual cancer cells. On the other hand, histopathological analyses of specimens from cancer patients and of cancer invasion model animals have revealed that cancer cells often exhibit collective invasion, characterized by sustained cell-to-cell adhesion and polarized invasion as cell clusters. Interestingly, it has recently become evident that during collective invasion of cancer cells, the cells localized at invasion front (leader cells) and the cells following them (follower cells) exhibit distinct cellular characteristics, and that there exist the cells expressing representative proteins related to both epithelial and mesenchymal properties simultaneously, designated as hybrid epithelial-to-mesenchymal transition (EMT)-induced cells, in cancer tissue. Furthermore, the findings that cells adopted in hybrid EMT state form clusters and show collective invasion in vitro emphasize an importance of hybrid EMT-induced cells in collective cancer invasion. In this article, we overview recent findings of the mechanism underlying collective invasion of cancer cells and discuss the possibility of controlling cancer invasion and metastasis by targeting this process.
    Corresponding, Apr. 2020, Journal of biochemistry, 167(4) (4), 347 - 355, English, International magazine
    [Refereed]
    Scientific journal

  • Taro Ikeda, Michiru Nishita, Kyoka Hoshi, Takashi Honda, Yoshihiro Kakeji, Yasuhiro Minami
    Bone marrow-derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a-Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co-cultured MKN45 gastric cancer cells via the CXCL16-CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co-cultured MKN45 cells. We also show that MSC-derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co-injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti-CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co-injected with MSC. These results suggest that CXCL16 produced through Ror2-mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6-STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.
    Apr. 2020, Cancer science, 111(4) (4), 1254 - 1265, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Mitsuharu Endo, Yuki Tanaka, Mako Otsuka, Yasuhiro Minami
    Ror2 signaling has been shown to regulate the cell cycle progression in normal and cancer cells. However, the molecular mechanism of the cell cycle progression upon activation of Ror2 signaling still remains unknown. Here, we found that the expression levels of Ror2 in G1-arrested NIH/3T3 fibroblasts are low and are rapidly increased following the cell cycle progression induced by basic fibroblast growth factor (bFGF) stimulation. By expressing wild-type or a dominant negative mutant of E2F1, we show that E2F1 mediates bFGF-induced expression of Ror2, and that E2F1 binds to the promoter of the Ror2 gene to activate its expression. We also found that G1/S phase transition of bFGF-stimulated NIH/3T3 cells is delayed by the suppressed expression of Ror2. RNA-seq analysis revealed that the suppressed expression of Ror2 results in the decreased expression of various E2F target genes concomitantly with increased expression of Forkhead box O (FoxO) target genes, including p21Cip1 , and p27Kip1 . Moreover, the inhibitory effect of Ror2 knockdown on the cell cycle progression can be restored by suppressed expression of p21Cip1 , p27Kip1 ,or FoxO3a. Collectively, these findings indicate that E2F1-Ror2 signaling mediates the transcriptional activation and inhibition of E2F1-driven and FoxO3a-driven cell cycle-regulated genes, respectively, thereby promoting G1/S phase transition of bFGF-stimulated NIH/3T3 cells.
    Feb. 2020, FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(2) (2), 3413 - 3428, English, International magazine
    [Refereed]
    Scientific journal

  • Wenyu Miao, Katsuya Sakai, Hiroki Sato, Ryu Imamura, Nawaphat Jangphattananont, Junichi Takagi, Michiru Nishita, Yasuhiro Minami, Kunio Matsumoto
    Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion-metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain. MET-knockout cells were prepared and reconstituted with WT-MET or V370D-MET. HGF stimulation induced MET dimerization and biological responses in cells reconstituted with WT-MET, but HGF did not induce MET dimerization and failed to induce biological responses in V370D-MET cells. The V370D mutation abrogated HGF-dependent drug resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). Compared with WT-MET cells, V370D-MET cells showed different activation patterns in receptor tyrosine kinases upon exposure to survival/growth-stressed conditions. Surface plasmon resonance analysis indicated that affinity between the extracellular region of V370D-MET and HGF was reduced compared with that for WT-MET. Further analysis of the association between V370D-MET and the separate domains of HGF indicated that the SP domain of HGF was unchanged, but its association with the NK4 domain of HGF was mostly lost in V370D-MET. These results indicate that the V370D mutation in the MET receptor impairs the functional association with HGF and is therefore a loss-of-function mutation. This mutation may change the dependence of cancer cell growth/survival on signaling molecules, which may promote cancer cell characteristics under certain conditions.
    Oct. 2019, Cancer science, 110(10) (10), 3340 - 3349, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 骨格筋組織幹細胞におけるRor1およびRor2の機能解析
    紙崎 孝基, 土井 亮助, 金川 基, 戸田 達史, 上住 聡芳, 深田 宗一朗, 遠藤 光晴, 南 康博
    日本筋学会, Aug. 2019, 日本筋学会学術集会プログラム・抄録集, 5回, 99 - 99, Japanese

  • Tomoaki Aoki, Michiru Nishita, Junya Sonoda, Taro Ikeda, Yoshihiro Kakeji, Yasuhiro Minami
    Collective invasion is an important strategy of cancers of epithelial origin, including colorectal cancer (CRC), to infiltrate efficiently into local tissues as collective cell groups. Within the groups, cells at the invasive front, called leader cells, are highly polarized and motile, thereby providing the migratory traction that guides the follower cells. However, its underlying mechanisms remain unclear. We have previously shown that signaling emanating from the receptor tyrosine kinase Ror2 can promote invasion of human osteosarcoma cells and that intraflagellar transport 20 (IFT20) mediates its signaling to regulate Golgi structure and transport. Herein, we investigated the role of Ror2 and IFT20 in collective invasion of CRC cells, where Ror2 expression is either silenced or nonsilenced. We show by cell biological analyses that IFT20 promotes collective invasion of CRC cells, irrespective of expression and function of Ror2. Intraflagellar transport 20 is required for organization of Golgi-associated, stabilized microtubules, oriented toward the direction of invasion in leader cells. Our results also indicate that IFT20 promotes reorientation of the Golgi apparatus toward the front side of leader cells. Live cell imaging of the microtubule plus-end binding protein EB1 revealed that IFT20 is required for continuous polarized microtubule growth in leader cells. These results indicate that IFT20 plays an important role in collective invasion of CRC cells by regulating organization of Golgi-associated, stabilized microtubules and Golgi polarity in leader cells.
    Apr. 2019, Cancer science, 110(4) (4), 1306 - 1316, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Martina Weissenböck, Richard Latham, Michiru Nishita, Lena Ingeborg Wolff, Hsin-Yi Henry Ho, Yasuhiro Minami, Christine Hartmann
    Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2-/- mutant mice. In contrast, Ror1-/- mutant mice are viable and show no limb phenotype. Ror1-/- ;Ror2-/- double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1hyp ) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a-/- single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2-/- mutants. Ror2-/- ;Wnt9a-/- double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1hyp/hyp ;Wnt9a-/- double mutants. In addition, Ror1hyp/hyp ;Wnt9a-/- double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.
    Apr. 2019, Genes to cells : devoted to molecular & cellular mechanisms, 24(4) (4), 307 - 317, English, International magazine
    [Refereed]
    Scientific journal

  • IFT20は微小管ダイナミックスを制御することで大腸癌細胞の浸潤能亢進に寄与する(IFT20 promotes invasiveness of colorectal cancer cells by regulating microtubule dynamics)
    青木 丈明, 西田 満, 掛地 吉弘, 南 康博
    (一社)日本癌学会, Sep. 2018, 日本癌学会総会記事, 77回, 1333 - 1333, English

  • Keishi Kishimoto, Masaru Tamura, Michiru Nishita, Yasuhiro Minami, Akira Yamaoka, Takaya Abe, Mayo Shigeta, Mitsuru Morimoto
    Tube morphogenesis is essential for internal-organ development, yet the mechanisms regulating tube shape remain unknown. Here, we show that different mechanisms regulate the length and diameter of the murine trachea. First, we found that trachea development progresses via sequential elongation and expansion processes. This starts with a synchronized radial polarization of smooth muscle (SM) progenitor cells with inward Golgi-apparatus displacement regulates tube elongation, controlled by mesenchymal Wnt5a-Ror2 signaling. This radial polarization directs SM progenitor cell migration toward the epithelium, and the resulting subepithelial morphogenesis supports tube elongation to the anteroposterior axis. This radial polarization also regulates esophageal elongation. Subsequently, cartilage development helps expand the tube diameter, which drives epithelial-cell reshaping to determine the optimal lumen shape for efficient respiration. These findings suggest a strategy in which straight-organ tubulogenesis is driven by subepithelial cell polarization and ring cartilage development.
    Jul. 2018, Nature communications, 9(1) (1), 2816 - 2816, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Takeshi Saji, Michiru Nishita, Hiroyuki Ogawa, Takefumi Doi, Yasuhiro Sakai, Yoshimasa Maniwa, Yasuhiro Minami
    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis and closely related to exposure to asbestos. MPM is a heterogeneous tumor with three main histological subtypes, epithelioid, sarcomatoid, and biphasic types, among which sarcomatoid type shows the poorest prognosis. The Ror-family of receptor tyrosine kinases, Ror1 and Ror2, is expressed in various types of tumor cells at higher levels and affects their aggressiveness. However, it is currently unknown whether they are expressed in and involved in aggressiveness of MPM. Here, we show that Ror1 and Ror2 are expressed in clinical specimens and cell lines of MPM with different histological features. Studies using MPM cell lines indicate that expression of Ror2 is associated tightly with high invasiveness of MPM cells, whereas Ror1 can contribute to their invasion in the absence of Ror2. However, both Ror1 and Ror2 promote proliferation of MPM cells. We also show that promoted invasion and proliferation of MPM cells by Ror signaling can be mediated by the Rho-family of small GTPases, Rac1, and Cdc42. These findings elucidate the critical role of Ror signaling in promoting invasion and proliferation of MPM cells.
    Jul. 2018, Genes to cells : devoted to molecular & cellular mechanisms, 23(7) (7), 606 - 613, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Atsushi Sudo, Motoi Kanagawa, Mai Kondo, Chiyomi Ito, Kazuhiro Kobayashi, Mitsuharu Endo, Yasuhiro Minami, Atsu Aiba, Tatsushi Toda
    Congenital muscular dystrophies (CMDs) are characterized by progressive weakness and degeneration of skeletal muscle. In several forms of CMD, abnormal glycosylation of α-dystroglycan (α-DG) results in conditions collectively known as dystroglycanopathies, which are associated with central nervous system involvement. We recently demonstrated that fukutin, the gene responsible for Fukuyama congenital muscular dystrophy, encodes the ribitol-phosphate transferase essential for dystroglycan function. Brain pathology in patients with dystroglycanopathy typically includes cobblestone lissencephaly, mental retardation, and refractory epilepsy; however, some patients exhibit average intelligence, with few or almost no structural defects. Currently, there is no effective treatment for dystroglycanopathy, and the mechanisms underlying the generation of this broad clinical spectrum remain unknown. Here, we analysed four distinct mouse models of dystroglycanopathy: two brain-selective fukutin conditional knockout strains (neuronal stem cell-selective Nestin-fukutin-cKO and forebrain-selective Emx1-fukutin-cKO), a FukutinHp strain with the founder retrotransposal insertion in the fukutin gene, and a spontaneous Large-mutant Largemyd strain. These models exhibit variations in the severity of brain pathology, replicating the clinical heterogeneity of dystroglycanopathy. Immunofluorescence analysis of the developing cortex suggested that residual glycosylation of α-DG at embryonic day 13.5 (E13.5), when cortical dysplasia is not yet apparent, may contribute to subsequent phenotypic heterogeneity. Surprisingly, delivery of fukutin or Large into the brains of mice at E12.5 prevented severe brain malformation in Emx1-fukutin-cKO and Largemyd/myd mice, respectively. These findings indicate that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain development and modulation of glycosylation during the fetal stage could be a potential therapeutic strategy for dystroglycanopathy.
    Apr. 2018, Human molecular genetics, 27(7) (7), 1174 - 1185, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Daiki Takahashi, Hiroaki Suzuki, Yasumasa Kakei, Kimi Yamakoshi, Yasuhiro Minami, Takahide Komori, Michiru Nishita
    The submandibular gland (SMG) is one of the major salivary glands that play important roles for variety of physiological functions, such as digestion of foods, prevention of infection, and lubrication of the mouth. Dysfunction of the SMG, often associated with a salivary inflammation, adversely influences a person's quality of life. However, the mechanism underlying inflammation-driven dysfunction of the SMG is largely unknown. Here, we used a mouse model in which the main excretory duct of the SMG is ligated unilaterally to induce inflammation of the gland and examined the expression of Wnt5a, Ror1 and Ror2 genes, encoding Wnt5a ligand and its cognate receptors, which have been implicated in tissue damage or inflammatory responses in variety of tissues. We show that expression levels of Ror1, Ror2, and Wnt5a are increased in the ligated SMG undergoing interstitial fibrosis, which is accompanied by robust expression of fibrosis-associated genes, such as TGF-β1, TNF-α, IL-1β, and MMP-2. Increased immunostaining signal of Ror2 was detected in the fibrotic tissues with abundant accumulation of fibroblasts and collagen fibers in the ligated SMG, suggesting that Ror2-mediated signaling might be activated in response to tissue damage and associated with progression of fibrosis in the SMG.Key words: submandibular gland, Ror2, Wnt5a, fibrosis, inflammation.
    Dec. 2017, Cell structure and function, 42(2) (2), 159 - 167, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • がん細胞浸潤突起の伸長・成熟におけるKIF1Cの機能
    佐事 武, 西田 満, 岡田 康志, 南 康博
    生命科学系学会合同年次大会運営事務局, Dec. 2017, 生命科学系学会合同年次大会, 2017年度, [1P - 0371], Japanese
    [Refereed]

  • Koki Kamizaki, Ryosuke Doi, Makoto Hayashi, Takeshi Saji, Motoi Kanagawa, Tatsushi Toda, So-Ichiro Fukada, Hsin-Yi Henry Ho, Michael Eldon Greenberg, Mitsuharu Endo, Yasuhiro Minami
    Sep. 2017, The Journal of biological chemistry, 292(38) (38), 15939 - 15951, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • グリア細胞の機能と細胞内情報伝達 脳の損傷修復における増殖性アストロサイトの役割
    遠藤 光晴, 大田 絢斗, 南 康博
    日本組織細胞化学会, Sep. 2017, 日本組織細胞化学会総会・学術集会講演プログラム・予稿集, 58回, 42 - 42, Japanese

  • Shunsuke Uehara, Nobuyuki Udagawa, Hideyuki Mukai, Akihiro Ishihara, Kazuhiro Maeda, Teruhito Yamashita, Kohei Murakami, Michiru Nishita, Takashi Nakamura, Shigeaki Kato, Yasuhiro Minami, Naoyuki Takahashi, Yasuhiro Kobayashi
    Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation. Mice with an osteoclast-specific deficiency in Ror2 (Ror2ΔOcl/ΔOcl) had increased bone mass. Osteoclasts derived from these mice exhibited impaired bone resorption and actin ring formation, defects that were rescued by overexpression of constitutively active RhoA. These osteoclasts also exhibited reduced interaction between c-Src and Pkn3 and reduced c-Src kinase activity. Similar to Ror2ΔOcl/ΔOcl mice, mice with a global deficiency of Pkn3 (Pkn3-/-) had increased bone mass. The proline-rich region and kinase domain of Pkn3 were required to restore the bone-resorbing activity of osteoclasts derived from Pkn3 -/- mice. Thus, Pkn3 promotes bone resorption downstream of Wnt5a-Ror2-Rho signaling, and this pathway may be a therapeutic target for bone diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease.
    Aug. 2017, Science signaling, 10(494) (494), English, International magazine
    [Refereed]
    Scientific journal

  • Wnt5a-Ror2シグナルによる骨吸収活性調節の病態モデルにおける役割
    上原 俊介, 山下 照仁, 中村 貴, 加藤 茂明, 宇田川 信之, 高橋 直之, 小林 泰浩, 西田 満, 南 康博, 向井 秀幸, 菊池 章
    (一社)日本骨代謝学会, Jul. 2017, 日本骨代謝学会学術集会プログラム抄録集, 35回, 158 - 158, Japanese

  • 受容体型チロシンキナーゼRor2による炎症応答制御機構の解析
    遠藤 光晴, 大田 絢斗, 大西 怜子, 南 康博
    (一社)日本細胞生物学会, May 2017, 日本細胞生物学会大会講演要旨集, 69回, 48 - 48, Japanese

  • Kai Kessenbrock, Prestina Smith, Sander Christiaan Steenbeek, Nicholas Pervolarakis, Raj Kumar, Yasuhiro Minami, Andrei Goga, Lindsay Hinck, Zena Werb
    Mar. 2017, Proceedings of the National Academy of Sciences of the United States of America, 114(12) (12), 3121 - 3126, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Michiru Nishita, Seung-Yeol Park, Tadashi Nishio, Koki Kamizaki, ZhiChao Wang, Kota Tamada, Toru Takumi, Ryuju Hashimoto, Hiroki Otani, Gregory J Pazour, Victor W Hsu, Yasuhiro Minami
    Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.
    Jan. 2017, Scientific reports, 7(1) (1), 1 - 1, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Mitsuharu Endo, Guljahan Ubulkasim, Chiho Kobayashi, Reiko Onishi, Atsu Aiba, Yasuhiro Minami
    Jan. 2017, Glia, 65(1) (1), 182 - 197, English, International magazine
    [Refereed]
    Scientific journal

  • Oscar Diaz-Horta, Clemer Abad, Levent Sennaroglu, Joseph Foster 2nd, Alexandra DeSmidt, Guney Bademci, Suna Tokgoz-Yilmaz, Duygu Duman, F Basak Cengiz, M'hamed Grati, Suat Fitoz, Xue Z Liu, Amjad Farooq, Faiqa Imtiaz, Benjamin B Currall, Cynthia Casson Morton, Michiru Nishita, Yasuhiro Minami, Zhongmin Lu, Katherina Walz, Mustafa Tekin
    Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.
    May 2016, Proceedings of the National Academy of Sciences of the United States of America, 113(21) (21), 5993 - 8, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Mouse models for developmental biology: Functional analysis of ror and Wnt signaling
    Isao Oishi, Akinori Yoda, Shuichi Kani, Yasuhiro Minami
    CRC Press, Apr. 2016, Genetically Engineered Mice Handbook, 295 - 302, English
    In book

  • Xiaoyuan Qi, Yuka Okinaka, Michiru Nishita, Yasuhiro Minami
    Spatiotemporally regulated interaction between the metanephric mesenchyme (MM) and Wolffian duct (WD) is essential for the induction of a single ureteric bud (UB). The MM then interacts with the tip of the UB to induce outgrowth and branching of the UB, which in turn promotes growth of the adjacent MM. The Ror family receptor tyrosine kinases, Ror1 and Ror2, have been shown to act as receptors for Wnt5a to mediate noncanonical Wnt signaling. Previous studies have shown that Ror2-mutant mice exhibit ectopic formation of the UB, due to abnormal juxtaposition of the MM to the WD. We show here that both Ror1 and Ror2 are expressed in the mesenchyme between the MM and WD during UB formation. Although Ror1-mutant mice show no apparent defects in UB formation, Ror1;Ror2-double-mutant mice exhibit either defects in UB outgrowth and branching morphogenesis, associated with the loss of the MM from the UB domain, or ectopic formation of the UB. We also show genetic interactions between Ror1 and Wnt5a during UB formation. These findings suggest that Wnt5a-Ror1/Ror2 signaling regulates cooperatively the formation of the MM at the proper position to ensure normal development of the UB.
    Apr. 2016, Genes to cells : devoted to molecular & cellular mechanisms, 21(4) (4), 325 - 34, English, International magazine
    [Refereed]
    Scientific journal

  • Gosuke Takiguchi, Michiru Nishita, Kana Kurita, Yoshihiro Kakeji, Yasuhiro Minami
    Wnt5a-Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell-autonomous manner. However, little is known about its function in cancer-associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a-Ror2 signaling in bone marrow-derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Coculture of a gastric cancer cell line, MKN45, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to coculture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a-Ror2 signaling, and that recombinant chemokine (C-X-C motif) ligand (CXCL)16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect coculture with MSCs. Importantly, we show that MKN45 cells express chemokine (C-X-C motif) receptor (CXCR)6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect coculture with MSCs. These findings indicate that Wnt5a-Ror2 signaling enhances expression of CXCL16 in MSCs and, as a result, enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation.
    Mar. 2016, Cancer science, 107(3) (3), 290 - 7, English, International magazine
    [Refereed]
    Scientific journal

  • 受容体型チロシンキナーゼRor2は静止期のアストロサイトが増殖を再開するために必要である
    遠藤 光晴, 小林 千穂, 疋田 壮舞, Guljahan Ubulkasim, 稲垣 貴彦, 南 康博
    (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [2T23p - 03(2P0118)], Japanese

  • TNFαによって誘導されたRor1は筋芽細胞の増殖を促進する
    紙崎 孝基, 土井 亮助, 加藤 英, 佐事 武, 遠藤 光晴, 金川 基, 戸田 達史, 深田 宗一朗, 林 真琴, 南 康博
    (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [3P0188] - [3P0188], Japanese

  • Wnt5a-Ror2シグナルは繊毛タンパク質IFT20の発現誘導を介してがん細胞の浸潤を制御する
    西田 満, 西尾 忠, 紙崎 孝基, 王 志超, 榎本 真宏, 玉田 紘太, 内匠 透, Hsu Victor W., Pazour Gregory J., 南 康博
    (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [4T16L - 08(3P0029)], Japanese

  • Wnt5a-Ror2シグナルによる腸管炎症の増悪機構の解析
    佐藤 朗, 香山 尚子, 庄嶋 健作, 松本 真司, 小山 浩史, 南 康博, 野島 聡, 森井 英一, 本田 浩章, 竹田 潔, 菊池 章
    (公社)日本生化学会, Dec. 2015, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [1P0170] - [1P0170], English

  • Akira Sato, Hisako Kayama, Kensaku Shojima, Shinji Matsumoto, Hirofumi Koyama, Yasuhiro Minami, Satoshi Nojima, Eiichi Morii, Hiroaki Honda, Kiyoshi Takeda, Akira Kikuchi
    Jun. 2015, Scientific reports, 5, 10536 - 10536, English, International magazine
    [Refereed]
    Scientific journal

  • Mitsuharu Endo, Michiru Nishita, Ryosuke Doi, Makoto Hayashi, Yasuhiro Minami
    Springer International Publishing, Jan. 2015, Receptor Tyrosine Kinases: Family and Subfamilies, 593 - 640, English
    [Refereed]
    In book

  • Wnt5a-Ror2シグナルによる腸管炎症の増悪機構の解析
    佐藤 朗, 香山 尚子, 庄嶋 健作, 松本 真司, 小山 浩史, 南 康博, 野島 聡, 森井 英一, 本田 浩章, 竹田 潔, 菊池 章
    (公社)日本生化学会, Oct. 2014, 日本生化学会大会プログラム・講演要旨集, 87回, [2T09p - 07], English

  • Michiru Nishita, Sen Qiao, Mari Miyamoto, Yuka Okinaka, Makiko Yamada, Ryuju Hashimoto, Kazumoto Iijima, Hiroki Otani, Christine Hartmann, Ryuichi Nishinakamura, Yasuhiro Minami
    Development of the metanephric kidney begins with the induction of a single ureteric bud (UB) on the caudal Wolffian duct (WD) in response to GDNF (glial cell line-derived neurotrophic factor) produced by the adjacent metanephric mesenchyme (MM). Mutual interaction between the UB and MM maintains expression of GDNF in the MM, thereby supporting further outgrowth and branching morphogenesis of the UB, while the MM also grows and aggregates around the branched tips of the UB. Ror2, a member of the Ror family of receptor tyrosine kinases, has been shown to act as a receptor for Wnt5a to mediate noncanonical Wnt signaling. We show that Ror2 is predominantly expressed in the MM during UB induction and that Ror2- and Wnt5a-deficient mice exhibit duplicated ureters and kidneys due to ectopic UB induction. During initial UB formation, these mutant embryos show dysregulated positioning of the MM, resulting in spatiotemporally aberrant interaction between the MM and WD, which provides the WD with inappropriate GDNF signaling. Furthermore, the numbers of proliferating cells in the mutant MM are markedly reduced compared to the wild-type MM. These results indicate an important role of Wnt5a-Ror2 signaling in morphogenesis of the MM to ensure proper epithelial tubular formation of the UB required for kidney development.
    Aug. 2014, Molecular and cellular biology, 34(16) (16), 3096 - 105, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Shunsuke Fukuyo, Kunihiro Yamaoka, Koshiro Sonomoto, Koichi Oshita, Yosuke Okada, Kazuyoshi Saito, Yasuhiro Yoshida, Tamotsu Kanazawa, Yasuhiro Minami, Yoshiya Tanaka
    Oxford University Press, Jul. 2014, Rheumatology (Oxford, England), 53(7) (7), 1282 - 90, English, International magazine
    [Refereed]
    Scientific journal

  • Ryosuke Doi, Mitsuharu Endo, Kimi Yamakoshi, Yuji Yamanashi, Michiru Nishita, So-ichiro Fukada, Yasuhiro Minami
    Activation of Wnt/β-catenin signal in muscle satellite cells (mSCs) of aged mice during myogenic differentiation has been appreciated as an important age-related feature of the skeletal muscles, resulting in impairment of their regenerative ability following muscle injury. However, it remains elusive about molecules involved in this age-related alteration of Wnt/β-catenin signal in myogenic cells. To clarify this issue, we carried out expression analyses of Wnt receptor genes using real-time RT-PCR in mSCs isolated from the skeletal muscles of young and aged mice. Here, we show that expression of Frizzled1 (Fzd1) was detected at high levels in mSCs of aged mice. Higher expression levels of Fzd1 were also detected in mSC-derived myogenic cells from aged mice and associated with activation of Wnt/β-catenin signal during their myogenic differentiation in vitro. We also provide evidence that suppressed expression of Fzd1 in myogenic cells from aged mice results in a significant increase in myogenic differentiation, and its forced expression in those from young mice results in its drastic inhibition. These findings indicate the critical role of Fzd1 in altered myogenic differentiation associated with aging.
    Apr. 2014, Genes to cells : devoted to molecular & cellular mechanisms, 19(4) (4), 287 - 96, English, International magazine
    [Refereed]
    Scientific journal

  • Masanori Okamoto, Nobuyuki Udagawa, Shunsuke Uehara, Kazuhiro Maeda, Teruhito Yamashita, Yuko Nakamichi, Hiroyuki Kato, Naoto Saito, Yasuhiro Minami, Naoyuki Takahashi, Yasuhiro Kobayashi
    Mar. 2014, Scientific reports, 4, 4493 - 4493, English, International magazine
    [Refereed]
    Scientific journal

  • Kiyoshi Mori, Riko Kitazawa, Takeshi Kondo, Michiko Mori, Yasuhiro Hamada, Michiru Nishida, Yasuhiro Minami, Ryuma Haraguchi, Yutaka Takahashi, Sohei Kitazawa
    2014, PloS one, 9(7) (7), e102797, English, International magazine
    [Refereed]
    Scientific journal

  • Xin Li, Kaoru Yamagata, Michiru Nishita, Mitsuharu Endo, Nur Arfian, Yoshiyuki Rikitake, Noriaki Emoto, Ken-Ichi Hirata, Yoshiya Tanaka, Yasuhiro Minami
    Activation of Wnt5a-Ror2 signaling has been shown to be associated with epithelial-to-mesenchymal transition (EMT) of epidermoid carcinoma cells via induction of matrix metalloproteinase-2 (MMP-2). Because EMT has also been implicated in the progression of tissue fibrosis, we examined the possible association of Wnt5a-Ror2 signaling with renal fibrosis. Here, we show that expression of Wnt5a and Ror2 is induced in a damaged mouse kidney after unilateral ureteral obstruction (UUO) treatment. Immunofluorescent analysis showed that Ror2 expression is clearly induced in tubular epithelial cells during renal fibrosis, and these Ror2-expressing cells also express Snail and vimentin, markers of mesenchymal cells, suggesting that Ror2 might be induced in epithelial cells undergoing EMT. We also found that MMP-2 expression is induced at Ror2-positive epithelium adjacent to significantly disrupted tubular basement membrane (TBM). Interestingly, reduced expression of MMP-2 is detected at epithelium in damaged kidneys from Ror2(+/-) mice compared with those from wild-type Ror2(+/+) mice. Importantly, extents of TBM disruption are apparently reduced in damaged kidneys from Ror2(+/-) mice compared with those from wild-type mice. Collectively, these findings indicate that activation of Wnt5a-Ror2 signaling in epithelial cells undergoing EMT may play an important role in disrupting TBM via MMP-2 induction during renal fibrosis.
    Jul. 2013, Genes to cells : devoted to molecular & cellular mechanisms, 18(7) (7), 608 - 19, English, International magazine
    [Refereed]
    Scientific journal

  • 細胞極性制御の破綻と疾患の関連解析
    Minami Yasuhiro
    Dec. 2012, 上原記念生命科学財団研究報告集, 26, 1 - 5, Japanese
    [Refereed]
    Scientific journal

  • Mitsuharu Endo, Ryosuke Doi, Michiru Nishita, Yasuhiro Minami
    The Ror family receptor tyrosine kinases (RTKs), Ror1 and Ror2, have been shown to play crucial roles in developmental morphogenesis by acting as receptors or co-receptors to mediate Wnt5a-induced signaling. Although Ror1, Ror2 and Wnt5a are expressed in the developing brain, little is known about their roles in the neural development. Here we show that Ror1, Ror2 and their ligand Wnt5a are highly expressed in neocortical neural progenitor cells (NPCs). Small interfering RNA (siRNA)-mediated suppression of Ror1, Ror2 or Wnt5a in cultured NPCs isolated from embryonic neocortex results in the reduction of βIII-tubulin-positive neurons that are produced from NPCs possibly through the generation of T-box brain 2 (Tbr2)-positive intermediate progenitors. BrdU-labeling experiments further reveal that the proportion of proliferative and neurogenic NPCs, which are positive for neural progenitor cell marker (Pax6) but negative for glial cell marker (glial fibrillary acidic protein; GFAP), is reduced within a few days in culture following knockdown of these molecules, suggesting that Ror1, Ror2 and Wnt5a regulate neurogenesis through the maintenance of NPCs. Moreover, we show that Dishevelled 2 (Dvl2) is involved in Wnt5a-Ror1 and Wnt5a-Ror2 signaling in NPCs, and that suppressed expression of Dvl2 indeed reduces the proportion of proliferative and neurogenic NPCs. Interestingly, suppressed expression of either Ror1 or Ror2 in NPCs in the developing neocortex results in the precocious differentiation of NPCs into neurons, and their forced expression results in delayed differentiation. Collectively, these results indicate that Wnt5a-Ror1 and Wnt5a-Ror2 signaling pathways play roles in maintaining proliferative and neurogenic NPCs during neurogenesis of the developing neocortex.
    Apr. 2012, Journal of cell science, 125(Pt 8) (Pt 8), 2017 - 29, English, International magazine
    [Refereed]
    Scientific journal

  • Kaoru Yamagata, Xin Li, Shunkichi Ikegaki, Chitose Oneyama, Masato Okada, Michiru Nishita, Yasuhiro Minami
    It has been shown that constitutively active Wnt5a-Ror2 signaling in osteosarcoma cell lines plays crucial roles in induced expression of matrix metalloproteinase-13 (MMP-13), required for their invasiveness; however, it remains largely unclear about the molecular basis of MMP-13 gene induction by Wnt5a-Ror2 signaling. Here we show by reporter assay that the activator protein 1 (AP1) (binding site in the promoter region of MMP-13 gene is primarily responsible for its transcriptional activation by Wnt5a-Ror2 signaling in osteosarcoma cell lines SaOS-2 and U2OS. Chromatin immunoprecipitation assays revealed that c-Jun and ATF2 are crucial transcription factors recruited to the AP1-binding site in the MMP-13 gene promoter during Wnt5a-Ror2 signaling in SaOS-2 cells. Using siRNA-mediated suppression or specific inhibitors, we also show that Dishevelled2 (Dvl2) and c-Jun N-terminal kinase are required for MMP-13 gene induction presumably via phosphorylation of c-Jun and ATF2 during Wnt5a-Ror2 signaling in SaOS-2 cells. Interestingly, Dvl2 and Rac1, but not Dvl3, are required for MMP-13 expression in SaOS-2 cells, whereas Dvl3, but not Dvl2 and Rac1, is required for its expression in U2OS cells, indicating the presence of distinct intracellular signaling machineries leading to expression of the same gene, in this case MMP-13 gene in different osteosarcoma cell lines. Moreover, we provide evidence suggesting that Wnt5a-Ror2 signaling might also be required for expression of MMP-13 gene during the development of the cartilaginous tissue.
    Jan. 2012, The Journal of biological chemistry, 287(2) (2), 1588 - 99, English, International magazine
    [Refereed]
    Scientific journal

  • 前田 和洋, 小林 泰浩, 岡本 正則, 高田 伊知郎, 加藤 茂明, 可児 修一, 西田 満, 南 康博, 宇田川 信之, 丸毛 啓史, 高橋 直之
    (公社)日本整形外科学会, Aug. 2011, 日本整形外科学会雑誌, 85(8) (8), S1054 - S1054, Japanese

  • 細胞増殖・細胞分化・細胞死・幹細胞 新皮質発達過程においてRor-ファミリー受容体チロシンキナーゼは神経前駆細胞の維持を制御する(Cell proliferation/Differentiation/Apoptosis/Stem cells Ror-family receptor tyrosine kinases regulate maintenance of neural progenitor cells in the developing neocortex)
    遠藤 光晴, 西田 満, 南 康博
    (一社)日本細胞生物学会, May 2011, 日本細胞生物学会大会講演要旨集, 63回, 109 - 109, English

  • Sayuri Takahashi, Tomoyuki Watanabe, Maiko Okada, Kazuki Inoue, Takashi Ueda, Ichiro Takada, Tetsuro Watabe, Yoko Yamamoto, Toru Fukuda, Takashi Nakamura, Chihiro Akimoto, Tetsuya Fujimura, Maiko Hoshino, Yuuki Imai, Daniel Metzger, Kohei Miyazono, Yasuhiro Minami, Pierre Chambon, Tadaichi Kitamura, Takahiro Matsumoto, Shigeaki Kato
    Mar. 2011, Proceedings of the National Academy of Sciences of the United States of America, 108(12) (12), 4938 - 43, English, International magazine, Co-authored internationally
    Scientific journal

  • Dayong Ren, Yasuhiro Minami, Michiru Nishita
    Expression of Snail has been shown to mediate epithelial-mesenchymal transition (EMT) of epithelial cells and carcinomas, characterized by morphological alterations with disappearance and appearance of E-cadherin and vimentin, respectively. Here, we show that ectopic expression of Snail in human epidermoid carcinoma A431 cells (Snail/A431) induces the representative EMT, resulting in remarkable motile and invasive properties of the cells. Expression of Wnt5a, its receptor Ror2 and matrix metalloproteinase (MMP)-2 is induced in Snail/A431, but not in control A431 cells. Interestingly, suppressed expression of either Wnt5a or Ror2 in Snail/A431 cells results in the inhibition of in vitro cell motility and invasiveness, at least partly mediated by MMP-2, without affecting characteristics of EMT, i.e., mesenchymal morphology, and down- and up-regulations of E-cadherin and vimentin, respectively. We further show that endogenous Snail is required for sustained expression of Wnt5a, Ror2 and MMP-13 in human osteosarcoma SaOS-2 cells. The results indicate that expression of both Wnt5a and Ror2 is induced during Snail-mediated EMT or malignant progression of cancer cells and that consequently activated Wnt5a-Ror2 signaling confers highly motile and invasive properties on cancer cells. Thus, Wnt5a-Ror2 signaling can be a target of cancer therapies to prevent cancer cells from undergoing invasion and metastasis.
    Mar. 2011, Genes to cells : devoted to molecular & cellular mechanisms, 16(3) (3), 304 - 15, English, International magazine
    Scientific journal

  • Bo Gao, Hai Song, Kevin Bishop, Gene Elliot, Lisa Garrett, Milton A English, Philipp Andre, James Robinson, Raman Sood, Yasuhiro Minami, Aris N Economides, Yingzi Yang
    Feb. 2011, Developmental cell, 20(2) (2), 163 - 76, English, International magazine, Co-authored internationally
    Scientific journal

  • Natalia Lyashenko, Martina Weissenböck, Amnon Sharir, Reinhold G Erben, Yasuhiro Minami, Christine Hartmann
    Aug. 2010, Developmental dynamics : an official publication of the American Association of Anatomists, 239(8) (8), 2266 - 77, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Michiru Nishita, Sumiyo Itsukushima, Akira Nomachi, Mitsuharu Endo, ZhiChao Wang, Daisuke Inaba, Sen Qiao, Shinji Takada, Akira Kikuchi, Yasuhiro Minami
    The receptor tyrosine kinase Ror2 acts as a receptor or coreceptor for Wnt5a to mediate Wnt5a-induced activation of the Wnt/JNK pathway and inhibition of the beta-catenin-dependent canonical Wnt pathway. However, little is known about how Ror2 cooperates with another receptor component(s) to mediate Wnt5a signaling. We show here that Ror2 regulates Wnt5a-induced polymerization of Dishevelled (Dvl) and that this Ror2-mediated regulation of Dvl is independent of the cytoplasmic region of Ror2. Ror2 can associate with Frizzled7 (Fz7) via its extracellular cysteine-rich domain to form a receptor complex that is required for the regulation of Dvl and activation of the AP-1 promoter after Wnt5a stimulation. Suppressed expression of Fz7 indeed results in the inhibition of Wnt5a-induced polymerization of Dvl and AP-1 activation. Interestingly, both the DIX and the DEP domains of Dvl are indispensable for Dvl polymerization and subsequent AP-1 activation after Wnt5a stimulation. We further show that polymerized Dvl is colocalized with Rac1 and that suppressed expression of Rac1 inhibits Wnt5a-induced AP-1 activation. Collectively, our results indicate that Ror2/Fz receptor complex plays an important role in the Wnt5a/Rac1/AP-1 pathway by regulating the polymerization of Dvl.
    Jul. 2010, Molecular and cellular biology, 30(14) (14), 3610 - 9, English, International magazine
    Scientific journal

  • Kentaro Nakagawa, Misato Sugahara, Tokiwa Yamasaki, Hiroaki Kajiho, Shinya Takahashi, Jun Hirayama, Yasuhiro Minami, Yasutaka Ohta, Toshio Watanabe, Yutaka Hata, Toshiaki Katada, Hiroshi Nishina
    Mar. 2010, The Biochemical journal, 427(2) (2), 237 - 45, English, International magazine
    [Refereed]
    Scientific journal

  • Makiko Yamada, Jun Udagawa, Akihiro Matsumoto, Ryuju Hashimoto, Toshihisa Hatta, Michiru Nishita, Yasuhiro Minami, Hiroki Otani
    The receptor tyrosine kinase Ror2 acts as a receptor for Wnt5a to mediate noncanonical Wnt signaling, and it plays essential roles in morphogenesis. Ror2-/- embryos exhibit phenotypes similar to, albeit generally milder than, those of Wnt5a-/- embryos. During mouse embryogenesis, Ror2 is expressed in various organs and regions, although little is known about its expression pattern and roles in the developing gut, while Wnt5a is expressed in the developing gut, where its absence causes abnormal phenotypes. Here, we demonstrated that Ror2 was strongly and differentially expressed in the rostral and middle midgut endoderm from embryonic day (E) 10.5 through embryonic day (E) 12.5. At E11.5, Ror2-/- embryos exhibited a shorter middle midgut with a larger diameter and more accumulation of epithelial cells in the middle midgut than control embryos, while the total cell numbers remained unaltered. These findings suggest that Ror2 plays important roles in midgut elongation by means of an epithelial convergent extension mechanism.
    Mar. 2010, Developmental dynamics : an official publication of the American Association of Anatomists, 239(3) (3), 941 - 53, English, International magazine
    [Refereed]
    Scientific journal

  • Amanda Mikels, Yasuhiro Minami, Roel Nusse
    Oct. 2009, The Journal of biological chemistry, 284(44) (44), 30167 - 76, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • M. Enomoto, S. Hayakawa, S. Itsukushima, D. Y. Ren, M. Matsuo, K. Tamada, C. Oneyama, M. Okada, T. Takumi, M. Nishita, Y. Minami
    Sep. 2009, ONCOGENE, 28(36) (36), 3197 - 3208, English
    [Refereed]
    Scientific journal

  • Masaki Kobayashi, Yasuyuki Shibuya, Junichiro Takeuchi, Maho Murata, Hiroaki Suzuki, Satoshi Yokoo, Masahiro Umeda, Yasuhiro Minami, Takahide Komori
    Mar. 2009, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics, 107(3) (3), 398 - 406, English, International magazine
    [Refereed]
    Scientific journal

  • Fenglei He, Wei Xiong, Xueyan Yu, Ramon Espinoza-Lewis, Chao Liu, Shuping Gu, Michiru Nishita, Kentaro Suzuki, Gen Yamada, Yasuhiro Minami, Yiping Chen
    Tissue and molecular heterogeneities are present in the developing secondary palate along the anteroposterior (AP) axis in mice. Here, we show that Wnt5a and its receptor Ror2 are expressed in a graded manner along the AP axis of the palate. Wnt5a deficiency leads to a complete cleft of the secondary palate, which exhibits distinct phenotypic alterations at histological, cellular and molecular levels in the anterior and posterior regions of the palate. We demonstrate that there is directional cell migration within the developing palate. In the absence of Wnt5a, this directional cell migration does not occur. Genetic studies and in vitro organ culture assays further demonstrate a role for Ror2 in mediating Wnt5a signaling in the regulation of cell proliferation and migration during palate development. Our results reveal distinct regulatory roles for Wnt5a in gene expression and cell proliferation along the AP axis of the developing palate, and an essential role for Wnt5a in the regulation of directional cell migration.
    The Company of Biologists, Dec. 2008, Development (Cambridge, England), 135(23) (23), 3871 - 9, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • 濃度勾配性因子による細胞極性・細胞運動の制御 組織構築、創傷治癒およびがんの浸潤・転移の機構解明を目指して Wnt5a/Ror2シグナルによる細胞運動制御
    Nishita Michiru, Minami Yasuhiro
    Nov. 2008, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集81回・31回, 巻, , pp. 4S14-5, Japanese
    International conference proceedings

  • Wnt5a/Ror2経路はMMP-13を介して骨肉腫細胞のinvadopodia形成と浸潤を制御する
    Nishita Michiru, Minami Yasuhiro
    (公社)日本生化学会, Nov. 2008, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集81回・31回, 巻, , pp. 3T12-6, 3T12 - 6, Japanese
    International conference proceedings

  • Akira Nomachi, Michiru Nishita, Daisuke Inaba, Masahiro Enomoto, Mayumi Hamasaki, Yasuhiro Minami
    The receptor tyrosine kinase Ror2 has recently been shown to act as an alternative receptor or coreceptor for Wnt5a and to mediate Wnt5a-induced migration of cultured cells. However, little is known about the molecular mechanism underlying this migratory process. Here we show by wound-healing assays that Ror2 plays critical roles in Wnt5a-induced cell migration by regulating formation of lamellipodia and reorientation of microtubule-organizing center (MTOC). Wnt5a stimulation induces activation of the c-Jun N-terminal kinase JNK at the wound edge in a Ror2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. We further show that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKCzeta. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKCzeta, to regulate polarized cell migration.
    Oct. 2008, The Journal of biological chemistry, 283(41) (41), 27973 - 27981, English, International magazine
    [Refereed]
    Scientific journal

  • 前田 和洋, 小林 泰浩, 石原 章弘, 成田 伸代, 宇田川 信之, 高田 伊知郎, 加藤 茂明, 西田 満, 南 康博, 丸毛 啓史, 高橋 直之
    (公社)日本整形外科学会, Aug. 2008, 日本整形外科学会雑誌, 82(8) (8), S1094 - S1094, Japanese

  • Akinori Yoda, Kyoko Toyoshima, Yasuhide Watanabe, Nobuyuki Onishi, Yuki Hazaka, Yusuke Tsukuda, Junichi Tsukada, Takeshi Kondo, Yoshiya Tanaka, Yasuhiro Minami
    Jul. 2008, The Journal of biological chemistry, 283(27) (27), 18969 - 79, English, International magazine
    [Refereed]
    Scientific journal

  • Shinji Yamamoto, Osamu Nishimura, Kazuyo Misaki, Michiru Nishita, Yasuhiro Minami, Shigenobu Yonemura, Hiroshi Tarui, Hiroshi Sasaki
    Vertebrate Wnt proteins activate several distinct pathways. Intrinsic differences among Wnt ligands and Frizzled (Fzd) receptors, and the availability of pathway-specific coreceptors, LRP5/6, and Ror2, affect pathway selection. Here, we show that a secreted glycoprotein, Cthrc1, is involved in selective activation of the planar cell polarity (PCP) pathway by Wnt proteins. Although Cthrc1 null mutant mice appeared normal, the introduction of a heterozygous mutation of a PCP gene, Vangl2, resulted in abnormalities characteristic of PCP mutants. In HEK293T cells, Cthrc1 activated the PCP pathway but suppressed the canonical pathway. Cell-surface-anchored Cthrc1 bound to Wnt proteins, Fzd proteins, and Ror2 and enhanced the interaction of Wnt proteins and Fzd/Ror2 by forming the Cthrc1-Wnt-Fzd/Ror2 complex. Consistent with this, Ror2 mutant mice also showed PCP-related abnormalities in the inner ear. These results suggest that Cthrc1 is a Wnt cofactor protein that selectively activates the Wnt/PCP pathway by stabilizing ligand-receptor interaction.
    Jul. 2008, Developmental cell, 15(1) (1), 23 - 36, English, International magazine
    [Refereed]
    Scientific journal

  • Changgong Li, Hongyan Chen, Lingyan Hu, Yiming Xing, Tomoyo Sasaki, Maria F Villosis, John Li, Michiru Nishita, Yasuhiro Minami, Parviz Minoo
    BACKGROUND: Wnt signaling is mediated through 1) the beta-catenin dependent canonical pathway and, 2) the beta-catenin independent pathways. Multiple receptors, including Fzds, Lrps, Ror2 and Ryk, are involved in Wnt signaling. Ror2 is a single-span transmembrane receptor-tyrosine kinase (RTK). The functions of Ror2 in mediating the non-canonical Wnt signaling have been well established. The role of Ror2 in canonical Wnt signaling is not fully understood. RESULTS: Here we report that Ror2 also positively modulates Wnt3a-activated canonical signaling in a lung carcinoma, H441 cell line. This activity of Ror2 is dependent on cooperative interactions with Fzd2 but not Fzd7. In addition, Ror2-mediated enhancement of canonical signaling requires the extracellular CRD, but not the intracellular PRD domain of Ror2. We further provide evidence that the positive effect of Ror2 on canonical Wnt signaling is inhibited by Dkk1 and Krm1 suggesting that Ror2 enhances an Lrp-dependent STF response. CONCLUSION: The current study demonstrates the function of Ror2 in modulating canonical Wnt signaling. These findings support a functional scheme whereby regulation of Wnt signaling is achieved by cooperative functions of multiple mediators.
    Jan. 2008, BMC molecular biology, 9, 11 - 11, English, International magazine, Co-authored internationally
    Scientific journal

  • Fumihiko Mouri, Junichi Tsukada, Takamitsu Mizobe, Takehiro Higashi, Yasuhiro Yoshida, Yasuhiro Minami, Hiroto Izumi, Yoshihiko Kominato, Kimitoshi Kohno, Yoshiya Tanaka
    Jan. 2008, European journal of haematology, 80(1) (1), 10 - 9, English, International magazine
    Scientific journal

  • Takamitsu Mizobe, Junichi Tsukada, Takehiro Higashi, Fumihiko Mouri, Ai Matsuura, Rena Tanikawa, Yasuhiro Minami, Yasuhiro Yoshida, Yoshiya Tanaka
    Dec. 2007, Experimental hematology, 35(12) (12), 1812 - 22, English, International magazine
    Scientific journal

  • Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2.
    Hiroyuki Yamamoto, Sa Kan Yoo, Michiru Nishita, Akira Kikuchi, Yasuhiro Minami
    The receptor tyrosine kinase Ror2 plays important roles in mediating non-canonical Wnt5a signaling by activating the Wnt-JNK pathway and inhibiting the beta-catenin-TCF pathway. It has been shown that Ror2 is phosphorylated and activated by casein kinase Iepsilon when both molecules are over-expressed in cultured cells. However, it remains unknown whether or not Ror2 is phosphorylated upon Wnt5a stimulation. Here we show that Ror2 is phosphorylated on serine/threonine residues upon stimulation of cultured cells, expressing Ror2 endogenously, with Wnt5a, but not Wnt3a. It was found that treatment of cells with glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl and SB216763) or small interfering RNAs (siRNAs) for GSK-3 (mainly GSK-3alpha) can inhibit Wnt5a-induced phosphorylation of Ror2. Immunoprecipitated Ror2 can also be phosphorylated by purified GSK-3alpha or GSK-3betain vitro, and ectopic co-expression of Ror2 and GSK-3 (mainly GSK-3alpha) in cultured cells results in Ror2 phosphorylation, irrespective of Wnt5a, that is sensitive to SB216763. These results indicate that GSK-3 is involved in Wnt5a-induced phosphorylation of Ror2. Moreover, it was found that Wnt5a-induced cell migration can be inhibited by SB216763 or by siRNA-mediated suppression of GSK-3alpha (and GSK-3beta) expression, further emphasizing the role(s) of GSK-3 in Wnt5a-induced signaling.
    Nov. 2007, Genes to cells : devoted to molecular & cellular mechanisms, 12(11) (11), 1215 - 23, English, International magazine
    Scientific journal

  • Shuichi Kani, Emiko Nakayama, Akinori Yoda, Nobuyuki Onishi, Nagako Sougawa, Yuki Hazaka, Tsuyoshi Umeda, Kohsuke Takeda, Hidenori Ichijo, Yasuhiro Hamada, Yasuhiro Minami
    Aug. 2007, Genes to cells : devoted to molecular & cellular mechanisms, 12(8) (8), 919 - 28, English, International magazine
    Scientific journal

  • Koji Taniguchi, Toranoshin Ayada, Kenji Ichiyama, Ri-Ichiro Kohno, Yoshikazu Yonemitsu, Yasuhiro Minami, Akira Kikuchi, Yoshihiko Maehara, Akihiko Yoshimura
    Jan. 2007, Biochemical and biophysical research communications, 352(4) (4), 896 - 902, English, International magazine
    [Refereed]
    Scientific journal

  • Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration.
    Michiru Nishita, Sa Kan Yoo, Akira Nomachi, Shuichi Kani, Nagako Sougawa, Yasutaka Ohta, Shinji Takada, Akira Kikuchi, Yasuhiro Minami
    The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt-JNK pathway and inhibiting the beta-catenin-TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not Wnt3a-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.
    Nov. 2006, The Journal of cell biology, 175(4) (4), 555 - 62, English, International magazine
    Scientific journal

  • Sathyavageeswaran Shreeram, Oleg N Demidov, Weng Kee Hee, Hiroshi Yamaguchi, Nobuyuki Onishi, Calvina Kek, Oleg N Timofeev, Crissy Dudgeon, Albert J Fornace, Carl W Anderson, Yasuhiro Minami, Ettore Appella, Dmitry V Bulavin
    Sep. 2006, Molecular cell, 23(5) (5), 757 - 64, English, International magazine, Co-authored internationally
    Scientific journal

  • Akinori Yoda, Xiao Zhou Xu, Nobuyuki Onishi, Kyoko Toyoshima, Hiroko Fujimoto, Naoko Kato, Isao Oishi, Takeshi Kondo, Yasuhiro Minami
    Aug. 2006, The Journal of biological chemistry, 281(34) (34), 24847 - 62, English, International magazine
    Scientific journal

  • H. Fujimoto, N. Onishi, N. Kato, M. Takekawa, X. Z. Xu, A. Kosugi, T. Kondo, M. Imamura, I. Oishi, A. Yoda, Y. Minami
    Jul. 2006, CELL DEATH AND DIFFERENTIATION, 13(7) (7), 1170 - 1180, English
    [Refereed]
    Scientific journal

  • Sa Kan Yoo, Nobuyuki Onishi, Naoko Kato, Akinori Yoda, Yasuhiro Minami
    Jun. 2006, Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology, 29(3) (3), 136 - 47, Japanese, Domestic magazine
    [Refereed]
    Scientific journal

  • Jun Udagawa, Ryuju Hashimoto, Hiroaki Suzuki, Toshihisa Hatta, Yusuke Sotomaru, Kyoji Hioki, Yukiko Kagohashi, Tatsuji Nomura, Yasuhiro Minami, Hiroki Otani
    Feb. 2006, Endocrinology, 147(2) (2), 647 - 58, English, International magazine
    [Refereed]
    Scientific journal

  • Takehiro Higashi, Junichi Tsukada, Yasuhiro Yoshida, Takamitsu Mizobe, Fumihiko Mouri, Yasuhiro Minami, Hiroaki Morimoto, Yoshiya Tanaka
    Dec. 2005, Genes to cells : devoted to molecular & cellular mechanisms, 10(12) (12), 1153 - 62, English, International magazine
    [Refereed]
    Scientific journal

  • マウス歯胚形成における受容体型チロシンキナーゼRor2の機能解析
    森山健太郎, 可児修一, 鈴木泰明, NISHITA, Michiru, MINAMI, Yasuhiro, KOMORI, Takahide
    Sep. 2005, 日本口腔外科学会雑誌, 51巻, Suppl., pp.190-190, Japanese
    International conference proceedings

  • DNA損傷とアポトーシス研究のがん治療への応用 DNA損傷に伴う細胞周期チェックポイントの作動・解除及びアポトーシスの制御機構とがんの分子標的治療への応用
    MINAMI, Yasuhiro, 大西伸幸, 近藤健, NISHITA, Michiru, YODA, Akinori
    Sep. 2005, 日本癌学会64回総会記事, pp.29-30, Japanese
    International conference proceedings

  • Yoko Sakakida, Yoichi Miyamoto, Emi Nagoshi, Makoto Akashi, Takahiro J Nakamura, Takayoshi Mamine, Megumi Kasahara, Yasuhiro Minami, Yoshihiro Yoneda, Toru Takumi
    Apr. 2005, The Journal of biological chemistry, 280(14) (14), 13272 - 8, English, International magazine
    [Refereed]
    Scientific journal

  • Marei Sammar, Sigmar Stricker, Georg C Schwabe, Christina Sieber, Anke Hartung, Michael Hanke, Isao Oishi, Jens Pohl, Yasuhiro Minami, Walter Sebald, Stefan Mundlos, Petra Knaus
    Dec. 2004, Genes to cells : devoted to molecular & cellular mechanisms, 9(12) (12), 1227 - 38, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Shuichi Kani, Isao Oishi, Hiroyuki Yamamoto, Akinori Yoda, Hiroaki Suzuki, Akira Nomachi, Kengo Iozumi, Michiru Nishita, Akira Kikuchi, Toru Takumi, Yasuhiro Minami
    Ror2, a member of the mammalian Ror family of receptor tyrosine kinases, plays important roles in developmental morphogenesis, although the mechanism underlying activation of Ror2 remains largely elusive. We show that when expressed in mammalian cells, Ror2 associates with casein kinase Iepsilon (CKIepsilon), a crucial regulator of Wnt signaling. This association occurs primarily via the cytoplasmic C-terminal proline-rich domain of Ror2. We also show that Ror2 is phosphorylated by CKIepsilon on serine/threonine residues, in its C-terminal serine/threonine-rich 2 domain, resulting in autophosphorylation of Ror2 on tyrosine residues. Furthermore, it was found that association of Ror2 with CKIepsilon is required for its serine/threonine phosphorylation by CKIepsilon. Site-directed mutagenesis of tyrosine residues in Ror2 reveals that the sites of phosphorylation are contained among the five tyrosine residues in the proline-rich domain but not among the four tyrosine residues in the tyrosine kinase domain. Moreover, we show that in mammalian cells, CKIepsilon-mediated phosphorylation of Ror2 on serine/threonine and tyrosine residues is followed by the tyrosine phosphorylation of G protein-coupled receptor kinase 2, a kinase with a developmental expression pattern that is remarkably similar to that of Ror2. Intriguingly, a mutant of Ror2 lacking five tyrosine residues, including the autophosphorylation sites, fails to tyrosine phosphorylate G protein-coupled receptor kinase 2. This indicates that autophosphorylation of Ror2 is required for full activation of its tyrosine kinase activity. These findings demonstrate a novel role for CKIepsilon in the regulation of Ror2 tyrosine kinase.
    Elsevier BV, Nov. 2004, The Journal of biological chemistry, 279(48) (48), 50102 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • Takeshi Kondo, Masanobu Kobayashi, Junko Tanaka, Akiko Yokoyama, Sachiko Suzuki, Naoko Kato, Masahiro Onozawa, Kohji Chiba, Satoshi Hashino, Masahiro Imamura, Yasuhiro Minami, Naoto Minamino, Masahiro Asaka
    Jun. 2004, The Journal of biological chemistry, 279(26) (26), 27315 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • Georg C Schwabe, Britta Trepczik, Kathrin Süring, Norbert Brieske, Abigail S Tucker, Paul T Sharpe, Yasuhiro Minami, Stefan Mundlos
    Feb. 2004, Developmental dynamics : an official publication of the American Association of Anatomists, 229(2) (2), 400 - 10, English, International magazine
    [Refereed]
    Scientific journal

  • N. Kato, H. Fujimoto, A. Yoda, I. Oishi, N. Matsumura, T. Kondo, J. Tsukada, Y. Tanaka, M. Imamura, Y. Minami
    2004, Cell Death and Differentiation, 11, S153 - S161, English
    [Refereed]
    Scientific journal

  • Kentaro Suzuki, Daniel Bachiller, YiPing P Chen, Mami Kamikawa, Hidenao Ogi, Ryama Haraguchi, Yukiko Ogino, Yasuhiro Minami, Yuji Mishina, Kyung Ahn, E Bryan Crenshaw 3rd, Gen Yamada
    Dec. 2003, Development (Cambridge, England), 130(25) (25), 6209 - 20, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Takeru Matsuda, Hiroaki Suzuki, Isao Oishi, Shuichi Kani, Yoshikazu Kuroda, Takahide Komori, Aya Sasaki, Ken Watanabe, Yasuhiro Minami
    Aug. 2003, The Journal of biological chemistry, 278(31) (31), 29057 - 64, English, International magazine
    [Refereed]
    Scientific journal

  • Isao Oishi, Hiroaki Suzuki, Nobuyuki Onishi, Ritsuko Takada, Shuichi Kani, Bisei Ohkawara, Ikue Koshida, Kentaro Suzuki, General Yamada, Georg C Schwabe, Stefan Mundlos, Hiroshi Shibuya, Shinji Takada, Yasuhiro Minami
    Jul. 2003, Genes to cells : devoted to molecular & cellular mechanisms, 8(7) (7), 645 - 54, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Dongmei Wu, Makoto Tadano, Hironori Edamatsu, Misa Masago-Toda, Yuriko Yamawaki-Kataoka, Toshio Terashima, Akira Mizoguchi, Yasuhiro Minami, Takaya Satoh, Tohru Kataoka
    Apr. 2003, The European journal of neuroscience, 17(8) (8), 1571 - 80, English, International magazine
    [Refereed]
    Scientific journal

  • Akinori Yoda, Isao Oishi, Yasuhiro Minami
    Receptor tyrosine kinases (RTKs) play crucial roles in various developmental processes. Ror-family RTKs are characterized by the intracellular tyrosine kinase domains, highly related to those of the Trk-family RTKs, and by the extracellular Frizzled-like cysteine-rich domains (CRDs) and Kringle domains. Rors are evolutionally conserved among Caenorhabditis elegans, Aplysia, Drosophila melanogaster, Xenopus, mice, and humans. In D. melanogaster and mammals, pairs of structurally related Rors are found, while a single Ror protein is identified in C. elegans or Aplysia. In Aplysia and D. melanogaster, Rors are expressed exclusively in developing nervous systems. On the other hand, rather widespread expression of Rors was observed in C. elegans and mammals. Mutations in Ror of C. elegans cause inappropriate axon outgrowth as well as defects in cell migration and asymmetric cell division. It has also been reported that the nematode Ror possesses kinase-dependent and kinase-independent functions. Mouse Rors, Ror1, and Ror2, are expressed mainly in migrating neural crest cells and mesenchymal cells, and Ror2-deficient mice exhibit skeletal abnormalities and ventricular septal defects in the heart. Although Ror1-deficient mice exhibit no apparent skeletal or cardiac abnormalities, Ror1/Ror2 double mutant mice show markedly enhanced skeletal and cardiac abnormalities compared with Ror2 mutant mice, indicating genetic interaction of Ror1 and Ror2. In humans, mutations within Ror2 have been found in two genetic skeletal disorders, recessive Robinow syndrome and dominant Brachydactyly type B (BDB), further emphasizing critical functions of Ror2 during developmental morphogenesis. In this article, we also discuss the signaling machinery mediated by Ror-family RTKs with a particular emphasis on our recent structure-function analyses of Ror-family RTKs.
    Informa UK Limited, Feb. 2003, Journal of receptor and signal transduction research, 23(1) (1), 1 - 15, English, International magazine
    [Refereed]
    Scientific journal

  • Osamu Yoneda, Toshio Imai, Miyuki Nishimura, Michihiko Miyaji, Tsuneyo Mimori, Toshiro Okazaki, Naochika Domae, Hiroko Fujimoto, Yasuhiro Minami, Takeshi Kono, Eda T Bloom, Hisanori Umehara
    Jan. 2003, European journal of immunology, 33(1) (1), 53 - 8, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • Takeshi Iida, Shinichiro Mine, Hiroko Fujimoto, Koji Suzuki, Yasuhiro Minami, Yoshiya Tanaka
    Feb. 2002, Genes to cells : devoted to molecular & cellular mechanisms, 7(2) (2), 143 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • Kenji Iwai, Isao Oishi, Xiao Zhou Xu, Yasuhiro Minami, Hirohei Yamamura
    Jan. 2002, Biochemical and biophysical research communications, 290(1) (1), 225 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • Hisanori Umehara, Hiroshi Inoue, Jianyong Huang, Takeshi Kono, Yasuhiro Minami, Yoshiya Tanaka, Toshiro Okazaki, Tsuneyo Mimori, Eda T Bloom, Naochika Domae
    Natural killer (NK) cells participate in both innate and adaptive immunity through the prompt secretion of cytokines and ability to lyse virally infected cells or tumor cells. Triggering of NK cells requires aggregation of surface receptors such as CD2 and CD16, and NK cell activity can be augmented in vitro by stimulation with IL-2. In this study, we examined the role of adapter proteins in the increased NK activation following CD2 crosslinking and IL-2 stimulation of NK3.3 cells. NK3.3 cells lysed NK-sensitive K562 cells in a CD2-dependent manner, and IL-2 markedly enhanced lytic activity in a 4h cytotoxic assay. IL-2 also enhanced spontaneous and CD2-mediated granule exocytosis from NK3.3 cells. CD2 crosslinking markedly induced tyrosine phosphorylation of Cbl associated with Grb2 or CrkL, Shc and LAT, compared with IL-2 stimulation. However, costimulation of IL-2 with CD2 crosslinking remarkably enhanced associations of Grb2-Shc and CrkL-Cbl, compared to IL-2 stimulation or CD2 crosslinking alone. In vitro binding studies using GST-fusion proteins revealed that interactions of Grb2-Shc and CrkL-Cbl were mediated through each SH2 domain in tyrosine phosphorylation-dependent manner. Furthermore, CD2 crosslinking, but not IL-2 stimulation, markedly induced tyrosine phosphorylation of LAT. Thus, tyrosine phosphorylation of different adapter proteins and consequent interactions between signaling molecules described here may explain the molecular mechanisms of the additive effects of IL-2 stimulation and CD2 crosslinking on NK cell activation.
    Elsevier BV, Jan. 2002, Molecular immunology, 38(8) (8), 587 - 96, English, International magazine, Co-authored internationally
    [Refereed]
    Scientific journal

  • M Nomi, Oishi, I, S Kani, H Suzuki, T Matsuda, A Yoda, M Kitamura, K Itoh, S Takeuchi, K Takeda, S Akira, M Ikeya, S Takada, Y Minami
    Dec. 2001, MOLECULAR AND CELLULAR BIOLOGY, 21(24) (24), 8329 - 8335, English
    [Refereed]
    Scientific journal

  • Rina-Susilowati, Ahmad Aulia Jusuf, Hiroyuki Sakagami, Satoshi Kikkawa, Hisatake Kondo, Yasuhiro Minami, Toshio Terashima
    Elsevier BV, Aug. 2001, Brain Research, 911(1) (1), 1 - 11, English
    [Refereed]
    Scientific journal

  • T Matsuda, M Nomi, M Ikeya, S Kani, Oishi, I, T Terashima, S Tawada, Y Minami
    Jul. 2001, MECHANISMS OF DEVELOPMENT, 105(1-2) (1-2), 153 - 156, English
    [Refereed]
    Scientific journal

  • Hisanori Umehara, Seiji Goda, Toshio Imai, Yutaka Nagano, Yasuhiro Minami, Yoshiya Tanaka, Toshiro Okazaki, Eda T Bloom, Naochika Domae
    Wiley, Jun. 2001, Immunology & Cell Biology, 79(3) (3), 298 - 302, English
    [Refereed]
    Scientific journal

  • H Fujimoto, Y Tanaka, ZJ Liu, H Yagita, K Okumura, A Kosugi, A Morinobu, H Umehara, H Yamamura, Y Minami
    Apr. 2001, GENES TO CELLS, 6(4) (4), 337 - 343, English
    [Refereed]
    Scientific journal

  • Oishi, I, K Iwai, Y Kagohashi, H Fujimoto, K Kariya, T Kataoka, H Sawa, H Okano, H Otani, H Yamamura, Y Minami
    Feb. 2001, MOLECULAR AND CELLULAR BIOLOGY, 21(4) (4), 1329 - 1335, English
    [Refereed]
    Scientific journal

  • Jian-Yong Huang, Hisanori Umehara, Hiroshi Inoue, Fazal H Tabassam, Toshiro Okazaki, Takeshi Kono, Yasuhiro Minami, Yoshiya Tanaka, Naochika Domae
    Elsevier BV, Dec. 2000, Molecular Immunology, 37(17) (17), 1057 - 1065, English
    [Refereed]
    Scientific journal

  • Y Tanaka, M Nomi, K Fujii, S Hubscher, A Maruo, S Matsumoto, Y Awazu, K Saito, S Eto, Y Minami
    Last, Nov. 2000, ARTHRITIS AND RHEUMATISM, 43(11) (11), 2513 - 2522, English
    [Refereed]
    Scientific journal

  • Y Tanaka, A Maruo, K Fujii, M Nomi, T Nakamura, S Eto, Y Minami
    Last, Oct. 2000, JOURNAL OF BONE AND MINERAL RESEARCH, 15(10) (10), 1912 - 1923, English
    [Refereed]
    Scientific journal

  • Itsuko Ishihara, Yasuhiro Minami, Tomoyuki Nishizaki, Toshiyuki Matsuoka, Hirohei Yamamura
    Elsevier BV, Jan. 2000, Neuroscience Letters, 279(2) (2), 97 - 100, English
    [Refereed]
    Scientific journal

  • S Takeuchi, K Takeda, Oishi, I, M Nomi, M Ikeya, K Itoh, S Tamura, T Ueda, T Hatta, H Otani, T Terashima, S Takada, H Yamamura, S Akira, Y Minami
    Jan. 2000, GENES TO CELLS, 5(1) (1), 71 - 78, English
    [Refereed]
    Scientific journal

  • H-ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells
    Y Tanaka, Y Minami, S Mine, H Hirano, CD Hu, H Fujimoto, K Fujii, K Saito, J Tsukada, Y van Kooyk, CG Figdor, T Kataoka, S Eto
    Dec. 1999, JOURNAL OF IMMUNOLOGY, 163(11) (11), 6209 - 6216, English, Co-authored internationally
    [Refereed]
    Scientific journal

  • Distribution and intracellular localization of a mouse homolog of Ca++/calmodulin-dependent protein kinase Ibeta2 in the nervous system.
    Ueda T, Sakagami H, Abe K, Oishi I, Maruo A, Kondo H, Terashima T, Ichihashi M, Yamamura H, Minami Y
    Nov. 1999, J. Neurochem., 73(5) (5), 2119 - 2129, English
    [Refereed]
    Scientific journal

  • A Maruo, Oishi, I, K Sada, M Nomi, T Kurosaki, Y Minami, H Yamamura
    Sep. 1999, INTERNATIONAL IMMUNOLOGY, 11(9) (9), 1371 - 1380, English
    [Refereed]
    Scientific journal

  • Oishi, I, S Takeuchi, R Hashimoto, A Nagabukuro, T Ueda, ZJ Liu, T Hatta, S Akira, Y Matsuda, H Yamamura, H Otani, Y Minami
    Jan. 1999, GENES TO CELLS, 4(1) (1), 41 - 56, English
    [Refereed]
    Scientific journal

  • A novel role for H-Ras in the regulation of very late antigen-4 integrin and VCAM-1 via c-Myc-dependent and -independent mechanisms
    Zhao-Jun Liu, Yoshiya Tanaka, Hiroko Fujimoto, Shinichiro Mine, Akio Morinobu, Hideo Yagita, Ko Okumura, Isao Oishi, Jun Udagawa, Hirohei Yamamura, Yasuhiro Minami
    1999, Journal of Immunology, 163(9) (9), 4901 - 4908, English
    Scientific journal

  • Functional cooperation of cyclin C and c-Myc in mediating homotypic cell adhesion via very late antigen-4 activation and vascular cell adhesion molecule-1 induction
    Zhao-Jun Liu, Yoshiya Tanaka, Shinichiro Mine, Akio Morinobu, Hideo Yagita, Ko Okumura, Tadatsugu Taniguchi, Hirohei Yamamura, Yasuhiro Minami
    Dec. 1998, Blood, 92(12) (12), 4700 - 4711, English
    [Refereed]
    Scientific journal

  • ZJ Liu, T Ueda, T Miyazaki, N Tanaka, S Mine, Y Tanaka, T Taniguchi, H Yamamura, Y Minami
    Jun. 1998, MOLECULAR AND CELLULAR BIOLOGY, 18(6) (6), 3445 - 3454, English
    [Refereed]
    Scientific journal

  • Oishi, I, S Sugiyama, H Otani, H Yamamura, Y Nishida, Y Minami
    Feb. 1998, MECHANISMS OF DEVELOPMENT, 71(1-2) (1-2), 49 - 63, English
    [Refereed]
    Scientific journal

  • Kiyonao Sada, Yasuhiro Minami, Hirohei Yamamura
    Wiley, Sep. 1997, European Journal of Biochemistry, 248(3) (3), 827 - 833, English
    [Refereed]
    Scientific journal

  • Suofu Qin, Yasuhiro Minami, Tomohiro Kurosaki, Hirohei Yamamura
    Elsevier BV, Jul. 1997, Journal of Biological Chemistry, 272(29) (29), 17994 - 17999, English
    [Refereed]
    Scientific journal

  • Min Chen, Alan Cheng, Yi-Qing Chen, Anka Hymel, Eric P. Hanson, Lida Kimmel, Yasuhiro Minami, Tadatsugu Taniguchi, Paul S. Changelian, John J. O’Shea
    JAK3 is a protein tyrosine kinase that specifically associates with the common γ chain (γ c ), a shared subunit of receptors for interleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or γ c presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3–γ c interaction. Despite the key roles of JAK3 and γ c in lymphocytic development and function, the molecular basis of this interaction remains poorly understood. In this study, we have characterized the regions of JAK3 involved in γ c association. By developing a number of chimeric JAK3–JAK2 constructs, we show that the binding specificity to γ c can be conferred to JAK2 by transferring the N-terminal domains of JAK3. Moreover, those JAK3–JAK2 chimeras capable of binding γ c were also capable of reconstituting IL-2 signaling as measured by inducible phosphorylation of the chimeric JAK3–JAK2 protein, JAK1, the IL-2 receptor β chain, and signal transducer and activator of transcription 5A. Subsequent deletion analyses of JAK3 have identified the N-terminal JH7-6 domains as a minimal region sufficient for γ c association. Furthermore, expression of the mutant containing only the JH7-6 domains effectively competed with full-length JAK3 for binding to γ c . We conclude that the JH7-6 domains of JAK3 are necessary and sufficient for γ c association. These studies offer clues toward a broader understanding of JAK-mediated cytokine signaling and may provide a target for the development of novel therapeutic modalities in immunologically mediated diseases.
    Proceedings of the National Academy of Sciences, Jun. 1997, Proceedings of the National Academy of Sciences, 94(13) (13), 6910 - 6915, English
    [Refereed]
    Scientific journal

  • Oishi, I, S Sugiyama, ZJ Liu, H Yamamura, Y Nishida, Y Minami
    May 1997, JOURNAL OF BIOLOGICAL CHEMISTRY, 272(18) (18), 11916 - 11923, English
    [Refereed]
    Scientific journal

  • Masaaki Adachi, Masaho Ishino, Toshihiko Torigoe, Yasuhiro Minami, Takashi Matozaki, Tadaaki Miyazaki, Tadatsugu Taniguchi, Yuji Hinoda, Kohzoh Imai
    Springer Science and Business Media LLC, Apr. 1997, Oncogene, 14(13) (13), 1629 - 1633, English
    [Refereed]
    Scientific journal

  • N Ueno, Oishi, I, S Sugiyama, Y Nishida, Y Minami, H Yamamura
    Mar. 1997, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 232(1) (1), 126 - 129, English
    [Refereed]
    Scientific journal

  • Suofu Qin, Yasuhiro Minami, Masahiko Hibi, Tomohiro Kurosaki, Hirohei Yamamura
    Elsevier BV, Jan. 1997, Journal of Biological Chemistry, 272(4) (4), 2098 - 2103, English
    [Refereed]
    Scientific journal

  • Interleukin-2 (IL-2) up regulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta chain.
    Adachi M, Sekiya M, Torigoe T, Takayama S, Reed J.C, Miyazaki T, Minami Y, Taniguchi T, Hinoda Y, Imai K
    Dec. 1996, Blood, 88(11) (11), 4118 - 4123, English
    [Refereed]
    Scientific journal

  • [Roles of protein tyrosine kinases in activation, proliferation and apoptosis of immuno-hematopoietic cells].
    Minami Y, Sada K, Oishi I, Yamamura H
    Sep. 1996, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 41(12 Suppl) (12 Suppl), 1666 - 1672
    [Refereed]

  • Modulation of T cell receptor-mediated signaling pathway by thyme shared antigen-1 (TSA-1)/ stem cell antigen-2 (Sca-2).
    Saitoh S, Kosugi A, Noda S, Yamamoto N, Ogata M, Minami Y, Miyake K, Hamaoka T
    Dec. 1995, J. Immunol., 155(12) (12), 5574 - 5581, English
    [Refereed]
    Scientific journal

  • Masaaki Adachi, Toshihiko Torigoe, Masuo Sekiya, Yasuhiro Minami, Tadatsugu Taniguchi, Yuji Hinoda, Akira Yachi, John C. Reed, Kohzoh Imai
    Wiley, Sep. 1995, FEBS Letters, 372(1) (1), 113 - 118, English
    [Refereed]
    Scientific journal

  • Atsuo Kawahara, Yasuhiro Minami, Tadaaki Miyazaki, James N. Ihle, Tadatsugu Taniguchi
    Proceedings of the National Academy of Sciences, Sep. 1995, Proceedings of the National Academy of Sciences of the United States of America, 92(19) (19), 8724 - 8728, English
    [Refereed]
    Scientific journal

  • TADATSUGU TANIGUCHI, TADAAKI MIYAZAKI, YASUHIRO MINAMI, ATSUO KAWAHARA, HODAKA FUJII, YOKO NAKAGAWA, MASANORI HATAKEYAMA, ZHAO-JUN LIU
    Wiley, Sep. 1995, Annals of the New York Academy of Sciences, 766(1 Receptor Acti) (1 Receptor Acti), 235 - 244, English
    [Refereed][Invited]
    Scientific journal

  • M. Asahi, Y. Tanaka, S.F. Qin, M. Tsubokawa, K. Sada, Y. Minami, H. Yamamura
    Elsevier BV, Jul. 1995, Biochemical and Biophysical Research Communications, 212(3) (3), 887 - 893, English
    [Refereed]
    Scientific journal

  • Hodaka Fujii, Yoko Nakagawa, Ulrike Schindler, Atsuo Kawahara, Hisashi Mori, Fabrice Gouilleux, Bernd Groner, James N. Ihle, Yasuhiro Minami, Tadaaki Miyazaki, Adatsugu Taniguchi
    Proceedings of the National Academy of Sciences, Jun. 1995, Proceedings of the National Academy of Sciences of the United States of America, 92(12) (12), 5482 - 5486, English
    [Refereed]
    Scientific journal

  • Tadaaki Miyazaki, Zhao Jun Liu, Atsuo Kawahara, Yasuhiro Minami, Kyoko Yamada, Yoshihide Tsujimoto, Edward L. Barsoumian, Roger M. Perlmutter, Tadatsugu Taniguchi
    Apr. 1995, Cell, 81(2) (2), 223 - 231
    Scientific journal

  • Stimulation of natural killer (NK) cells via leukocyte function-associated antigen (LFA)-1: Possible involvement of LFA-1-associated tyrosine kinase in signal transduction following recognition of NK target cells.
    Sugie K, Minami Y, Kawakami T, Uchida A
    Feb. 1995, J. Immunol., 154(4) (4), 1691 - 1698, English
    [Refereed]
    Scientific journal

  • Yasuhiro Minami, Tadatsugu Taniguchi
    Lead, Elsevier BV, Jan. 1995, Current Opinion in Cell Biology, 7(2) (2), 156 - 162, English
    [Refereed][Invited]
    Scientific journal

  • Yasuhiro Minami, Yoko Nakagawa, Atsuo Kawahara, Tadaski Miyazaki, Kiyonao Sada, Hirohei Yamamura, Tadatsugu Taniguchi
    Lead, Jan. 1995, Immunity, 2(1) (1), 89 - 100
    Scientific journal

  • T MIYAZAKI, A KAWAHARA, H FUJII, Y NAKAGAWA, Y MINAMI, ZJ LIU, OISHI, I, O SILVENNOINEN, BA WITTHUHN, JN IHLE, T TANIGUCHI
    Nov. 1994, SCIENCE, 266(5187) (5187), 1045 - 1047, English, Co-authored internationally
    [Refereed]
    Scientific journal

  • Atsuo Kawahara, Yasuhiro Minami, Tadatsugu Taniguchi
    American Society for Microbiology, Aug. 1994, Molecular and Cellular Biology, 14(8) (8), 5433 - 5440, English
    [Refereed]
    Scientific journal

  • SIGNAL-TRANSDUCTION MEDIATED BY THE RECONSTITUTED IL-2 RECEPTOR - EVIDENCE FOR A CELL-TYPE-SPECIFIC FUNCTION OF IL-2 RECEPTOR BETA-CHAIN
    Y MINAMI, OISHI, I, ZJ LIU, S NAKAGAWA, T MIYAZAKI, T TANIGUCHI
    Lead, Jun. 1994, JOURNAL OF IMMUNOLOGY, 152(12) (12), 5680 - 5690, English
    [Refereed]
    Scientific journal

  • Hisanori Umehara, Yasuhiro Minami, Naochika Domae, Eda T. Bloom
    Oxford University Press (OUP), 1994, International Immunology, 6(7) (7), 1071 - 1080, English
    [Refereed]
    Scientific journal

  • Takeshi Kono, Yasuhiro Minami, Tadatsugu Taniguchi
    Elsevier BV, Oct. 1993, Seminars in Immunology, 5(5) (5), 299 - 307, English
    [Refereed][Invited]
    Scientific journal

  • Naoki Kobayashi, Shigeto Nakagawa, Yasuhiro Minami, Tadatsugu Taniguchi, Takeshi Kono
    Elsevier BV, Aug. 1993, Gene, 130(2) (2), 303 - 304, English
    [Refereed]
    Scientific journal

  • N Kobayashi, T Kono, M Hatakeyama, Y Minami, T Miyazaki, R M Perlmutter, T Taniguchi
    The binding of interleukin 2 (IL-2) to the IL-2 receptor (IL-2R) induces a rapid increase in tyrosine phosphorylation of cellular proteins. In a previous study, we have shown that p56lck (lck), a src-family protein tyrosine kinase (src-PTK), physically and functionally associates with the IL-2R beta chain (IL-2R beta). To further investigate a role of src-PTKs in IL-2 signaling, we analyzed a mouse pro-B-cell line, in which lck is not expressed detectably. We observed that in this cell line, IL-2 induces activation of at least two src-PTKs, p59fyn (fyn) and p53/56lyn (lyn). Interestingly, stimulation of this cell line with IL-3 also induces activation of src-PTKs. The activation of fyn or lyn seems to be selective for stimulation with IL-2 or IL-3 since stimulation with IL-6 fails to activate them. Furthermore, we provide evidence for the physical association of fyn with IL-2R beta. Taken together with previous results, our current study suggests that different src-PTKs, each of which is expressed in a cell-type-specific manner, can participate in the IL-2 signal transduction.
    Proceedings of the National Academy of Sciences, May 1993, Proceedings of the National Academy of Sciences, 90(9) (9), 4201 - 4205, English
    [Refereed]
    Scientific journal

  • T Taniguchi, Y Minami
    Last, Elsevier BV, Apr. 1993, Cell, 73(1) (1), 5 - 8, English
    [Refereed][Invited]
    Scientific journal

  • Y Minami, T Kono, T Miyazaki, T Taniguchi
    Lead, Annual Reviews, Apr. 1993, Annual Review of Immunology, 11(1) (1), 245 - 268, English
    [Refereed][Invited]
    Scientific journal

  • Y. Minami, T. Kono, K. Yamada, N. Kobayashi, A. Kawahara, R.M. Perlmutter, T. Taniguchi
    Lead, Wiley, Feb. 1993, The EMBO Journal, 12(2) (2), 759 - 768, English
    [Refereed]
    Scientific journal

  • H UMEHARA, A TAKASHIMA, Y MINAMI, ET BLOOM
    Jan. 1993, INTERNATIONAL IMMUNOLOGY, 5(1) (1), 19 - 27, English, Co-authored internationally
    [Refereed]
    Scientific journal

  • Y Minami, T Kono, K Yamada, T Taniguchi
    Lead, Elsevier BV, Dec. 1992, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1114(2-3) (2-3), 163 - 177, English
    [Refereed][Invited]
    Scientific journal

  • Association of human lymph node homing receptor (Leu 8) with the TCR/CD3 complex.
    Murakawa Y, Minami Y, Strober W, James S.P
    Mar. 1992, J. Immunol., 148(6) (6), 1771 - 1776, English
    [Refereed]
    Scientific journal

  • Interleukin 2-induced activation of Ras requires two domains of interleukin 2 receptor β subunit, the essential region for growth stimulation and Lck-binding domain
    T. Satoh, Y. Minami, T. Kono, K. Yamada, A. Kawahara, T. Taniguchi, Y. Kaziro
    1992, Journal of Biological Chemistry, 267(35) (35), 25423 - 25427, English
    [Refereed]
    Scientific journal

  • Novel redistribution of an intracellular pool of CD45 accompanies T cell activation.
    Minami y, Stafford F.J, Lippincott-Schwartz J, Yuan L.C, Klausner R.D
    Lead, May 1991, J. Biol. Chem., 266(14) (14), 9222 - 9230, English
    [Refereed]
    Scientific journal

  • P Garcia-Morales, Y Minami, E Luong, R D Klausner, L E Samelson
    Activation of T cells induces rapid tyrosine phosphorylation on the T-cell receptor zeta chain and other substrates. These phosphorylations can be regulated by a number of protein-tyrosine kinases (ATP: protein-tyrosine O-phosphotransferase, EC 2.7.1.112) and protein-tyrosine-phosphatases (protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48). In this study, we demonstrate that phenylarsine oxide can inhibit tyrosine phosphatases while leaving tyrosine kinase function intact. We use this reagent to investigate the effect of tyrosine phosphatase inhibition in a murine T-cell hybridoma. Increasing concentrations of phenylarsine oxide result in an increase in tyrosine phosphate on a number of intracellular substrates in unstimulated T cells, suggesting that a protein-tyrosine kinase is constitutively active in these cells. The effect of phenylarsine oxide on T cells stimulated with an anti-Thy 1 monoclonal antibody is more complex. At low concentrations of drug, there is a synergistic increase in the level of tyrosine phosphate on certain cellular substrates. At higher concentrations, anti-Thy 1-stimulated tyrosine phosphorylation is inhibited. These results indicate that tyrosine phosphorylation in T cells is tightly regulated by tyrosine phosphatases. Partial inhibition of these enzymes results in enhanced substrate phosphorylation. Inhibition of all stimulated tyrosine phosphorylation by high doses of phenylarsine oxide suggests that tyrosine kinase activity is regulated by tyrosine phosphatases.
    Proceedings of the National Academy of Sciences, Dec. 1990, Proceedings of the National Academy of Sciences, 87(23) (23), 9255 - 9259, English
    [Refereed]
    Scientific journal

  • T cell activation induces rapid tyrosine phosphorylation of a limited number of cellular substrates.
    Hsi E.D, Siegel J.N, Minami Y, Luong E. T, Klausner R.D, Samuelson L.E
    Jun. 1989, J. Biol. Chem., 264(18) (18), 10836 - 10842, English
    [Refereed]
    Scientific journal

  • Internalization and cycling of the T cell antigen receptor: role of protein kinase C.
    Minami Y, Samelson, L. E, Klausner, R. D
    Lead, Sep. 1987, J. Biol. Chem., 262(27) (27), 13342 - 13347, English
    [Refereed]
    Scientific journal

  • Y Minami, A M Weissman, L E Samelson, R D Klausner
    The murine T-cell antigen receptor consists of at least seven chains and six different proteins. The two clonotypic chains alpha and beta are glycoproteins of 40-45 kDa present as a disulfide-linked heterodimer. Four clonally invariant chains include delta (a 26-kDa glycoprotein), gamma (a 21-kDa glycoprotein), epsilon (a 25-kDa protein), and zeta (a 16-kDa protein). zeta is found in the complex as a disulfide-linked homodimer. The clonotypic chains and the invariant chains form a noncovalent complex on the cell surface. We have developed antibodies against each of the chains and used them to examine the assembly of the mature complex in the murine antigen-specific T-cell hybridoma 2B4. Pulse-chase studies of metabolically labeled cells demonstrate that many of the chains are synthesized in great excess over the amount assembled into the mature complex. These excess chains, either as free components or as partially assembled complexes, are rapidly degraded. This degradation most likely takes place in the lysosomes. The complete complex is quite stable with a long half-life. A specific hierarchy of partially assembled complexes can be discerned.
    Lead, Proceedings of the National Academy of Sciences, May 1987, Proceedings of the National Academy of Sciences, 84(9) (9), 2688 - 2692, English
    [Refereed]
    Scientific journal

  • Induction of metallothionein synthesis in Menke's and normal lymphoid cells is controlled by the level of intracellular copper.
    Sone T, Yamaoka K, Minami Y, Tsunoo H
    Apr. 1987, J. Biol. Chem., 262, 5878 - 5885, English
    [Refereed]
    Scientific journal

■ MISC
  • Regulatory mechanism of astrocytes fatty acid metabolism by Ror1 signaling
    田中祐紀, 遠藤光晴, 南康博
    2022, 日本分子生物学会年会プログラム・要旨集(Web), 45th

  • Analysis of molecular mechanism producing functional heterogeneity in reactive astrocytes
    田中祐紀, BRETHEAU Floriane, 遠藤光晴, LACROIX Steve, 南康博
    2021, 日本分子生物学会年会プログラム・要旨集(Web), 44th

  • マウス尿道形成過程における新たなWnt5aの機能
    鈴木堅太郎, アルカンタラ メリッサ, アルビン アセベド, 坂本裕樹, 西田満, 南康博, 菊池章, 山田源
    2021, 日本先天異常学会学術集会プログラム・抄録集, 61st (CD-ROM)

  • グリオブラストーマ細胞におけるRor1の発現制御機構
    小倉安加, 石川智弘, 篠山隆司, 遠藤光晴, 南康博
    2020, 日本分子生物学会年会プログラム・要旨集(Web), 43rd

  • 浸潤突起形におけるKIF1Cの機能
    佐事武, 西田満, 西田満, 遠藤光晴, 岡田康志, 岡田康志, 岡田康志, 南康博
    2020, 日本分子生物学会年会プログラム・要旨集(Web), 43rd

  • 【Wntシグナルと骨】非古典的Wntシグナルと細胞応答
    西田 満, 佐事 武, 南 康博
    非古典的Wntシグナルは平面内細胞極性経路やCa2+経路を含む多岐にわたるシグナル伝達系であり,動物の発生における形態形成や組織・器官構築などで重要な役割を担っている。Ror2受容体型チロシンキナーゼはWnt5a受容体として非古典的Wntシグナルを活性化するとともに,古典的Wntシグナルを阻害する機能も担っており,そのシグナル異常は,様々な形態形成異常を引き起こすのみならず,がんの進展などにも関わっている。最近では,Ror2を介した非古典的Wntシグナルが,糸状突起による周辺細胞へのWntの輸送と古典的Wntシグナルの活性化を誘導することも明らかになっている。(著者抄録)
    (株)医薬ジャーナル社, Feb. 2019, Clinical Calcium, 29(3) (3), 291 - 297, Japanese

  • 損傷脳内の反応性アストロサイトにおける受容体型チロシンキナーゼRor2の発現誘導機構とその役割
    田中祐紀, 遠藤光晴, 南康博
    2019, 日本分子生物学会年会プログラム・要旨集(Web), 42nd

  • 骨格筋組織幹細胞におけるRor1およびRor2の機能解析
    紙崎孝基, 土井亮助, 金川基, 戸田達史, 上住聡芳, 深田宗一朗, 遠藤光晴, 南康博
    2019, 日本筋学会学術集会プログラム・抄録集, 5th

  • Mitsuharu Endo, Yasuhiro Minami
    John Wiley and Sons Inc., Jan. 2018, Developmental dynamics : an official publication of the American Association of Anatomists, 247(1) (1), 24 - 32, English, International magazine
    [Refereed]

  • ジストログリカノパチーモデルマウスの中枢神経病態の解析
    首藤 篤史, 金川 基, 近藤 舞, 小林 千浩, 遠藤 光晴, 南 康博, 戸田 達史
    生命科学系学会合同年次大会運営事務局, Dec. 2017, 生命科学系学会合同年次大会, 2017年度, [4LT02 - 1095)], Japanese

  • Michiru Nishita, Tomoko Satake, Yasuhiro Minami, Atsushi Suzuki
    Proper organization of microtubule (MT) arrays is essential for numerous cellular functions, including intracellular transport and cell migration. Although the centrosome generally serves as the primary MT-organizing centre in proliferating animal cells, MTs are also organized at the Golgi apparatus in a wide range of cell types to regulate Golgi ribbon formation that is required for polarized cell migration. Furthermore, differentiated epithelial cells and neurons possess organized non-centrosomal MTs predominantly at the apical cortical regions and the axonal and dendritic neurites, respectively, to establish and maintain their highly polarized morphology. Unlike radial arrays of centrosomal MTs, non-centrosomal MTs are organized into non-radial asymmetric network, which facilitates polarized transport and cell polarization. In this review, we will focus on recent advances in our understanding of the regulatory mechanisms and cellular functions of non-centrosomal MTs.
    01 Jul. 2017, Journal of biochemistry, 162(1) (1), 1 - 10, English, International magazine

  • Rorファミリー受容体型チロシンキナーゼは脳損傷に伴うアストロサイトの応答を制御する
    遠藤光晴, 大田絢斗, 小林千穂, 大西怜子, 南康博
    2016, 日本分子生物学会年会プログラム・要旨集(Web), 39th

  • エピジェネティック機構を介した受容体型チロシンキナーゼRor2の発現誘導によるアストロサイトの細胞周期制御
    遠藤光晴, 小林千穂, グリジャハンオブリカスム, 南康博
    2016, 日本生物学的精神医学会(Web), 38th

  • 【知る・見る・活かす!シグナリング研究2015 シグナル伝達の要素発見から時空間ダイナミクスへ】 (第2章)シグナリングから見た生命現象 その破綻と疾患の理解 Wnt5a-Ror2シグナルによるがんの浸潤制御
    Nishita Michiru, 西尾忠, Minami Yasuhiro
    Jun. 2015, 実験医学, 33(10号) (10号), 1612 - 1616, Japanese
    [Invited]
    Introduction commerce magazine

  • Mitsuharu Endo, Michiru Nishita, Masanori Fujii, Yasuhiro Minami
    2015, INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY, VOL 314, 314, 117 - 148, English, International magazine
    [Refereed]

  • Kaoru Yamagata, Sally Fujiyama, Saya Ito, Takashi Ueda, Takuya Murata, Masanori Naitou, Ken-ichi Takeyama, Yasuhiro Minami, Bert W. O'Malley, Shigeaki Kato
    May 2014, MOLECULAR CELL, 54(3) (3), 536 - 536, English
    Others

  • 尿管芽形成におけるWnt5a-Ror2シグナルの役割
    Nishita Michiru, 喬 森, 宮本 真里, 沖中 由佳, 山田 真紀子, Iijima Kazumoto, 大谷 浩, Hartmann Christine, 西中村 隆一, Minami Yasuhiro
    Apr. 2014, 発達腎研究会誌, 22(1号) (1号), 11 - 14, Japanese
    Introduction scientific journal

  • 受容体型チロシンキナーゼRor1による骨格筋再生制御
    加藤英, 土井亮助, 遠藤光晴, 深田宗一朗, 金川基, 戸田達史, 南康博
    2014, 日本分子生物学会年会プログラム・要旨集(Web), 37th

  • Wnt5a-Ror2シグナルを標的とした創薬によるがん細胞の浸潤突起制御 (平成24年度研究助成金受領報告) -- (メンブレンダイナミクスと創薬)
    南 康博
    東京生化学研究会, 2014, 東京生化学研究会助成研究報告集, 29, 46 - 50, Japanese

  • [Regulation of cellular responses by non-canonical Wnt signaling].
    Michiru Nishita, Mitsuharu Endo, Yasuhiro Minami
    Signal transduction, elicited by Wnt-family of secreted proteins, can be classified intoβ-catenin-dependent canonical Wnt signaling and -independent non-canonical Wnt signaling. Non-canonical Wnt signaling contains planar cell polarity (PCP) pathway and Ca (+ +) pathway, which play central roles in developmental morphogenesis, by regulating cellular functions, including cell polarity and cell migration. In this article, we will overview the molecular basis of non-canonical Wnt signaling, with a particular emphasis on the roles of non-canonical Wnt signaling mediated by Wnt5a and its cognate receptors, Ror-family of receptor tyrosine kinases (Ror1, Ror2) , and will introduce up-to-date information on non-canonical Wnt signaling obtained from recent studies about pathological conditions, including cancer progression and chronic inflammation.
    Jun. 2013, Clinical calcium, 23(6) (6), 809 - 15, Japanese, Domestic magazine

  • Nishita Michiru, Endo Mitsuharu, Minami Yasuhiro
    (株)医薬ジャーナル社, May 2013, Clinical Calcium, 23(6号) (6号), 809 - 815, Japanese
    [Invited]
    Introduction commerce magazine

  • 反応性アストロサイトにおけるRorファミリー受容体型チロシンキナーゼの役割
    遠藤光晴, 加藤英, 疋田壮舞, 南康博
    2013, 日本分子生物学会年会プログラム・要旨集(Web), 36th

  • みなしご受容体からWnt5a受容体となって（せるてく・あらかると）
    南 康博
    Lead, 2013, 細胞工学, 32(4) (4), 419 - 420, Japanese
    [Invited]
    Introduction commerce magazine

  • 【細胞極性の制御】 非古典的Wntシグナルによる極性と幹細胞性維持の制御
    Endo Mitsuharu, Minami Yasuhiro
    Jun. 2012, 生体の科学, 63(3号) (3号), 224 - 228, Japanese
    [Invited]
    Introduction commerce magazine

  • Kazuhiro Maeda, Yasuhiro Kobayashi, Nobuyuki Udagawa, Shunsuke Uehara, Akihiro Ishihara, Toshihide Mizoguchi, Yuichiro Kikuchi, Ichiro Takada, Shigeaki Kato, Shuichi Kani, Michiru Nishita, Keishi Marumo, T. John Martin, Yasuhiro Minami, Naoyuki Takahashi
    Mar. 2012, NATURE MEDICINE, 18(3) (3), 405 - U166, English, International magazine

  • 骨格筋分化・再生モデルを用いたRorシグナルの機能解析
    土井亮助, 遠藤光晴, 南康博
    2012, 日本分子生物学会年会プログラム・要旨集(Web), 35th

  • Mitsuharu Endo, Michiru Nishita, Yasuhiro Minami
    Planar cell polarity (PCP) pathway of Wnt signaling plays a crucial role to establish the polarization of cells during tissue development. Our recent findings using in vitro analyses have revealed that Ror2, a member of the Ror-family receptor tyrosine kinases, acts as a receptor or co-receptor for Wnt5a and plays a crucial role for Wnt5a-induced polarized cell migration through activating PCP pathway. Indeed, analyses of both Wnt5a and Ror2 mutant mice have shown that Wnt5a-Ror2 signaling is involved in establishing the PCP in epithelial tissues in vivo, indicating that in vitro analyses of polarized cell migration and PCP signaling induced by Wnt5a can be useful tools to explore putative regulators involved in Wnt/PCP pathway. Here, we introduce in vitro methods using cultured cells to monitor polarized cell migration and PCP signaling induced by Wnt5a.
    2012, Methods in molecular biology (Clifton, N.J.), 839, 201 - 14, English, International magazine
    [Refereed]

  • 【生体システムとしてのWntシグナル・ネットワーク研究】 Wntシグナルと細胞応答 Wnt5aとRor2によるシグナル伝達と細胞機能制御
    Nishita Michiru, Minami Yasuhiro
    Jun. 2010, 医学のあゆみ, 233巻, 10号, pp. 955-959, Japanese
    Introduction scientific journal

  • Michiru Nishita, Masahiro Enomoto, Kaoru Yamagata, Yasuhiro Minami
    Jun. 2010, TRENDS IN CELL BIOLOGY, 20(6) (6), 346 - 354, English, International magazine
    Book review

  • Yasuhiro Minami, Isao Oishi, Mitsuharu Endo, Michiru Nishita
    The Ror-family receptor tyrosine kinases (RTKs) play crucial roles in the development of various organs and tissues. In mammals, Ror2, a member of the Ror-family RTKs, has been shown to act as a receptor or coreceptor for Wnt5a to mediate noncanonical Wnt signaling. Ror2- and Wnt5a-deficient mice exhibit similar abnormalities during developmental morphogenesis, reflecting their defects in convergent extension movements and planar cell polarity, characteristic features mediated by noncanonical Wnt signaling. Furthermore, mutations within the human Ror2 gene are responsible for the genetic skeletal disorders dominant brachydactyly type B and recessive Robinow syndrome. Accumulating evidence demonstrate that Ror2 mediates noncanonical Wnt5a signaling by inhibiting the beta-catenin-TCF pathway and activating the Wnt/JNK pathway that results in polarized cell migration. In this article, we review recent progress in understanding the roles of noncanonical Wnt5a/Ror2 signaling in developmental morphogenesis and in human diseases, including heritable skeletal disorders and tumor invasion.
    Jan. 2010, Developmental dynamics : an official publication of the American Association of Anatomists, 239(1) (1), 1 - 15, English, International magazine
    [Refereed]

  • K. Maeda, Y. Kobayashi, A. Ishihara, S. Uehara, I. Takada, S. Kato, M. Nishita, Y. Minami, K. Marumo, N. Udagawa, N. Takahashi
    May 2009, BONE, 44, S50 - S50, English
    Summary international conference

  • Wnt5a regulates directional cell migration and cell proliferation via Ror2-mediated noncanonical pathway in mammalian palatogenesis
    Fenglei He, Wei Xiong, Xueyan Yu, Ramon Espinoza-Lewis, Chao Liu, Shuping Gu, MIchiru Nishita, Yasuhiro Minami, Gen Yamada, Kentaro Suzuki, Yiping Chen
    Apr. 2009, FASEB JOURNAL, 23, English
    Summary international conference

  • 【シグナル伝達研究 2008'09 疾患発症の分子メカニズムと実現化する分子標的薬開発】 シグナル伝達研究 因子から現象へ 受容体型チロシンキナーゼRor2によるWntシグナルの制御
    Nishita Michiru, Minami Yasuhiro
    Last, Sep. 2008, 実験医学, 26巻, 15号, pp. 2368-2372(15) (15), 68 - 72, Japanese
    Introduction scientific journal

  • Synergistic transactivation of the sis-inducible element by STAT4/STAT3 heterodimer in cytokine signal cascade.
    Takehiro Higashi, Junichi Tsukada, Takamitsu Mizobe, Fumihiko Mouri, Ai Matsuura, Yasuhiro Minami, Yasuhiro Yoshida, Yoshiya Tanaka
    Nov. 2006, BLOOD, 108(11) (11), 332A - 333A, English
    Summary international conference

  • 【分子メカニズムから解き明かす疾患のサイエンス】 癌 DNA損傷応答システムとその破綻による癌化
    YODA AKINORI, NISHITA MICHIRU, MINAMI YASUHIRO
    Last, Jun. 2006, 実験医学, 24巻, 10号, pp. 1408-1415(10) (10), 28 - 35, Japanese
    Introduction scientific journal

  • DNA損傷応答関連遺伝子の異常と悪性腫瘍・自己免疫疾患との関連について
    YODA AKINORI, MINAMI YASUHIRO
    Last, Jun. 2006, 日本臨床免疫学会会誌, 29巻, 3号, pp. 136-147(3) (3), 136 - 147, Japanese
    Introduction scientific journal

  • 受容体型チロシンキナーゼRor2によるWnt/PCP経路の制御とその細胞運動における役割
    西田満, 野町昭, 可児修一, 菊池章, 南康博
    25 Nov. 2005, 日本分子生物学会年会講演要旨集, 28th, 81, Japanese

  • Ror2-mediated cytoskeletal reorganization by differential regulation of Dishevelled proteins
    Akira Nomachi, Michiru Nishita, Shuichi Kani, Akira Kikuchi, Akinori Yoda, Yasuhiro Minami
    Jun. 2005, CELL STRUCTURE AND FUNCTION, 30, 107 - 107, English
    Summary international conference

  • 細胞周期チェックポイントのオン・オフ機構
    大西伸幸, NISHITA, Michiru, YODA, Akinori, MINAMI, Yasuhiro
    Last, 放射線生物研究会, Jun. 2005, 放射線生物研究, 40巻, 2号, pp.67-81(2) (2), 67 - 81, Japanese
    Introduction scientific journal

  • 細胞周期調節による癌の治療
    加藤 菜穂子, 藤本 浩子, 大西 伸幸, 南 康博
    Last, 2005, 分子標的療法の基礎と臨床, 55 - 65, Japanese
    [Invited]
    Introduction scientific journal

  • Expression of the Chk2 gene is downregulated in Hodgkin's lymphoma cell lines via epigenetic mechanisms.
    N Kato, T Kondo, J Tsukada, Y Tanaka, Y Minami, J Tanaka, M Imamura
    Nov. 2004, BLOOD, 104(11) (11), 126A - 126A, English
    Summary international conference

  • DNA損傷応答におけるチェックポイントとDNA修復のクロストーク機構の解析
    NISHITA, Michiru, YODA, Akinori, 大西伸幸, MINAMI, Yasuhiro
    Last, 放射線生物研究会, Sep. 2004, 放射線生物研究, 39巻, 3号, pp. 244-257(3) (3), 244 - 257, Japanese
    Introduction scientific journal

  • DNA損傷応答におけるWip1による細胞周期チェックポイントの解除機構
    大西伸幸, YODA, Akinori, 武川睦寛, 近藤健, NISHITA, Michiru, MINAMI, Yasuhiro
    Sep. 2004, Cancer Science, 95巻, Suppl., pp. 440-440, Japanese
    Introduction scientific journal

  • WntとRor2によるPCP経路の制御
    YODA, Akinori, 可児 修一, MINAMI, Yasuhiro
    Last, 秀潤社, Jun. 2004, 細胞工学, 23巻, 6, pp. 642-646(6) (6), 642 - 646, Japanese
    Introduction scientific journal

  • Structure-function analyses of protein kinase and phosphatase involved in intranuclear signaling in response to DNA damage
    Nobuyuki Onishi, Hiroko Fujimoto, Naoko Kato, Xiao Zhou Xu, Marika Horiuchi, Mutsuhiro Takekawa, Akinori Yoda, Isao Oishi, Yasuhiro Minami
    May 2004, CELL STRUCTURE AND FUNCTION, 29, 80 - 80, English
    Summary international conference

  • The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase I epsilon
    Shuichi Kani, Isao Oishi, Hiroyuki Yamamoto, Akinori Yoda, Hiroaki Suzuki, Akira Nomachi, Akira Kikuchi, Toru Takumi, Yasuhiro Minami
    May 2004, CELL STRUCTURE AND FUNCTION, 29, 76 - 76, English
    Summary international conference

  • Regulation of outgrowth and apoptosis for the terminal appendage: external genitalia development by concerted actions of BMP signaling (vol 130, pg 6209, 2003)
    K Suzuki, D Bachiller, YP Chen, M Kamikawa, H Ogi, R Haraguchi, Y Ogino, Y Minami, Y Mishina, K Ahn, EB Crenshaw, G Yamada
    Dec. 2003, DEVELOPMENT, 130(26) (26), 6643 - 6643, English
    Others

  • Fractalkine刺激によるNK細胞のIFN-γ産生とその解析
    米田 修, 井上 博, 西村 美由希, 今井 俊夫, 南 康博, 堂前 尚親, 梅原 久範
    (NPO)日本免疫学会, Oct. 2002, 日本免疫学会総会・学術集会記録, 32, 161 - 161, Japanese

  • Yoshiya Tanaka, Shingo Nakayamada, Hiroko Fujimoto, Yosuke Okada, Hisanori Umehara, Tohru Kataoka, Yasuhiro Minami
    Last, Elsevier BV, 14 Jun. 2002, The Journal of biological chemistry, 277(24) (24), 21446 - 52, English, International magazine

  • フラクタルカイン- NK細胞からのIFN-gamma産生を誘導するケモカイン
    米田 修, 南 康博, 堂前 尚親, 梅原 久範
    2002, 臨床免疫, 38(6) (6), 571 - 576, Japanese
    [Invited]
    Introduction commerce magazine

  • 接着分子と細胞動態・細胞特性：リンパ球を中心として
    藤本 浩子, 米田 修, 南 康博, 田中 良哉
    科学評論社, 2002, 臨床免疫, 37(6) (6), 744 - 750, Japanese
    [Invited]
    Introduction commerce magazine

  • DNA損傷応答におけるChk2キナーゼの機能及びChk2の異常と悪性腫瘍の関連：放射線生物研究
    藤本 浩子, 加藤菜穂子, 依田 成玄, 南 康博
    Last, 放射線生物研究会, 2002, 放射線生物研究, 37(3) (3), 289 - 298, Japanese
    [Invited]
    Introduction scientific journal

  • FractalkineによるNK細胞のIFN-γ産生能とその解析
    米田 修, 井上 博, 西村 美由希, 今井 俊夫, 南 康博, 堂前 尚親, 梅原 久範
    (NPO)日本免疫学会, Dec. 2001, 日本免疫学会総会・学術集会記録, 31, 310 - 310, Japanese

  • 血管内皮細胞におけるHIF-1α遺伝子導入によるアポトーシスの誘導
    飯田 武, 峯 信一郎, 齋藤 和義, 岡田 洋右, 藤本 浩子, 南 康博, 田中 良哉
    日本炎症・再生医学会, Jul. 2001, 炎症・再生, 21(4) (4), 499 - 499, Japanese

  • 特発性大腿骨頭壊死症におけるHypoxia-inducible factor(HIF)-1αの関与と血管内皮細胞におけるHIF-1α遺伝子導入によるアポトーシスの誘導
    飯田 武, 岡田 洋右, 齋藤 和義, 内田 宗志, 中村 利孝, 南 康博, 田中 良哉
    (一社)日本骨代謝学会, Jul. 2001, 日本骨代謝学会雑誌, 19(2) (2), 136 - 136, Japanese

  • ICAM-1-positive osteoblasts are involved in the regulation of osteoclastogenesis and cell cycle-dependent kinase.
    Y Tanaka, K Fujii, Y Okada, T Nakamura, Y Minami
    Sep. 2000, JOURNAL OF BONE AND MINERAL RESEARCH, 15, S177 - S177, English
    Summary international conference

  • ICAM-1高発現骨芽細胞の細胞特性 破骨細胞誘導と細胞死
    田中 良哉, 藤井 幸一, 岡田 洋右, 中村 利孝, 江藤 澄哉, 南 康博
    (一社)日本骨代謝学会, Jun. 2000, 日本骨代謝学会雑誌, 18(2) (2), 138 - 138, Japanese

  • 接着分子の活性・発現制御の分子機構
    藤本 浩子, 田中 良哉, 南 康博
    Last, 2000, Annual Review免疫2001, 179 - 187, Japanese
    [Invited]
    Introduction commerce magazine

  • ICAM-1発現によりもたらされるRA関節滑膜細胞の機能特性
    田中 良哉, 南 康博
    Last, 2000, リウマチ科, 23(4) (4), 381 - 388, Japanese
    [Invited]
    Introduction commerce magazine

  • ヒト骨芽細胞の細胞外基質とのインテグリン依存性接着・アポトーシスの誘導における H-ras の関与
    田中 良哉, 藤井 幸一, 藤本 浩子, 峯 信一郎, 齋藤 和義, 藤崎 丈詞, 森本 勲夫, 中村 利孝, 江藤 澄哉, 南 康博
    26 Jun. 1999, 日本骨代謝学会雑誌 = Japanese journal of bone metabolism, 17(2) (2), 193 - 193, Japanese

  • H-Ras is involved in integrin-mediated T cell adhesion.
    Y Tanaka, Y Minami, S Mine, K Fujii, S Eto
    Mar. 1999, FASEB JOURNAL, 13(5) (5), A1136 - A1136, English
    Summary international conference

  • 細胞外ストレスによるシグナル伝達過程におけるSykの役割
    高野 智子, 南 康博, 山村 博平
    1999, 臨床免疫, 32(5) (5), 586 - 595, Japanese
    [Invited]
    Introduction commerce magazine

  • 細胞増殖調節分子によるリンパ球の接着制御
    藤本 浩子, 南 康博
    Last, 1999, 組織細胞工学, 25(6) (6), 6 - 10, Japanese
    [Invited]
    Introduction commerce magazine

  • Expression and functional analyses of novel protein kinases isolated from mouse PGC-specific cDNA library
    UEDA Takahiro, SAKAGAMI Hiroyuki, ABE Kuniya, MARUO Akihiro, OISHI Isao, SUGIYAMA Shin, YAMAMURA Hirohei, MINAMI Yasuhiro
    01 Dec. 1998, 日本分子生物学会年会プログラム・講演要旨集, 21, 613 - 613, Japanese

  • Role of protein-tyrosine kinase Lyn in apoptosis of Bcells induced by topoisomerase II inhibitors
    NOMI Masashi, MARUO Akihiro, OISHI Isao, SADA Kiyonao, KUROSAKI Tomohiro, MINAMI Yasuhiro, YAMAMURA Hirohei
    01 Dec. 1998, 日本分子生物学会年会プログラム・講演要旨集, 21, 567 - 567, Japanese

  • 骨芽細胞はICAM-1の発現強度により細胞特性・細胞周期の異なる2つのサブポピュレーションに分類される
    田中 良哉, 南康 博, 圓尾 明弘, 平野 英保, 藤井 幸一, 斎藤 和義, 森本 勲夫, 中村 利孝, 江藤 澄哉
    07 Jul. 1998, 日本骨代謝学会雑誌 = Japanese journal of bone metabolism, 16(2) (2), 141 - 141, Japanese

  • Molecular and Morphological Analysis of the Function of Novel Receptor Tyrosine Kinases mRor1 and mRor2 in the Mouse Embryo : Poster Sessions
    HASHIMOTO R., MORIYAMA K., OISHI I., TAKEUCHI S., HATTA T., UEDA T., LIU Z., MATSUDA Y., MINAMI Y., OTANI H.
    The Japanese Teratology Society, 30 Nov. 1997, Congenital anomalies, 37(3) (3), 305 - 305, English

  • 非受容体型チロシンキナーゼSykの構造と生理的役割
    定 清直, 圓尾 明弘, 南 康博, 山村 博平
    1997, アレルギー科（科学評論社）Allergology, 3(1) (1), 100 - 106, Japanese
    [Invited]
    Introduction commerce magazine

  • 細胞質型チロシンホスファターゼ遺伝子とその機能
    安達 正晃, 石埜 正穂, 鳥越 俊彦, 宮崎 忠昭, 谷口 維紹, 南 康博, 高岡 晃教, 関谷 増夫, 矢和田 敦, 日野田 祐治, 今井 浩三
    Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 46 - 46, Japanese

  • BAG-1遺伝子発現にかかわるIL-2シグナル刺激後の伝達機構
    関谷 増夫, 安達 正晃, 宮地 敏樹, 木村 裕一, 高村 毅典, 奥田 博介, 鳥越 俊彦, 宮崎 忠昭, 谷口 維紹, 南 康博, 日野田 裕治, 今井 浩三
    01 Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 845 - 845, Japanese

  • 発生に関わる新規タンパク質キナーゼの遺伝子クローニング及び機能解析III : 中枢神経特異的に発現する新規受容体型チロシンキナーゼ
    大石 勲, 杉山 伸, 劉 照軍, 山村 博平, 西田 育巧, 南 康博
    01 Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 672 - 672, Japanese

  • 血小板における非受容体型チロシンキナーゼp72^とp125^の刺激依存性の会合とその様式の解析
    定 清直, 南 康博, 大石 勲, REZAUL Karim MD, 秦 鎖富, 山村 博平
    01 Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 609 - 609, Japanese

  • 血液・免疫系細胞の活性化・増殖および細胞死の過程におけるチロシンキナーゼの役割
    南 康博, 定 清直, 大石 勲, 山村 博平
    Lead, 1996, 蛋白質核酸酵素（増刊号）, 41(12) (12), Japanese
    [Invited]
    Introduction commerce magazine

  • インターロイキン2受容体を介する細胞内シグナル伝達
    南 康博
    Lead, 1996, 免疫・Immunology Frontier, 6(4) (4), 15 - 20, Japanese
    [Invited]
    Introduction commerce magazine

  • Syk/ZAP-70 family protein-tyrosine kinases (PTKs)の機能と活性制御
    定 清直, 南 康博, 山村 博平
    1996, 実験医学（羊土社）, 14(6) (6), 57 - 61, Japanese
    [Invited]
    Introduction commerce magazine

  • Messages from the edge: Decoding the cell's signalling mechanisms.
    Minami Y, Taniguchi T
    1996, Odyssey (The Glaxo Wellcome Journal of Innovation in Healthcare), 2, 14 - 19, English
    [Invited]
    Introduction other

  • IL-2 SIGNALING - FUNCTIONAL ACTIVATION OF JAK1 AND JAK3 KINASES THROUGH SELECTIVE ASSOCIATION WITH THE IL-2IR BETA AND GAMMA CHAINS
    T MIYAZAKI, A KAWAHARA, H FUJII, Y NAKAGAWA, Y MINAMI, ZJ LIU, OISHI, I, EL BARSOUMIAN, O SILVENNOINEN, BA WITTHUHN, JN IHLE, T TANIGUCHI
    Mar. 1995, JOURNAL OF CELLULAR BIOCHEMISTRY, 78 - 78, English
    Summary international conference

  • IL-2受容体を介するシグナル伝達
    南 康博
    Lead, 1995, 細胞工学, 14(10) (10), 1147 - 1152, Japanese
    [Invited]
    Introduction commerce magazine

  • リンパ球の活性化におけるSyk/ZAP-70チロシンキナーゼの役割
    南 康博, 大石 勲, 山村 博平
    Lead, 1995, 臨床免疫, 28(1) (1), 139 - 144, Japanese
    Introduction commerce magazine

  • LFA-1-mediated signal transduction
    梅原 久範, 南 康博, 堂前 尚親
    1994, Medical Immunology, 28(3) (3), 403 - 411, Japanese
    [Invited]
    Introduction commerce magazine

  • インターロイキン2受容体（IL-2R）を介するシグナル伝達
    南 康博, 大石 勲, 谷口 維紹
    Lead, 1994, Biotherapy, 8(7) (7), 943 - 949, Japanese
    [Invited]
    Introduction commerce magazine

  • IL-2 RECEPTOR AND ITS TARGET GENES IN THE HEMATOPOIETIC-CELL CYCLE
    T TANIGUCHI, Y MINAMI, H SHIBUYA, T KONO, N KOBAYASHI, M YONEYAMA, A KAWAHARA, K YAMADA, S MINAMOTO, M HATAKEYAMA, RM PERLMUTTER
    Jan. 1993, JOURNAL OF CELLULAR BIOCHEMISTRY, 53 - 53, English
    Summary international conference

  • 梅原 久範, 南 康博, 堂前 尚親
    The Japan Society for Clinical Immunology, 1993, Jpn. J. Clin. Immunol., 16(6) (6), 473 - 479, Japanese
    Introduction scientific journal

  • インターロイキン
    南 康博
    Lead, 1993, Biomedica, 8(9) (9), 24 - 28, Japanese
    [Invited]
    Introduction commerce magazine

  • IL-2レセプターを介したシグナル伝達 - p56lckチロシンキナーゼの役割
    河野 剛志, 南 康博, 谷口 維紹
    1993, 実験医学, 11(19) (19), 60 - 65, Japanese
    [Invited]
    Introduction commerce magazine

  • サイトカインのsignal transduction - IL-2のsignal transductionを中心に -
    宮崎 忠昭, 南 康博, 谷口 維紹
    1993, 最新医学, 48(5) (5), 23 - 33, Japanese
    [Invited]
    Introduction commerce magazine

  • インターロイキン2受容体（IL-2R）を介する細胞内シグナル伝達機構
    南 康博
    Lead, 1993, 免疫・Immunology Frontier, 3(2) (2), 17 - 23, Japanese
    [Invited]
    Introduction commerce magazine

  • リンパ球におけるSrcファミリーチロシンキナーゼの役割
    南 康博
    Lead, 1993, Annual Review 免疫, 153 - 159, Japanese
    [Invited]
    Introduction commerce magazine

  • T細胞活性化におけるリンフォカインと細胞内情報伝達
    山田 恭子, 南 康博, 谷口 維紹
    1993, nano GIGA, 2(1) (1), 118 - 124, Japanese
    [Invited]
    Introduction commerce magazine

  • T細胞活性化とシグナル伝達
    南 康博
    Lead, 1992, Medical Immunology, 23(2) (2), 105 - 115, Japanese
    [Invited]
    Introduction commerce magazine

  • Fc epsilon RI-情報伝達におけるzeta鎖ファミリーの役割-
    南 康博
    Lead, 1991, Medical Immunology, 21(1) (1), 85 - 93, Japanese
    [Invited]
    Introduction commerce magazine

  • T細胞受容体と細胞内シグナル伝達
    南 康博, 島田 眞路
    Lead, 1990, 実験医学（羊土社）, 8(8) (8), 41 - 47, Japanese
    [Invited]
    Introduction commerce magazine

  • T細胞抗原レセプター複合体の構造と機能
    南 康博
    Lead, 1990, 実験医学（羊土社）, 8(2) (2), 62 - 66, Japanese
    [Invited]
    Introduction commerce magazine

  • T細胞抗原レセプター複合体の合成と分解
    南 康博
    Lead, 1987, 実験医学（羊土社）, 5(7) (7), 76 - 79, Japanese
    [Invited]
    Introduction commerce magazine

■ Books And Other Publications
  • 遺伝情報の維持と発現 / イラストレイテッド生化学
    Minami Yasuhiro
    Joint translation, 丸善株式会社, 2019, Japanese
    Textbook

  • 知る・見る・活かす！シグナリング研究2015 / 知る・見る・活かす！シグナリング研究2015 概論 シグナリング研究の流れとめざすところ
    Minami Yasuhiro
    Joint editor, 羊土社, Jun. 2015, Japanese
    Scholarly book

  • 膨大なデータを徹底整理するサイトカイン・増殖因子キーワード辞典 / Ror1/2
    Endo Mitsuharu, Minami Yasuhiro
    Others, Ror1/2（p. 363-365）, 羊土社, 2015, Japanese
    Scholarly book

  • Receptor Tyrosine Kinases: Family and Subfamilies / The Ror Receptor Family.
    EndoM, Nishita Michiru, DoiR, HayashiM, Minami Yasuhiro
    Contributor, Springer, 2015, English
    Scholarly book

  • Progenitor Cells: Biology, Characterization and Potential Clinical Applications (Horton P.M., Lawrence B.E. edited)
    Endo M, Minami Y
    Contributor, Regulation of neuronal progenitor cells by Wnt5a-signaling in the developmental central nervous system. (Chapter 4, p. 71-86), Nova Science Publishers, Inc., 2013

  • Genetically Engineered Mice Handbook / Mouse Models for Developmental Biology: Functional Analysis for Ror and Wnt Signaling
    OISHI ISAO, YODA AKINORI, KANI SHUICHI, MINAMI YASUHIRO
    Joint work, Mouse models for developmental biology (Chapter 22, p. 295-302), Taylor & Francis, 2006, English
    Scholarly book

  • バイオサイエンスの新世紀 第5巻 酸化ストレス・レドックスの生化学
    南 康博, 山村 博平
    Joint work, キナーゼとレドックス制御 （p .84-91), 共立出版, 2000

  • Redox regulation of cell signaling and its clinical application
    Packer, Lester, 淀井, 淳司
    Joint work, Role of Syk protein tyrosine kinase in stress-induced signaling in B cells, Marcel Dekker, Apr. 1999, English, ISBN: 0824719611

  • ブレインサイエンスレビュー1999（p.81-93）
    南 康博
    Joint work, 神経特異的受容体型チロシンキナーゼの機能解析, 医学書院, 1999

  • 細胞機能とマップ
    植野 望, 南 康博, 山村 博平
    Joint work, ホルモン（p.146-149）, 東京化学同人, 1998

  • 分子細胞生物学辞典
    大石 勲, 南 康博
    Contributor, 東京化学同人, 1997

  • Kinases and Phosphatases in Lymphocyte and Neuronal Signaling
    Liu Z-J, Ueda T, Tanaka N, Miyazaki T, Taniguchi T, Yamamura H, Minami Y
    Contributor, Functional cooperation of cyclin C with c-Myc in the promotion of hematopoietic cell proliferation., Springer Tokyo, 1997

  • Kinases and Phosphatases in Lymphocyte and Neuronal Signaling (Yakura H. (ed.))
    Oishi I, Takeuchi S, Liu Z-J, Ueda T, Sugiyama S, Nishida Y, Yamamura H, Akira S, Otani H, Minami Y
    Contributor, Identification and characterization of Ror family receptor tyrosine kinases expressed in the developing nervous system, Springer, Tokyo, 1997

  • Encyclopedia of Human Biology, Second Edition, vol. 5
    Minami Y, Taniguchi T
    Contributor, Interleukin-2 and the IL-2 receptor (p.125-131), Academic Press, 1997

  • 免疫研究法ハンドブック 改訂2版
    劉 照軍, 南 康博
    Joint work, antisense DNAおよびRNAの使用法（p.469-471）, 中外医学社, Nov. 1996

  • Molecular Mechanisms of Immunological Self-Recognition
    Samelson L.E, Siegel J.N, Phillips A.F, Garcia-Morales P, Minami Y, Klausner R.D
    Contributor, The T cell antigen receptor: Biochemical aspects of signal transduction, Academic Press, Inc., 1993

  • タンパク質精製法（ロバート Ｋ．スコープ著）
    塚田 欣司, 寺岡 弘文, 沢井 保子, 南 康博
    Joint translation, シュプリンガー・フェアラーク東京(1985), 1987

■ Lectures, oral presentations, etc.
  • Molecular mechanisms of age-related dysregulation of cellular morphology and motility
    Minami Yasuhiro
    AMED「老化メカニズムの解明・制御プロジェクト」第1回リトリート, Feb. 2018, Japanese, AMED老化研究プロジェクト, 淡路, Domestic conference
    Oral presentation

  • Ror2による神経炎症制御と脳老化メカニズム解明へのアプローチ
    Endo Mitsuharu, Minami Yasuhiro
    AMED「老化メカニズムの解明・制御プロジェクト」第1回リトリート, Feb. 2018, Japanese, AMED老化研究プロジェクト, 淡路, Domestic conference
    Poster presentation

  • Rif低分子量Gタンパク質による核膜タンパク質の動態制御と老化との関連
    Nishita Michiru, Minami Yasuhiro
    AMED「老化メカニズムの解明・制御プロジェクト」第1回リトリート, Feb. 2018, Japanese, AMED老化研究プロジェクト, 淡路, Domestic conference
    Poster presentation

  • Function of KIF1C in elongation and maturation of invadopodia
    佐事 武, Nishita Michiru, 岡田 康志, Minami Yasuhiro
    2017年度生命科学系学会合同年次大会, Dec. 2017, Japanese, 日本分子生物学会、日本生化学会, 神戸, KIF1Cはkinesin-3ファミリーの一員であり、微小管プラス端集積因子CLASPによって細胞内局在が制御され、ポドソーム形成に寄与することが知られている。ポドソームはアクチンの集積した細胞膜突起構造であり、生理的状況下で破骨細胞などによる細胞外基質の分解に関与している。一方、がん細胞においては、ポドソームと類似した細胞膜突起構造である浸潤突起（invadopodia）が細胞外基質の分解および浸潤に関与している。しかし、がん細胞の浸潤突起形成や浸潤能とKIF1Cとの関連は明らかにされていない。そこで、本研究では、がん細胞の浸潤突起形成・伸長過程におけるKIF1Cの役割について検討した。まず、がん細胞を薄い細胞外基質でコートしたガラス上で培養しKIF1Cの細胞内局在について検討した。その結果、細胞外基質の分解とアクチンの集積を伴う浸潤突起の形成が観, Domestic conference
    Poster presentation

  • Wnt5a-dependent and -independent functions of Ror family receptor tyrosine kinases
    Minami Yasuhiro
    Wnt研究会2017, Dec. 2017, Japanese, Wnt研究会, 神戸, Domestic conference
    [Invited]
    Invited oral presentation

  • Role of Ror2 receptor tyrosine kinase in regulating the cell-cycle progression of neural stem/progenitor cells in the developing neocortex
    Endo Mitsuharu, 大田 絢斗, Minami Yasuhiro
    Wnt研究会2017, Dec. 2017, Japanese, Wnt研究会, 神戸, Domestic conference
    Oral presentation

  • Pathological analysis of central nervous system in dystroglycanopathy mouse models
    首藤 篤史, Kanagawa Motoi, 近藤 舞, Kobayashi Kazuhiro, Endo Mitsuharu, Minami Yasuhiro, Toda Tatsushi
    ConBio2017, Dec. 2017, Japanese, 日本分子生物学会, 日本生化学会, 神戸, Domestic conference
    Oral presentation

  • 筋ジストロフィーモデルマウスの中枢神経病態の解析
    首藤 篤史, Kanagawa Motoi, Kobayashi Kazuhiro, Endo Mitsuharu, Minami Yasuhiro, Toda Tatsushi
    第12回 筋ジストロフィー治療研究会, Nov. 2017, Japanese, 不明, 熱海, Domestic conference
    Oral presentation

  • Ror family tyrosine kinases regulate skeletal muscle regeneration
    紙崎 孝基, 土井 亮助, Kanagawa Motoi, Toda Tatsushi, 深田 宗一郎, Endo Mitsuharu, Minami Yasuhiro
    第5回 若手による骨格筋細胞研究会, Nov. 2017, Japanese, Society of Skeletal Muscle Cells, 神戸, 骨格筋は再生能の高い組織であり、再生過程では骨格筋特異的な組織幹細胞である衛星細胞が必須の役割を担っている。通常、衛星細胞は静止期にあるが、骨格筋損傷後には活性化し細胞増殖を開始する。増殖した衛星細胞は筋芽細胞に分化し、最終的に新たな筋線維形成に寄与することで骨格筋の損傷部位の修復に貢献する。これまでに衛星細胞は骨格筋再生に必須であることが報告されてきているが、その制御機構については不明な点も多い。また、骨格筋常在性の間葉系幹細胞であるFibro/adipogenic progenitor cells(FAPs)が骨格筋再生時の衛星細胞の機能を制御することが近年報告されている。FAPsは筋疾患で観察される線維化や脂肪化の原因の一つとして考えられており、その機能制御機構は重要と考えられているが、未解明な点が多い。これらのことから、骨格筋再生メカニズムを, Domestic conference
    Oral presentation

  • 脳の損傷修復における増殖性アストロサイトの役割
    Endo Mitsuharu, 大田 絢斗, Minami Yasuhiro
    第58回日本組織細胞化学会, Sep. 2017, Japanese, Japan Society of Histochemistry and Cytochemistry, 愛媛, 外傷や虚血などにより脳が損傷を受けると、壊れた血管から進入したマクロファージなどの免疫細胞や損傷に応答して活性化したミクログリアが炎症を引き起こすことで組織修復が促される。一方で、過剰な炎症応答は正常なニューロンに対して傷害作用を示すことから、炎症の拡大や持続による二次的な神経組織傷害が問題視されている。近年、グリア細胞の一種であるアストロサイトが、損傷部周囲で増殖して数を増やし、損傷部における炎症細胞を取り囲むことで、炎症の拡大を最小限にとどめていることが明らかになってきた。我々は、最近、損傷を受けた脳内のアストロサイトでは、bFGFなどの増殖因子のシグナルにより発生過程の神経幹細胞に高発現している受容体型チロシンキナーゼRor2の発現誘導が起こることを突き止め、Ror2シグナルによってアストロサイトの増殖が促進されることを明らかにした。加えて、ア, Domestic conference
    [Invited]
    Invited oral presentation

  • Critical role of Ror2 receptor tyrosine kinase in regulating inflammatory response
    Endo Mitsuharu, 大田 絢斗, 大西 怜子, Minami Yasuhiro
    第69回日本細胞生物学会, Jun. 2017, Japanese, Japan Society for Cell Biology, 仙台, 受容体型チロシンキナーゼRor2は液性因子Wnt5aの受容体として働き、細胞極性・運動・増殖・分化などを制御することで発生過程の形態形成や組織・器官形成に重要な役割を担う。我々はRor2が発生過程の大脳皮質において、盛んに増殖する神経系前駆細胞に高発現していることや成熟した大脳皮質においても、その損傷修復時に増殖を再開したアストロサイトで発現誘導されることを明らかにしている。これらの細胞におけるRor2の発現低下は増殖因子存在下での細胞増殖能を低下させ、主に細胞周期G1期での停止をもたらす。正常細胞の分裂回数には制限があり、分裂寿命を迎えた細胞は増殖因子存在下でも細胞周期がG1期で停止することが知られており、この現象は細胞老化と呼ばれる。また、分裂寿命を迎えなくとも、酸化ストレスのようなDNA損傷シグナルを誘導する刺激によって細胞老化様の増殖停止が起, Domestic conference
    Oral presentation

  • Current overview of studies on the Ror-family receptor tyrosine kinases
    Minami Yasuhiro
    第9回シグナルネットワーク研究会, Jun. 2017, Japanese, 大鵬薬品工業株式会社、シグナルネットワーク研究会, 神奈川(CLST), Domestic conference
    Oral presentation

  • Role of Ror2 tyrosine kinase in ivasiveness of malignant pleural mesothelioma cells.
    Takeshi Saji, Nishita Michiru, Takefumi Doi, Maniwa Yoshimasa, Minami Yasuhiro
    International Joint Symposium in Kobe 2017 University of Washington University of Oslo and Kobe University, Mar. 2017, English, Kobe University, University of Washington, University of Oslo, 神戸, Malignant mesothelioma is a highly aggressive tumour originated from mesothelial cells of the pleura, pericardium or peritoneum. Among them, malignant pleural mesothelioma (MPM) is most common with increasing frequency throughout the world and closely related to exposure to asbestos. It can be classified histologically into epithelioid, sarcomatoid and biphasic types, among wh, International conference
    Poster presentation

  • Novel role of Ror2 signaling in regulating Golgi structure and polarity for tumor cell invasion
    Nishita Michiru, Minami Yasuhiro
    International Joint Symposium in Kobe 2017 University of Washington University of Oslo and Kobe University, Mar. 2017, English, Kobe University, University of Washington, University of Oslo, 神戸, Ror2 is a receptor tyrosine kinase that plays essential roles in developmental morphogenesis by mediating Wnt5a signaling. In tumor cells, Ror2 signaling is constitutively activated, due to sustained expression of Ror2, leading to the formation of invadopodia for tumor invasion. However, the mechanisms underlying Ror2-induced invadopodia formation remain unclear. We show that R, International conference
    [Invited]
    Invited oral presentation

  • Novel function of Ror2 receptor tyrosine kinase in cancer cell invasion
    佐事 武, 西尾 忠, 紙崎 孝基, Nishita Michiru, Minami Yasuhiro
    第39回日本分子生物学会年会, Dec. 2016, Japanese, The Molecular Biology Society of Japan, 横浜, Ror2はWnt5aをリガンドとする受容体型チロシンキナーゼであり、非古典的Wntシグナル経路を活性化することで、発生過程における様々な組織・器官の構築に重要な役割を担っている。また、Ror2とWnt5aは様々ながんにおいて高発現し、がんの浸潤・転移にも関与している。私たちはこれまでに、骨肉腫細胞において、恒常的に活性化されたRor2シグナルがc-Srcキナーゼを介して浸潤突起形成を促進することを明らかにしている。また最近、線毛内輸送や一次線毛形成に重要な役割を担うIFT20 (Intraflagellar transport 20)がRor2シグナルによって発現誘導され、骨肉腫細胞などの浸潤突起形成を促進することを明らかにしている。本研究では、Ror2シグナルによるがん細胞浸潤の分子機構の解明を目的として、各種Ror2変異体などを用いて解析を行った, Domestic conference
    Oral presentation

  • Ror-family of receptor tyrosine kinases play a crucial role in regulating astrocytic response to brain injury
    Endo Mitsuharu, 大田 絢斗, 小林 千穂, 大西 怜子, Minami Yasuhiro
    第39回日本分子生物学会年会, Dec. 2016, Japanese, The Molecular Biology Society of Japan, 横浜, 受容体型チロシンキナーゼRor1、Ror2はともにWnt5aの受容体として働き、神経系においては、主に発生期の神経幹細胞に発現するなど、発生過程の組織形成において重要な役割を担っている。発生過程と比べ、成熟した脳内でのそれらの発現量はごくわずかであるが、我々は脳損傷マウスモデルを用いた解析から、損傷部周囲の脳組織ではRor1とRor2の発現量が上昇することを見出した。免疫組織染色法を用いた解析により、少なくともRor2は損傷部周囲のアストロサイトで発現上昇することが明らかになった。脳損傷後の損傷領域では、bFGF等の増殖因子が産生され、損傷部周囲のアストロサイトの増殖を促進することで組織の修復が促される。培養アストロサイトを用いた解析から、Ror2はbFGFシグナルによって発現量が上昇し、bFGFによるアストロサイトの増殖を促進する働きを持つことが示, Domestic conference
    Oral presentation

  • IFT20 regulates Ror2 signal-dependent tumor cell invasion by promoting microtubule formation at the Golgi apparatus
    Nishita Michiru, 西尾 忠, 紙崎 孝基, 内匠 透, 大谷 浩, Minami Yasuhiro
    第39回日本分子生物学会年会, Dec. 2016, Japanese, The Molecular Biology Society of Japan, 横浜, 受容体型チロシンキナーゼRor2は骨肉腫などのがん細胞で高発現し、がんの増悪・進展に関与しているが、その分子機構については未だ不明な点がある。私たちは、Ror2がIFT20 (Intraflagellar transport 20)の発現を誘導して骨肉腫細胞などのがん細胞の浸潤を促進することを見出した。IFT20は、一次線毛において鞭毛内輸送(IFT)を担うIFT複合体の構成因子であるが、これら構成因子の中で唯一ゴルジ体にも局在することが知られており、IFT20はゴルジ体において一次線毛非依存的な機能を担っていることが示唆される。実際、Ror2を高発現している骨肉腫細胞SaOS2などの悪性度の高いがん細胞は一次線毛を形成せず、IFT20の局在は主にゴルジ体のシス嚢に認められた。これらの細胞においてRor2やIFT20の発現を抑制すると、ゴルジ体のリボ, Domestic conference
    [Invited]
    Invited oral presentation

  • 神経幹細胞由来アストロサイトの増殖制御機構の解析
    Endo Mitsuharu, 大田 絢斗, 小林 千穂, 饗場 篤, Minami Yasuhiro
    第38回神経組織培養研究会, Nov. 2016, Japanese, 神経組織培養研究会, 横浜, 我々は、発生過程における組織形成に重要な役割を担う受容体型チロシンキナーゼRor2が、発生期の大脳皮質神経幹細胞に高発現しており、Wnt5aの受容体として働くことで、その未分化性の維持に働くことを明らかにしてきた。胎生後期から生後初期のマウス大脳皮質において、神経幹細胞は主にアストロサイトに分化する。この時期のマウス大脳皮質から単離した神経幹細胞は、bFGF等の増殖因子の存在下で培養すると未分化な状態で増殖を続け、BMPや血清存在下で培養すると増殖を停止し、アストロサイトの分化が誘導される。我々は、アストロサイトへの分化に伴いRor2の発現量が低下することを見出している。分化したアストロサイトをbFGFで刺激すると一部のアストロサイトにおいてはRor2の発現が誘導され、増殖を再開する様子が認められる。本発表では、脳損傷時に誘導されるアストロサイトの増, Domestic conference
    Oral presentation

  • 骨格筋修復過程におけるRor1を介した衛星細胞の増殖制御
    紙崎 孝基, Minami Yasuhiro
    第4回神緑会ヤングインベスティゲーターアワード発表会, Oct. 2016, Japanese, 神戸大学, 神戸, Domestic conference
    Poster presentation

  • Function of Ror2 receptor tyrosine kinase as an onco-fetal protein
    Minami Yasuhiro, Nishita Michiru
    第75回日本癌学会総会学術総会, Oct. 2016, English, Japanese Cancer Association, 横浜, Domestic conference
    [Invited]
    Invited oral presentation

  • Epigenetic regulation of Ror2 plays a critical role in regulating cell cycle progression of astrocytes
    Endo Mitsuharu, 小林 千穂, グリジャハン オブリカスム, Minami Yasuhiro
    第59回日本神経化学会大会, Sep. 2016, Japanese, The Japanese Society for Neurochemistry, 福岡, グリア細胞のひとつであるアストロサイトは、脳全体に分布しており、脳機能に重要な役割を担っている。通常アストロサイトは細胞増殖を停止した状態にあるが、脳損傷時には増殖を再開することで損傷後の組織修復に関わることが知られている。しかしながら、アストロサイトの増殖を制御する分子機構については未だ不明な点が多い。我々は、発生過程における組織形成に重要な役割を担うRorファミリー受容体型チロシンキナーゼRor2が、発生期の神経幹細胞に高発現しており、その未分化性の維持に働くことを明らかにしてきた。発生過程と比較して、成獣マウス脳内ではRor2の発現はごく僅かであるが、脳損傷後のアストロサイトではその発現が上昇することを見出した。培養アストロサイトを用いた解析から、Ror2はアストロサイトの増殖促進活性をもつbasic fibroblast growth fac, Domestic conference
    Oral presentation

  • 受容体型チロシンキナーゼRor1は骨格筋損傷後の衛星細胞の増殖に重要である
    紙崎 孝基, 土井 亮助, Endo Mitsuharu, 佐事 武, Kanagawa Motoi, Toda Tatsushi, 深田 宗一朗, Hayashi Makoto, Minami Yasuhiro
    第2回日本筋学会学術集会, Aug. 2016, Japanese, 日本筋学会, 東京, Domestic conference
    Poster presentation

  • 脳損傷によるRor2の発現誘導を介したアストロサイトの増殖制御
    Endo Mitsuharu, Minami Yasuhiro
    第8回シグナルネットワーク研究会, May 2016, Japanese, 大鵬薬品工業株式会社、シグナルネットワーク研究会, 大阪, Domestic conference
    Oral presentation

  • 炎症性サイトカインによるRor1の発現誘導を介した骨格筋損傷修復機構
    佐事 武, Minami Yasuhiro
    第8回シグナルネットワーク研究会, May 2016, Japanese, 大鵬薬品工業株式会社、シグナルネットワーク研究会, 大阪, Domestic conference
    Oral presentation

  • Crucial role of the Ror-family rcceptor tyosine kinases in regulating tissue stem cells
    Koki Kamizaki, Ryosuke Doi, Takeshi Saji, Kanagawa Motoi, So-ichiro Fukada, Toda Tatsushi, Hayashi Makoto, Endo Mitsuharu, Minami Yasuhiro
    Trans-Pacific Network for Drug Discovery and Identification of New Therapeutic Targets Kick-off Symposium, Mar. 2016, English, Kobe University, University of Washington, 神戸, International conference
    Poster presentation

  • Identification of substrates for Ror2 receptor tyrosine kinase, which regulate invasion of osteosarcoma cells
    Hayashi Makoto, Takeshi Saji, Nishita Michiru, Endo Mitsuharu, Minami Yasuhiro
    The Tenth American Association for Cancer Research (AACR) and Japanese Cancer Association (JCA) Joint Conference on “Breakthroughs in Cancer Research: From Biology to Therapeutics,”, Feb. 2016, English, Japanese Cancer Association, American Association for Cancer Research, Maui, USA, Osteosarcoma is a malignant tumor in a bone, which is one of the major tumors in childhood and adolescence. Prognosis of patients with osteosarcoma is correlated with invasive potential of osteosarcoma cells. Therefore, the inhibition of invasion and metastasis of osteosarcoma cells is thought to improve treatment outcome. Ror2 receptor tyrosine kinase, which is a receptor for, International conference
    Poster presentation

  • The receptor tysosine kinase Ror2 is required for cell cycle re-entry of quiescnt astrocytes
    Endo Mitsuharu, 小林 千穂, 疋田 壮舞, グリジャハン オブリカスム, 稲垣 貴彦, Minami Yasuhiro
    第38回日本分子生物学会年会, Dec. 2015, Japanese, The Molecular Biology Society of Japan, 神戸, Astrocytes are the most abundant cell type in the brain and play essential roles in maintaining brain homeostasis. It has been well known that quiescent mature astrocytes dedifferentiate and proliferate in response to brain injury. These activated astrocy, Domestic conference
    Oral presentation

  • Wnt5a-Ror2 signaling induces expression of the ciliary protein IFT20 to regulate tumor cell invasion
    Nishita Michiru, 西尾 忠, 紙崎 孝基, 王 志超, 榎本 真宏, 玉田 紘太, 内匠 透, Victor W. Hsu, Gregory J. Pazour, Minami Yasuhiro
    第38回日本分子生物学会年会, Dec. 2015, Japanese, The Molecular Biology Society of Japan, 神戸, 受容体型チロシンキナーゼRor2はWnt5a受容体としてβ-カテニン非依存的Wntシグナル経路を制御している。Wnt5aとRor2は多くのヒト骨肉腫細胞で高発現しその高浸潤性に寄与しているが、その分子機構については不明な点が多い。私たちはこれまでに、ヒト骨肉腫細胞株SaOS2において、恒常的なWnt5a-Ror2シグナルが細胞外基質の分解に必要なマトリックスメタロプロテアーゼ(MMP)-13の発現を誘導することで、浸潤能を促進することを明らかにしてきた。今回、同様に恒常的Wnt5a-Ror2シグナルによって発現誘導される遺伝子としてIFT20 (Intraflagellar transport 20)を同定した。IFT20は鞭毛内輸送(IFT)を司るIFT複合体の構成因子である。IFT複合体はキネシンまたはダイニンによって、基底小体とそれから伸びる微, Domestic conference
    Oral presentation

  • Ror1 receptor tyrosine kinase induced by inflammatory cytokines play a crucial role in promoting myoblast proliferation
    紙崎 孝基, 土井 亮助, 加藤 英, 佐事 武, Endo Mitsuharu, Kanagawa Motoi, Toda Tatsushi, 深田 宗一朗, Hayashi Makoto, Minami Yasuhiro
    第38回日本分子生物学会年会, Dec. 2015, Japanese, The Molecular Biology Society of Japan, 神戸, 骨格筋は運動において必要不可欠な組織であり、加齢に伴う筋力低下は筋組織に存在する筋組織特異的幹細胞（衛星細胞）の増殖能の低下に起因すると考えられる。しかし、衛星細胞の増殖を制御する分子機構は未だ不明な点が多い。本研究では衛星細胞の増殖機構を解明するため、カルディオトキシンによる筋損傷修復モデルマウスおよびマウス筋芽細胞株C2C12細胞を用いて解析を行った。筋損傷修復モデルマウスの解析から、修復早期の筋組織では受容体型チロシンキナーゼRor1の発現が亢進し、また、それに先行して炎症性サイトカインTNFαの発現が亢進することが確認され、TNFαによるRor1の発現誘導の可能性が示唆された。実際、低濃度血清培地（分化培地）で培養したC2C12細胞をTNFαにより刺激した際にRor1の発現誘導が観察された。TNFαによるRor1の発現誘導は、NF-κB経路の, Domestic conference
    Poster presentation

  • Naoe T. Treatment with Hedgehog signaling inhibitor attenuates leukemia-propagating potential in acute myeloid leukemia cells.
    Minami Yasuhiro, Fukushima N, Sakiuchi S, Kiyoi H, Minami Hironobu
    第74回日本癌学会学術集会, Oct. 2015, English, 日本癌学会, 名古屋, Domestic conference
    Oral presentation

  • 筋再生における Ror1 の役割
    Hayashi Makoto, Minami Yasuhiro
    第16回運動器科学研究会, Sep. 2015, Japanese, 運動器科学研究会, 鹿児島, Domestic conference
    Oral presentation

  • Novel role for Wnt5a-Ror2 signaling in regulating polarity and structure of the Golgi apparatus in osteosarcoma cells.
    Nishita Michiru, Minami Yasuhiro
    University of Washington-Kobe University Joint Symposium on Cell Signaling, Sep. 2015, English, University of Washington, Kobe University, Seattle, USA, Ror2 is a receptor for Wnt5a and activates -catenin-independent Wnt pathway. We have previously shown that Wnt5a-Ror2 signaling is constitutively activated, due to sustained expression of Wnt5a and Ror2, in human osteosarcoma (OS) cells. Aberrant activation of Wnt5a-Ror2 signaling confers invasive properties on OS cells, at least partly, by inducing expression of matrix metall, International conference
    [Invited]
    Invited oral presentation

  • Wnt5a-Ror2 signaling induces expression of the ciliary protein IFT20 to regulate the integrity of the Golgi apparatus and reorientation of the centrosome during tumor cell invasion
    Koki Kamizaki, Nishita Michiru, Tadashi Nishio, ZhiChao Wang, Masahiro Enomoto, Kota Tamada, Toru Takumi, Gregory J. Pazour, Minami Yasuhiro
    Epithelial Tubulology; The Second International Meeting, Aug. 2015, English, 新学術領域研究「上皮管腔組織形成」, 札幌, Ror2 is a receptor for Wnt5a and activates β-catenin-independent Wnt pathway. We have previously shown that Wnt5a-Ror2 signaling is constitutively activated, due to sustained expression of Wnt5a and Ror2, in human osteosarcoma (OS) cells. Aberrant activation of Wnt5a-Ror2 signaling confers invasive properties on OS cells, at least partly, by inducing expression of matrix metall, International conference
    Poster presentation

  • Role of Wnt5a-Ror signaling in morphogenesis of the metanephric mesenchyme during ureteric budding
    Nishita Michiru, Sen Qiao, Xiaoyuan Qi, Mari Miyamoto, Yuka Okinaka, Makiko Yamada, Ryuju Hashimoto, Iijima Kazumoto, Hiroki Otani, Christine Hartmann, Ryuichi Nishinakamura, Minami Yasuhiro
    Epithelial Tubulology; The Second International Meeting, Aug. 2015, English, 新学術領域研究「上皮管腔組織形成」, 札幌, Development of the metanephric kidney begins with the induction of a single ureteric bud (UB) on the caudal Wolffian duct (WD) in response to GDNF produced by the adjacent metanephric mesenchyme (MM). Mutual interaction between the UB and MM maintains expression of GDNF in the MM, thereby supporting further outgrowth and branching morphogenesis of the UB, while the MM also grow, International conference
    Poster presentation

  • 繊毛タンパク質IFT20による骨肉腫細胞の浸潤制御
    Nishita Michiru, Minami Yasuhiro
    第7回シグナルネットワーク研究会, Jun. 2015, Japanese, 大鵬薬品工業株式会社、シグナルネットワーク研究会, 沖縄県国頭郡恩納村, Domestic conference
    Oral presentation

  • 筋芽細胞におけるRor1のNF-kBを介した発現誘導機構
    紙崎 孝基, Minami Yasuhiro
    第7回シグナルネットワーク研究会, Jun. 2015, Japanese, 大鵬薬品工業株式会社、シグナルネットワーク研究会, 沖縄県国頭郡恩納村, Domestic conference
    Oral presentation

  • 受容体型チロシンキナーゼRor1による骨格筋再生制御
    加藤 英, 土井 亮助, Endo Mitsuharu, 深田 宗一郎, Kanagawa Motoi, Toda Tatsushi, Minami Yasuhiro
    第37回日本分子生物学会年会, Nov. 2014, Japanese, 日本分子生物学会, 横浜, 骨格筋は高い再生能を有し、損傷が生じても速やかに再生し、その機能を回復する。成体骨格筋には、筋幹細胞として機能する筋衛星細胞と呼ばれる単核の細胞が存在する。筋組織に損傷が生じると静止期にある筋衛星細胞は活性化され、増殖を開始し、筋芽細胞へと分化することで筋再生に寄与する。また、損傷がなくとも、筋衛星細胞は必要に応じて活性化され増殖を再開し、筋組織の恒常性維持に働くことが知られている。損傷修復や恒常性維持の過程で、活性化された筋衛星細胞の一部は、未分化状態を維持し静止期に至ることにより、筋衛星細胞の枯渇が防がれている。しかし、骨格筋における筋衛星細胞の活性化及び維持の分子機構は未だ不明な点が多い。Rorファミリー受容体型チロシンキナーゼ（Ror1、Ror2）は、 発生過程の様々な組織で発現し、組織形成において重要な役割を担っている。我々は、成体マウス骨, Domestic conference
    Poster presentation

  • Efficacy and biomarker analyses of treatment with the Hedgehog inhibitor PF-913, in AML cells.
    Minami Yasuhiro, Fukushima N, Kuwatsuka Y, Hayakawa F, Kakiuchi S, Minami Hironobu, Catriona J, Kiyoi H, Naoe T
    第76回日本血液学会学術集会, Oct. 2014, English, 日本血液学会, 大阪, Domestic conference
    Oral presentation

  • Roles of Wnt5a-Ror Signaling in Pathological Conditions
    Minami Yasuhiro
    UNIVERSITY OF WASHINGTON-KOBE UNIVERSITY SYMPOSIUM ON MEMBRANE BIOLOGY, Mar. 2014, English, UW & Kobe Univ., UW, Seattle, USA, Wnt5a and its cognate receptors, the Ror-family of receptortyrosine kinases, Ror1 and Ror2, have been shown toplay crucial roles in the developmental morphogenesisby regulating convergent extension (CE) movements andplanar cell polarity (PCP). Studies with cultured cells haverevealed that Wnt5a-Ror signalings play important roles inthe regulation of various cellular functions,, International conference
    [Invited]
    Invited oral presentation

  • Role of Wnt5a-Ror2 signaling in patterning the metanephric mesenchyme during ureteric budding
    Nishita Michiru, Sen Qiao, Mari Miyamoto, Yuka Okinaka, Makiko Yamada, Ryuju Hashimoto, Iijima Kazumoto, Hiroki Otani, Christine Hartmann, Ryuichi Nishinakamura, Minami Yasuhiro
    Keystone Symposia "Developmental Pathways and Cancer: Wnt, Notch and Hedgehog(J7)", Feb. 2014, English, Keystone Symposia on Molecular and Cellular Biology, Banff, Canada, Development of the metanephric kidney begins with the induction of a single ureteric bud (UB) on the caudal Wolffian duct (WD) in response to GDNF produced by the adjacent metanephric mesenchyme (MM). The UB then grows and undergoes branching morphogenesis, while the MM aggregates around the branched tips of the UB and undergoes mesenchymal-epithelial transition and tubulogenes, International conference
    Poster presentation

  • 反応性アストロサイトにおけるRorファミリー受容体型チロシンキナーゼの役割
    Endo Mitsuharu, 加藤 英, 疋田 壮舞, Minami Yasuhiro
    第36回日本分子生物学会年会, Dec. 2013, Japanese, 日本分子生物学会, 神戸, Ror family receptor tyrosine kinases, Ror1 and Ror2 have been shown to activate non-canonical Wnt signaling by acting as receptors for Wnt5a, and play crucial roles in developmental tissue- and organo-genesis. We have recently shown that Ror1 and Ror2 are highly expressed in the developing neural progenitor cells (NPCs), and that Wnt5a-Ror signaling plays a role in maintaining, Domestic conference
    Poster presentation

  • Functional analysis of Wnt5a-Ror signaling in regulation of progenitor proliferation during neocortical neurogenesis
    Mtisuharu Endo, Minami Yasuhiro
    Neuroscience 2013, Nov. 2013, English, Society for Neuroscience, San Diego, USA, In the developing neocortex, a large number of neurons are generated from neural progenitor cells (NPCs). NPCs divide and differentiate in a precisely regulated manner, and a balance between proliferation and differentiation of NPCs is crucial for generating a sufficient number of neurons to properly form a functional neocortex. During neurogenic stages, NPCs differentiate into, International conference
    Poster presentation

  • 尿管芽形成におけるWnt5a-Ror2シグナルの役割と腎尿路奇形
    Nishita Michiru, 喬 森, 宮本 真里, 沖中 由佳, 山田 真紀子, Iijima Kazumoto, 大谷 浩, Christine Hartmann, 西中村 隆一, Minami Yasuhiro
    第22回発達腎研究会, Sep. 2013, Japanese, 発達腎研究会, 高槻, 哺乳類の腎臓（後腎）の発生はウォルフ管から尿管芽が誘導されることによって開始する。マウスでは、胎生10.5日目にウォルフ管の後部傍らに局在する後腎間葉からGDNFが分泌され、それがウォルフ管に発現する受容体型チロシンキナーゼRetに結合することによってRet-Erk経路を活性化し、その結果、1本の尿管芽が誘導される。尿管芽は伸長・分岐を繰り返し最終的に集合管を形成するが、一方、後腎間葉は上皮化と管腔形成を経て最終的に尿細管や糸球体等を形成する。受容体型チロシンキナーゼRor2はWnt5a受容体として非古典的Wnt経路を活性化し、形態形成やがんの浸潤・転移などにおいて重要な役割を担っている。また、Ror2が原因である常染色体劣性遺伝性Robinow症候群の患者において低形成腎、嚢胞腎、水腎といった腎奇形が認められることから、Wnt5a-Ror2シグナル, Domestic conference
    Oral presentation

  • 炎症性サイトカインによりアストロサイトで発現誘導されるRor1受容体の機能解析
    Endo Mitsuharu, 土井 亮助, Nishita Michiru, Minami Yasuhiro
    2013年度包括脳ネットワーク夏のワークショップ, Aug. 2013, Japanese, 包括型脳科学研究推進支援ネットワーク, 名古屋, 分化・成熟したアストロサイトは中枢神経系の恒常性維持に働くが、炎症反応を伴う中枢神経傷害時には活性化され、増殖能の亢進や未分化な性質を再獲得することが知られている。損傷時におけるアストロサイトの活性化は損傷を受けた中枢神経系の回復過程で重要な役割を担っていると考えられるが、アストロサイトの未分化性獲得の分子機構とその意義については不明な点が多い。我々は、アストロサイトの活性化を誘導するIL-1βなどの炎症性サイトカインの刺激により、アストロサイトにおいてRorファミリー受容体型チロシンキナーゼRor1の発現が誘導されることを見出した。Rorファミリー受容体型チロシンキナーゼ（Ror1、Ror2）はWnt5aの受容体として機能することで、Wnt5aによる非古典的Wntシグナルを活性化する。我々はこれまでにRor1とRor2が発生過程の大脳皮質神経幹細胞, Domestic conference
    Poster presentation

  • Roles of Wnt/PCP signaling in pathological conditions of epithelial tubular tissues
    Minami Yasuhiro, Kaoru Yamagata, Endo Mitsuharu, Hiroki Otani, Ryuichi Nishinakamura, Nishita Michiru
    First International Meeting for Epithelial Tubulology, Jun. 2013, English, 新学術領域研究, Sapporo, Hokkaido, Japan, Wnt/PCP (Wnt5a-Ror2) signaling has been shown to play crucial roles during developmental morphogenesis by regulating convergent extension movements and PCP. Studies with cultured cells have revealed important roles of Wnt/PCP signaling in regulating various cellular functions, i.e. cell polarity, migration/invasion, proliferation, differentiation, and stemness. Wnt/PCP signalin, International conference
    [Invited]
    Invited oral presentation

  • 筋損傷・再生過程における受容体型チロシンキナーゼRor1の発現解析
    土井 亮助, Endo Mitsuharu, Minami Yasuhiro
    第60回日本生化学会近畿支部例会, May 2013, Japanese, 日本生化学会近畿支部, 大阪, 骨格筋細胞系譜の最終分化細胞は巨大な多核細胞（筋繊維）である。筋繊維の細胞膜上には、単核の細胞が接着しており、これが筋肉の幹細胞(筋サテライト細胞)である。成体筋組織中の筋サテライト細胞は、骨格筋の損傷時に放出される炎症性サイトカインなどにより活性化され増殖を開始し、基底膜を通り抜けた後、筋芽細胞に分化する。分化した筋芽細胞は、活発に分裂・増殖を繰り返しながら損傷部位へと遊走し、互いにあるいは残存する筋繊維と細胞融合して筋管細胞を形成することで最終的に筋繊維が再生される。これまでの研究から、Wntタンパク質が筋損傷後に誘導され、筋サテライト細胞の増殖・分化を制御し筋再生に関与することが示唆されている1)。しかしながら、Wntタンパク質による筋再生制御の分子レベルでの機構については、不明な部分が多い。我々の研究室ではこれまでに、Wntタンパク質のなかで, Domestic conference
    Oral presentation

  • Functional analysis od Ror signaling using differentiation/regeneration model of skeletal muscle
    土井 亮介, Endo Mitsuharu, Minami Yasuhiro
    第35回日本分子生物学会年会, Dec. 2012, Japanese, The Japanese Society of Molecular Biology, 福岡国際会議場・マリンメッセ, Domestic conference
    Poster presentation

  • Role of Wnt5a・Ror2 signaling in the development of mouse kidneys
    Nishita Michiru, 喬 森, 宮本 真理, 山田 真紀子, 大谷 浩, Christine Hartmann, 西中村 隆一, Minami Yasuhiro
    第35回日本分子生物学会年会, Dec. 2012, Japanese, The Japanese Society of Molecular Biology, 福岡国際会議場・マリンメッセ, Domestic conference
    Poster presentation

  • The Role of Ror-Family Receptor Tyrosine Kinases in Maintaining Neocortical Neural Progenitor Cells
    Endo Mitsuharu, 土井 亮助, Nishita Michiru, Minami Yasuhiro
    1st International Symposium Neocortical Organization, Mar. 2012, Japanese, 新学術領域「神経細胞の多様性と大脳新皮質の構築」, 岡崎, Domestic conference
    Poster presentation

  • Ror-family receptor tyrosine kinases regulate maintenance of neural progenitor cells in the developing neocortex
    Endo Mitsuharu, 土井 亮助, Nishita Michiru, Minami Yasuhiro
    第34回日本分子生物学会年会, Dec. 2011, Japanese, 日本分子生物学会, 横浜, Domestic conference
    Poster presentation

  • Dissection of Wnt5a-Ror2 signaling leading to matrix metalloproteinase(MMP)-13 expression
    山形 薫, 池垣俊吉, 李欣, Minami Yasuhiro
    第34回日本分子生物学会年会, Dec. 2011, Japanese, 日本分子生物学会, 横浜, Domestic conference
    Poster presentation

  • Ror-family receptor tyrosine kinases regulate maintenance of neural progenitor cells in the developing neocortex
    Endo Mitsuharu, Nishita Michiru, Minami Yasuhiro
    第63回日本細胞生物学会大会, Jun. 2011, Japanese, 日本細胞生物学会, 北海道, Domestic conference
    [Invited]
    Invited oral presentation

  • Regulation of cell polarity, migration, and tumor invasion by Wnt5a-Ror2 signaling
    Minami Yasuhiro, 山形 薫, Nishita Michiru
    第62回日本細胞生物学会大会, May 2010, Japanese, 日本細胞生物学会, 大阪, Domestic conference
    [Invited]
    Invited oral presentation

  • Expression and functional analysis of Ror-family RTKs during developmental neurogenesis
    Endo Mitsuharu, 任 大勇, 田中 浩之, Minami Yasuhiro
    第32回日本分子生物学会年会, Dec. 2009, Japanese, 日本分子生物学会, 横浜, Domestic conference
    Poster presentation

  • Roles of Protein Phosphorylation in the Regulation of Cell Polarity and Migration Mediated by Wnt5a and Ror2 receptor tyrosine kinase
    Minami Yasuhiro, Nishita Michiru
    第82回日本生化学会大会, Oct. 2009, Japanese, 日本生化学会大会, 神戸, Domestic conference
    Invited oral presentation

  • Ror2受容体型チロシンキナーゼを介したWnt5aシグナル伝達制御
    Nishita Michiru, Minami Yasuhiro
    第1回シグナルネットワーク研究会, May 2009, Japanese, シグナルネットワーク研究会, 東京, Domestic conference
    Oral presentation

  • Analysis of estrogen-regulated microRNA expression
    Yamagata Kaoru, Minami Yasuhiro
    第３１回日本分子生物学会年会, Dec. 2008, Japanese, 日本分子生物学会, 神戸, Domestic conference
    Poster presentation

  • Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A
    Nishita Michiru, Minami Yasuhiro
    第31回日本分子生物学会第81回日本生化学会大会合同大会, Dec. 2008, Japanese, 日本分子生物学会 日本生化学会, 神戸, Domestic conference
    Oral presentation

  • Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase.
    Yoda Akinori, Minami Yasuhiro
    第31回日本分子生物学会年会 第81回日本生化学学会大会 合同大会, Dec. 2008, Japanese, BMB2008, 神戸, Domestic conference
    Poster presentation

  • Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling
    Nin Daiyu, Nishita Michiru, Minami Yasuhiro
    第31回日本分子生物学会年会 第81回日本生化学会大会 合同大会, Dec. 2008, Japanese, 日本分子生物学会 日本生化学会大会, 神戸, Domestic conference
    Oral presentation

  • Regulation of cell migration by Wnt5a/Ror2 signaling
    Nishita Michiru, Minami Yasuhiro
    第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会, Dec. 2008, Japanese, 日本分子生物学会、日本生化学会, 神戸, Domestic conference
    Oral presentation

  • Wnt5a/Ror2 signaling regulates phosphorylation and polymerization of Dishevelled
    Nishita Michiru, Minami Yasuhiro
    第31回日本分子生物学会年会 第81回日本生化学会大会 合同大会, Dec. 2008, Japanese, 日本分子生物学会, 日本生化学会, 兵庫県神戸市, Domestic conference
    Poster presentation

  • Role of Ror2 receptor tyrosine kinase in invasion and metastasis of osteosarcoma cells
    Minami Yasuhiro
    第２回日韓共同研究プログラム合同ミーティング, Nov. 2008, English, 日本学術振興会, 広島, International conference
    Oral presentation

  • Ror2 Regulates Cytoskeletal Rearrangements to Mediate Wnt5a-induced Polarized Cell Migration
    Nishita Michiru, Minami Yasuhiro
    the47ndAmericanSocietyforCellBiologyAnnualMeeting, Dec. 2007, English, 米国細胞生物学会, Washingtoneee DC, アメ, International conference
    Poster presentation

  • Ror2 regulates cytoskeletal rearrangements to mediate Wnt5a-induced polarized cell migration
    Nishita Michiru, Minami Yasuhiro
    第30回日本分子生物学会, Dec. 2007, Japanese, 日本分子生物学会, 横浜, Domestic conference
    Oral presentation

  • Ror2 receptor tyrosine kinase and its implication in human diseases
    Minami Yasuhiro, Nishita Michiru
    日韓共同研究プログラム第１回二国間会議, Oct. 2007, English, 日韓共同研究プログラム, ソウル, 韓国, International conference
    Oral presentation

  • Role of Ror2 receptor tyrosine kinase in the regulation of Wnt5a-induced cell polarization and migration
    Nishita Michiru, Minami Yasuhiro
    日韓共同研究プログラム第１回二国間会議, Oct. 2007, English, 日韓共同研究プログラム, ソウル, 韓国, International conference
    Oral presentation

  • Chk1/Chk2 phosphorylates and stabilizes Wip1 in response to DNA damage.
    Yoda Akinori, Minami Yasuhiro
    第66回日本癌学会学術総会, Oct. 2007, Japanese, 日本癌学会, 横浜, Domestic conference
    Poster presentation

  • Roles of receptor tyrosine kinase Ror2 in Wnt5a-induced non-canonical Wnt signaling
    Minami Yasuhiro, Nishita Michiru
    WNT2007INLAJOLLA, Jun. 2007, English, WNT meeting, LA JOLLA, アメリカ, International conference
    Poster presentation

  • Wnt5aによる細胞移動におけるRor2の機能解析
    NISHITA MICHIRU, MINAMI YASUHIRO
    日本分子生物学会2006フォーラム, Dec. 2006, Japanese, 日本分子生物学会, 名古屋, Domestic conference
    Poster presentation

  • Wip1ホスファターゼによるATMキナーゼを介したDNA損傷応答シグナルの抑制機構
    YODA AKINORI, NISHITA MICHIRU, MINAMI YASUHIRO
    第65回日本癌学会学術総会, Sep. 2006, Japanese, 日本癌学会, 横浜, Domestic conference
    Poster presentation

  • Chk2キナーゼとWip1ホスファターゼの構造機能連関
    YODA AKINORI, Oishi Isao, MINAMI YASUHIRO
    第65回日本癌学会学術総会, Sep. 2006, Japanese, 日本癌学会, 横浜, Domestic conference
    Poster presentation

  • Regulation of cell-cycle checkpoint by nuclear protein kinases and phosphatase: Wip-ing off the fingerprints of ATM kinase by Wip1 phosphatase
    MINAMI YASUHIRO
    2006 international symposium of kobe university 21st century COE program on signsl transduction in memory of Prof. Yasutomi Nkaishizu, Aug. 2006, Japanese, 神戸大学, 神戸, International conference
    Others

  • Wip1 phosphatase is a negative regulator for ATM-mediated DNA damage response
    YODA AKINORI, NISHITA MICHIRU, MINAMI YASUHIRO
    20th IUBMB Congress, Jun. 2006, Japanese, 国際生化学・分子生物学会, 京都, International conference
    Poster presentation

  • Regulation of Wnt5a-induced cell migration by Ror2 receptor tyrosine kinase
    NISHITA MICHIRU, MINAMI YASUHIRO
    20th IUBMB Congress, Jun. 2006, English, IUBMB, 京都, International conference
    Poster presentation

  • Regulation of cell-cycle checkpoint by nuclear protein kinases and phosphatase: Wip-ing off the fingerprints of ATM kinase by Wip1 phosphatase
    MINAMI YASUHIRO
    2006 international symposium of kobe university 21st century COE program on signsl transduction in memory of Prof. Yasutomi Nishizuka, Feb. 2006, English, Kobe university, 神戸, International conference
    Others

  • 受容体型チロシンキナーゼRor2によるWnt/PCP経路の制御とその細胞運動における役割
    NISHITA, Michiru, 野町 昭, 可児 修一, 菊池 章, MINAMI, Yasuhiro
    第28回日本分子生物学会, Dec. 2005, Japanese, 日本分子生物学会, 福岡, Domestic conference
    Others

  • マウス発生過程における受容体型チロシンキナーゼRor2の神経堤由来細胞特異的な発現様式Unique expression pattern of the receptor tyrosine kinase Ror2 in neural crest-derived cells during mouse development
    可児 修一, 五百住 謙吾, 胡 晶イ, NISHITA, Michiru, 山田 源, 薛 富義, TERASHIMA, Toshio, MINAMI, Yasuhiro
    第28回日本分子生物学会, Dec. 2005, Japanese, 日本分子生物学会, 福岡（Yahoo doom）, Domestic conference
    Poster presentation

  • Wip1 phosphatase interacts with SQ/TQ domain of Chk2 kinase and dephosphorylates threonine68 through N-terminal region of Wip1
    YODA, Akinori, Xiao Zhou Xu, Nobuyuki Onishi, Hiroko Fujimoto, Naoko Kato, OISHI, Isao, KONDO, Takeshi, MINAMI, Yasuhiro
    The GlaxoSmithKline Symposium 2005, Nov. 2005, Japanese, グラクソスミスクライン, 筑波, Domestic conference
    Poster presentation

  • マウス歯胚形成における受容体型チロシンキナーゼRor2の機能解析
    森山 健太郎, 可児 修一, 鈴木 泰明, NISHITA, Michiru, MINAMI, Yasuhiro, KOMORI, Takahide
    第50回日本口腔外科学会総会, Oct. 2005, Japanese, 日本口腔外科学会, 大阪, Domestic conference
    Poster presentation

  • The analysis of the receptor tyrosine kinase Ror2 in mouse tooth development
    森山 健太郎, 可児 修一, 鈴木 泰明, NISHITA, Michiru, MINAMI, Yasuhiro, KOMORI, Takahide
    第50回口腔外科学会総会, Oct. 2005, Japanese, 日本口腔外科学会, 大阪, Domestic conference
    Poster presentation

  • DNA損傷応答における核内Chk2キナーゼ・Wip1ホスファターゼの構造・機能連関解析
    大西 伸幸, YODA, Akinori, 藤本 浩子, 加藤 菜穂子, 徐 暁洲, NISHITA, Michiru, MINAMI, Yasuhiro
    第52回日本生化学会近畿支部例会, Sep. 2005, Japanese, 日本生化学会, 神戸, Domestic conference
    Oral presentation

  • DNA損傷に伴う細胞周期チェックポイントの作動・解除及びアポトーシスの制御機構とがんの分子標的治療への応用
    MINAMI, Yasuhiro, 大西 伸幸, 近藤 健, NISHITA, Michiru, YODA, Akinori
    第64回日本癌学会学術総会, Sep. 2005, Japanese, 日本癌学会, 札幌, Domestic conference
    Others

  • Ror2-mediated cytoskeletal reorganization by differential regulation of Dishevelled proteins
    野町 昭, NISHITA, Michiru, 可児 修一, 菊池 章, YODA, Akinori, MINAMI, Yasuhiro
    第58回日本細胞生物学会大会, Jun. 2005, Japanese, 日本細胞生物学会, 埼玉, Domestic conference
    Poster presentation

  • 受容体型チロシンキナーゼRor2の細胞外･細胞内ドメイン依存的機能によるWntシグナルおよび細胞骨格系の制御
    野町 昭, NISHITA, Michiru, 可児 修一, 菊池 章, YODA, Akinori, MINAMI, Yasuhiro
    第52回日本生化学会近畿支部例会, May 2005, Japanese, 日本生化学会, 神戸, Domestic conference
    Oral presentation

  • 形態形成のシグナル伝達における受容体型チロシンキナーゼRor2とFGFR3の機能連関解析
    山本 裕之, 嶋田 直子, 可児 修一, 北川 元生, NISHITA, Michiru, YODA, Akinori, MINAMI, Yasuhiro
    第27回日本分子生物学会, Dec. 2004, Japanese, 日本分子生物学会, 神戸, Domestic conference
    Poster presentation

  • 放射線によるDNA損傷に伴う細胞周期チェックポイントのオン・オフ機構
    MINAMI, Yasuhiro, 大西 伸幸, 藤本 浩子, NISHITA, Michiru, YODA, Akinori
    日本放射線影響学会47回大会, Nov. 2004, Japanese, 日本放射線影響学会, 長崎, Domestic conference
    Others

  • DNA損傷応答におけるWip1を介した細胞周期チェックポイントの解除機構
    大西 伸幸, YODA, Akinori, 武川 睦寛, 近藤 健, NISHITA, Michiru, MINAMI, Yasuhiro
    第63回日本癌学会, Sep. 2004, Japanese, 日本癌学会, 福岡, Domestic conference
    Others

  • The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Ⅰε
    可児 修一, OISHI, Isao, 山本 裕之, YODA, Akinori, 鈴木 泰明, 野町 彰, 菊池 章, 内匠 透, MINAMI, Yasuhiro
    第57回日本細胞生物学会大会, May 2004, Japanese, 日本細胞生物学会, 大阪, Domestic conference
    Oral presentation

  • Structure-function analyses of protein kinase and phosphatase involved in intranuclear signaling in response to DNA damage
    Nobuyuki Onishi, Hiroko Fujimoto, Naoko Kato, Xiao Zhou Xu, Marika Horiuchi, Mutsuhiro Takekawa, YODA, Akinori, OISHI, Isao, MINAMI, Yasuhiro
    第57回日本細胞生物学会, May 2004, Japanese, 日本細胞生物学会, 大阪, Domestic conference
    Poster presentation

  • DNA損傷時の核内シグナル伝達のリン酸化・脱リン酸化による制御機構： Wip1ホスファターゼによるChk2キナーゼの活性制御機構
    MINAMI, Yasuhiro
    第26回日本分子生物学会, Dec. 2003, Japanese, 日本分子生物学会, 神戸, Domestic conference
    Others

  • CKIεによる受容体型チロシンキナーゼRor2の活性化機構
    可児 修一, OISHI, Isao, 山本 裕之, YODA, Akinori, 鈴木 泰明, 菊池 章, 内匠 透, MINAMI, Yasuhiro
    第26回日本分子生物学会年会, Dec. 2003, Japanese, 日本分子生物学会, 神戸, Domestic conference
    Oral presentation

  • CKIeによる受容体型チロシンキナーゼRor2の活性化機構
    可児 修一, OISHI, Isao, 山本 裕之, YODA, Akinori, 鈴木 泰明, 菊池 章, 内匠 透, MINAMI, Yasuhiro
    第26回日本分子生物学会, Dec. 2003, Japanese, 日本分子生物学会, 神戸, Domestic conference
    Poster presentation

  • DNA損傷応答における核内シグナル伝達に関わる蛋白質キナーゼ・ホスファターゼの構造・機能連関解析
    大西 伸幸, 藤本 浩子, 加藤 菜穂子, 徐 暁州, 堀内 真理佳, 武川 睦寛, YODA, Akinori, OISHI, Isao, MINAMI, Yasuhiro
    第75回日本生化学会, Oct. 2003, Japanese, 日本生化学会, 京都, Domestic conference
    Poster presentation

  • Developmental signaling mediated by Ror family receptor tyrosine kinases
    OISHI, Isao, MINAMI, Yasuhiro
    第75回日本生化学会, Oct. 2003, Japanese, 日本生化学会, 京都, Domestic conference
    Others

  • DNA損傷応答における核内Chk2キナーゼのWip1ホスファターゼによる活性制御機構
    藤本 浩子, 加藤 菜穂子, MINAMI, Yasuhiro
    日本癌学会62回総会, Sep. 2003, Japanese, 日本癌学会, 名古屋, Domestic conference
    Others

■ Research Themes
  • Study of support and promotion for aging research
    Yasuhiro Minami
    AMED, AMED-CREST, AMED-CREST, Graduate School of Medicine, Kobe University, Oct. 2022 - Mar. 2030, Principal investigator

  • Early diagnosis of ovarian cancer using vaginal secretion extracted miRNA and development of nucleic acid therapy using artificial exosomes
    寺井 義人, 高橋 良輔, 笹川 勇樹, 出口 雅士, 長又 哲史, 犬伏 祥子, 竹内 俊文, 南 康博, 谷村 憲司, 若橋 宣, 遠藤 光晴
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, Apr. 2024 - Mar. 2027

  • 膵がん治療のためのRhoファミリーGTPaseとその共役分子阻害剤の検証
    南 康博
    日本医療研究開発機構, 創薬ブースター（創薬支援ネットワーク）, 神戸大学大学院医学研究科, Apr. 2025 - Mar. 2026, Principal investigator

  • Challenge toward the Control of Intractable Cancer through Understanding of Molecular, Cellular, and Interorgan Networks
    Yasuhiro Minami
    CAO, ムーンショット型研究開発制度2, 2050年までに超早期に疾患の予測・予防をすることができる社会を実現, 神戸大学大学院医学研究科, Dec. 2020 - Nov. 2025, Others

  • miR-622内包人工エクソソームによる卵巣癌の浸潤・転移と微小環境制御
    寺井 義人, 高橋 良輔, 谷野 裕一, 長又 哲史, 南 康博, 遠藤 光晴, 鈴木 嘉穂
    日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 01 Apr. 2020 - 31 Mar. 2023
    卵巣癌は早期から腹膜浸潤・転移を引き起こす予後の悪い癌であり、癌の進展の中心的な働きをするEMT現象をターゲットとし、より特異的で効果的な卵巣癌治療の開発基盤を構築することを目指し、卵巣癌細胞のみならずニッチを構成するCAFs及びTAM（M2-THP-1）にも注目し、卵巣癌における卵巣癌細胞やCAFs、TAMなどニッチ構成細胞群全体の制御を目指している。ここで、卵巣癌の耐性性に影響を与えている鉄硫黄クラスターを含む、低分子の酸性タンパク質でステロイドの生合成、その他のミトコンドリアのCYP450の反応に重要な役割を持つFerredoxin 1に注目した。白金製剤感受性株のA2780、OVK18および白金製剤耐性株のA2780cisを用いて、Ferredoxin 1がCisplatin耐性化に影響を与えるか機能解析を行い、卵巣癌のkey drugである白金製剤のCisplatinの感受性を高め、卵巣癌の進展の中心的な働きをするEMT現象への影響を卵巣癌のニッチを構成するCAFs及びTAM（M2-THP-1）への影響を解析し、卵巣癌における卵巣癌細胞やCAFs、TAMなどニッチ構成細胞群全体の制御を目指している。今回の実験では、様々な癌の制御に大きく関与するFerroptosis(鉄依存性細胞死)との関連についての研究を行い、siRNAを用いてFerredoxin 1をknock downさせることでCisplatin耐性を解除し、有意差をもってCisplatin感受性が高くなりFerroptosisを誘導できていることを確認した。さらに、増殖能、浸潤能への影響を調べている。

  • Elucidation of the osteoclast-derived cytokine-Wnt signaling network responsible for coupling between bone resorption and formation.
    Takahashi Naoyuki
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Matsumoto Dental University, 01 Apr. 2016 - 31 Mar. 2019
    Clastokines secreted by osteoclasts were analyzed. (1) Osteoclasts secreted LIF, which suppressed the secretion of sclerostin by osteocytes. Thus, osteoclasts promoted osteoblastic bone formation through the up-regulation of Wnt-βcatenin signals. (2) W9 peptides suppressed bone resorption activity of osteoclasts and suppressed sclerostin expression by osteocytes. Thus, W9 increased the alveolar bone mass. (3) Osteoclasts abundantly secreted Wnt5a. Wnt5a binds to its receptor, Ror2, which is expressed by osteoclasts. The Wnt5a-Ror2 signal in osteoclasts induced bone-resorbing activity through Daam2→ Rho→ PKN3→ cSrc/Pyk2 signals. (4) Osteoclasts specifically secreted HtrA1, which degraded OPG, suggesting that osteoclasts potentially prepare a microenvironment that is suitable for osteoclastogenesis. Thus, osteoclasts secrete various Clastokines that are involved in bone metabolism.

  • 南 康博
    科学研究費補助金／基盤研究(B), Apr. 2016 - Mar. 2019, Principal investigator
    Competitive research funding

  • (AMED)老化機構・制御研究拠点/加齢に伴う細胞形態・運動制御の異常の分子機構
    南 康博
    国立大学法人大阪大学, 老化メカニズムの解明・制御プロジェクト, 2017, Principal investigator
    Competitive research funding

  • Regulation of polarity signaling during morphogenesis, remodeling, and breakdown of epithelial tubular structure
    Kikuchi Akira, MINAMI YASUHIRO, OHNO SHIGEO, SABE HISATAKA, OHTANI HIROKI, SUZUKI ATSUSHI, OHASHI KAZUMASA, TAKENAWA TADAOMI, MIYAJIMA ATSUSHI, HONDA HISAO
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Osaka University, 01 Apr. 2011 - 31 Mar. 2016
    Epithelial tubular tissues are essential structures of many organs, including lung, gut, kidney, exocrine glands, in multi-cellular organisms. The molecular mechanism underlying the regulation of cellular functions in an individual cell has been so far clarified. In the next decade the understanding of how cells form tissues or organs is one of the important issues in life science field. Moreover, research of diseases from the viewpoint of disruption of epithelial tubular tissues would contribute to solve various problems in medical science field. Therefore, we organized the research group that performs to clarify morphogenesis, remodeling, and breakdown of epithelial tubule structure. This five-year research program succeeded in demonstrating new results for the understanding of tubulogeneis and implication of its abnormality in diseases.

  • 南 康博
    学術研究助成基金助成金／挑戦的萌芽研究, Apr. 2014 - Mar. 2016, Principal investigator
    Competitive research funding

  • 南 康博
    科学研究費補助金／基盤研究(B), Apr. 2012 - Mar. 2015, Principal investigator
    Competitive research funding

  • MINAMI Yasuhiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Exploratory Research, Kobe University, Apr. 2011 - Mar. 2013, Principal investigator
    In this study it has been found that Rif, a member of the Rho-family of small G-proteins, and emerin, an integral nuclear membrane protein, play a critical role in the morphological regulation of plasma membrane and nuclear membrane by Wnt5a-Ror2 signaling. Furthermore, it has been indicated that Rif and its putative upstream regulator, Rap1GDS1, are involved in cancer cell proliferation in addition to their role in filopodia formation of cancer cells.
    Competitive research funding

  • 南 康博
    科学研究費補助金／新学術領域研究, 2011, Principal investigator
    Competitive research funding

  • 南 康博
    科学研究費補助金／基盤研究(B), 2009, Principal investigator
    Competitive research funding

  • 南 康博
    科学研究費補助金／基盤研究(B), 2007, Principal investigator
    Competitive research funding

  • 糖尿病をモデルとしたシグナル伝達病拠点
    春日 雅人
    2006
    Competitive research funding

  • 南 康博
    科学研究費補助金／萌芽研究, 2006, Principal investigator
    Competitive research funding

  • 南 康博
    科学研究費補助金／特定領域研究, 2005, Principal investigator
    Competitive research funding

  • 糖尿病をモデルとしたシグナル伝達病拠点
    春日 雅人
    2005
    Competitive research funding

  • 細胞周期制御機構の破綻と悪性腫瘍
    南 康博, 依田 成玄, 大石 勲
    日本学術振興会, 科学研究費助成事業, 特定領域研究, 神戸大学, 2003 - 2004
    細胞は内的・外的要因によりDNA損傷を受けると、細胞周期チェックポイント機構を作動させ、一時的に細胞周期を停止させ、損傷修復を行うかアポトーシスを誘導することにより、生体におけるゲノムの恒常性を維持している。DNA損傷後、まず(がん抑制遺伝子産物である)ATM, ATRキナーゼがリン酸化・活性化され、これらのキナーゼが(同じくがん抑制遺伝子産物であり)チェックポイントキナーゼであるChk1,Chk2キナーゼをリン酸化・活性化し、引き続きChk1,Chk2キナーゼがp53、Cdc25などの一連のエフェクター分子をリン酸化・活性制御することによりチェックポイント機構を作動させ、一時的な細胞周期停止を誘導することが知られている。しかしながら、DNA損傷修復後、細胞周期を再開させる"チェックポイントの解除機構"については不明であった。本研究により、DNA損傷後にp53依存的に発現誘導される(がん遺伝子産物である)Wip1ホスファターゼが、ATM, Chk1,Chk2キナーゼの活性化に必須のリン酸化部位(ATM : Ser-1981,Chk1:Ser-317,345,Chk2:Thr-68)を特異的に脱リン酸化し、不活化することによりチェックポイント機構を解除することが明らかとなった。また、Wip1ホスファターゼは、直後にグルタミンが続くリン酸化セリンまたはリン酸化スレオニンを選択的に脱リン酸化することが示された。さらに、放射線によるDNA損傷時において、Chk2はアポトーシス誘導に、またWip1はアポトーシス阻害に働き、両分子が拮抗的に作用することが見出された。

  • 形態形成過程における受容体型チロシンキナーゼRor1,2の機能解析
    南 康博
    日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2002 - 2002

  • 細胞周期制御機構の破綻と悪性腫瘍
    南 康博, 依田 成玄, 大石 勲
    日本学術振興会, 科学研究費助成事業, 特定領域研究, 神戸大学, 2001 - 2001
    本年度の研究においては、まず癌遺伝子産物であるH-Ras(H-RasV12)とc-Mycの協調作用を解析する目的で、これらの分子を単独あるいは両者を構成的に発現するリンパ球系細胞株を用いて、細胞接着能及び低酸素状態に対する感受性を比較検討した。その結果、(1)H-Ras, c-Myc両者を発現する細胞株においては、ラミニンの受容体であるalpha6インテグリンが(主に転写レベルでの制御により)発現抑制されており、実際ラミニン接着性が殆ど消失していること、また(2)この細胞株では、レポーターアッセイの結果HIF1の転写活性化能が顕著に亢進していること、また実際塩化コバルトにより引き起こされた低酸素状態によるアポトーシス誘導に対して耐性になっていることが見出された。次に、癌抑制遺伝子産物であるChk2キナーゼのDNA損傷時における機能を明らかにする目的で、既にyeast two hybridスクリーニングによりChk2と会合することが示唆されていたWip1ホスファターゼとChk2キナーゼとの物理的・機能的連関について、特にリン酸化・脱リン酸化による制御を念頭に置いて、細胞生物学的・生化学的解析を行った。その結果、Chk2とWip1が会合し、実際両分子が核内において共局在することが見出された。また、DNA損傷時にChk2のThr68が(ATMキナーゼまたは自己リン酸化により)リン酸化を受けることがその活性化に重要であることが知られていたが、Wip1がリン酸化を受けたThr68を脱リン酸化することが明らかとなった。さらに、DNA損傷時の細胞応答におけるChk2キナーゼの多彩な機能を解明する目的で、体系的なyeast two hybridスクリーニングを行い、Chk2と会合しうる分子として新たにPAPSS1、AF10、UMP/CMPキナーゼを同定することに成功した。

  • リンパ球系悪性腫瘍の浸潤・転移の分子機構解析
    南 康博, 大石 勲
    日本学術振興会, 科学研究費助成事業, 特定領域研究(C), 神戸大学, 2000 - 2000
    がん細胞の浸潤・転移の分子機構ならびに(放射線等の)DNA損傷刺激に対する感受性制御機構を解明することは、がんの病態を理解する上で重要であるのみならず、がんの診断・治療を行う上で有用な知見を提供するものと考えられる。本研究により、まずプロB細胞株BAF-B03において活性型H-Rasがalpha6インテグリンを活性化し、その結果ラミニンへの細胞接着性が亢進すること、また活性型H-Rasがc-Mycと協調的に作用することにより、VCAM-1の発現を誘導するとともに、alpha6インテグリンの発現を抑制することが明らかとなった。活性型H-Rasとc-Mycを構成的に発現するBAF-B03細胞はin vitroにおいて顕著な細胞凝集を呈するとともに、ヌードマウスに移植した際に腫瘍の浸潤・転移を引き起こすが、腫瘍細胞の原発巣からの離脱の過程において、alpha6の発現抑制によるラミニン接着性の低下が関与していることが考えられる。また、本年度の研究における一連のHodgkin,non-Hodgkinリンパ腫細胞株を用いた解析から、Chk2キナーゼがリンパ球系悪性腫瘍の放射線感受性を制御する重要な分子であることが明らかとなった。即ち、放射線感受性の高いHodgkinリンパ腫細胞株においては、放射線耐性のnon-Hodgkinリンパ腫細胞株に比べて、顕著にChk2の発現が低いことが明らかとなった。さらに今回、Chk2キナーゼと共役する分子として核内蛋白質ホスファターゼを同定することに成功した。

  • 減数分裂におけるDmnk/Cds1キナーゼ及びRNA結合蛋白質の機能解析
    南 康博, 大石 勲
    日本学術振興会, 科学研究費助成事業, 特定領域研究(A), 神戸大学, 2000 - 2000
    本年度の研究においては、まずショウジョウバエの生殖細胞核内に特異的に発現する蛋白質キナーゼDmnk(Drosophila maternal nuclear kinase)とRNA結合蛋白質Orbとの結合様式の解析を行った。その結果、DmnkのFHA(forkhead associated)ドメイン、リンカードメインが両者の会合に必要なこと、Dmnk-Lに存在する17アミノ酸残基の挿入部位が両者の結合に阻害的に働くことが明らかとなった。また、Orb蛋白質のQ-richドメインを含む領域が、両者の会合に必須であることが示された。さらに、EMSA法ならびに免疫沈降/PCR法により、Orb蛋白質がDmnk mRNAの3′UTRに結合することを明らかにした。線虫のDmnk相同分子(Ce-Cds-1)については、データベース解析によりCe-Cds-1に加え、Ce-Cds-2が存在する可能性を見出した。既に、Ce-Cds-1(Ce-Cds-2)が卵形成過程の減数分裂における相同組み換えに必須の役割を担うことを明らかにしていたが、本年度は、RNA干渉法によりCe-Cds-1(Ce-Cds-2)が精子形成過程においても必須の役割を担うことを示した。さらに本年度の研究においては、哺乳動物のDmnk,Ce-Cds-1,2相同分子であるChk2の遺伝子クローニングを行い、Chk2がリンパ球系悪性腫瘍の放射線感受性の制御に関わることを示唆する知見を得ている(未発表)。

  • Establishment of inflammatory and malignant tumor disease model mice based on abnormalities in adhesiveness of immune cells and its clinical application.
    MINAMI Yasuhiro, IIGO Yutaka, TANAKA Yoshiya
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B)., Kobe University, 1999 - 2000
    In this study we found that in mouse pro-B cell line, BAF-B03 cells, an active form of H-Ras activates α_4 and α_6 integrins, thereby enhancing cell adhesiveness to fibronectin and laminin. It was also found that functional cooperation of an active form of H-Ras and c-Myc results in the activation of α_4 integrin, the induction of VCAM-1, a counter-receptor for VLA-4 (α_4β_1), and in the down-regulation of α_6a integrin, leading to homophilic cell aggregation and to a loss of cell adhesiveness to laminin. Furthermore, it was shown that BAF-B03 cells constitutively expressing an active form of H-Ras and c-Myc form tumor and exhibit invasion and metastasis when injected into nude mice. Loss of laminin binding of BAF-B03 cells expressing active H-Ras and c-Myc may contribute to infiltration of tumor cells from primary nodules. It would be of interest to examine whether or not functional cooperation of H-Ras and c-Myc in regulating the expression and/or activity of cell adhesion molecules is cell-type specific. In this study, we also showed that synovial cells from patients of Rheumatoid Arthritis (RA) can be separated into two functionally distinct subsets on the basis of the expression levels of ICAM-1. ICAM-1-positive cells exhibit cell cycle arrest and undergo apoptosis, while ICAM-1-negative cells proliferate efficiently and continuously. It is assumed that ICAM-1-negative synovial cells in RA patients can be an important therapeutic target.

  • 生殖細胞成立に関わるキナーゼmRNAの動態及びキナーゼによる転写制御の機構解析
    南 康博, 杉山 伸
    日本学術振興会, 科学研究費助成事業, 特定領域研究(A), 神戸大学, 1999 - 1999
    本年度の研究においては、まずショウジョウバエの生殖細胞に特異的に発現する核内蛋白質キナーゼDmnk(Drosophila maternal nuclear kinase)に会合する分子の検索をyeast two hybrid法により行い、卵形成過程においてDmnkと類似の発現様式を呈するRNA結合蛋白質、Orbを同定することに成功した。また、Dmnk蛋白質には、択一的スプライシングの結果Dmnk-LとDmnk-Sが存在するが、Dmnk-SのみがOrbと会合することが明らかになった。我々はさらに、Orb蛋白質がDmnk mRNAに結合することを示唆する知見を得ている(論文準備中)。また我々は、データベースの解析結果をもとに、線虫のDmnk相同分子であるCe-Cds-1の同定、遺伝子クローニングを行った。 Ce-Cds-1もDmnkと同様にforkheadassociated(FHA)ドメインをN末端側に有しており、最近注目を集めているCds1/Chk2ファミリーに属することが示された。Ce-Cds-1の機能を解析する目的で、RNA干渉法(RNAi)を行ったところ、F_2progenyの大部分が胚性致死であり、生存したものについてはHIM(high incidence of male)の表現型が認められた。さらに詳細な解析の結果、Ce-Cds-1が減数分裂における相同組み換えに必須の役割を担う蛋白質キナーゼであることが明らかになった(論文投稿中)。

  • 生体防御と癌化を制御する遺伝子群の研究
    谷口 維紹, 田中 信之, 宮崎 忠昭, 瀧 伸介, 原田 久士, 南 康博
    日本学術振興会, 科学研究費助成事業, 特定領域研究(A), 1999 - 1999
    リンパ球増殖・分化におけるサイトカインシグナルの解析を受容体の下流のシグナル伝達分子の解析を中心に行ってきたが、非受容体型チロシンキナーゼPyk2がIFN-γによってJak2依存性に活性化されることを明らかにした。さらに、Pyk2のドミナントネガティブPKMを用いた実験より、Pyk2はIFN-γによるStat1のセリンリン酸化を担うエフェクター分子であることが解り、Stat1の転写活性化、更に抗ウイルス活性の誘導に深く関与する重要な分子であることを明らかにした。同時に、Jak2により活性化されたPyk2はIFN-γによるErk2の活性化経路にも関与していることも見出ている。また、IL-2シグナル伝達の解析から、IL-2Rγc鎖の膜直下にJak3を介さない新たなシグナル伝達ドメインが存在することを明らかにした。 転写因子IRF-1が細胞レベルでは癌抑制因子として機能し、細胞周期やアポトーシスの制御に重要であることを明らかにしてきたが、マウス個体での解析から、IRF-1欠損単独では自然発癌の発生は上昇しないが、Ha-ras遺伝子のトランスジェニックマウスやp53欠損マウスと掛け合わせることで、これらのマウスが有する潜在的な腫瘍発生の頻度が著明に上昇する事を見出した。特にIRF-1,p53両欠損マウスを作製し解析した結果、このマウスがp53単独欠損に比べ腫瘍の発生率が上昇し、早期に多臓器に腫瘍を発生することが明かとなった。このことから、IRF-1が新規の高発がん感受性遺伝子(tumor susceptibility gene)であることを明らかにした。

  • functional analyses of receptor tyrosine kinases mRor1 and mRor2 that are involved in the development of the nervous system.
    MINAMI Yasuhiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 1998 - 1999
    In this study, we first examined expression patterns of the receptor tyrosine kinases, mRor1 and mRor2, during mouse development. It was found that spatio-temporal expressions of mRor1 and mRor2 are differentially regulated during mouse development. mRor1 was expressed in limb buds (proximal part), branchial arches, lung, heart, and restricted regions of the nervous system, while mRor2 expression was detected in limb buds (distal part), tail buds, somites (dermatomyotomes), lung, heart, and the nervous system (forebrain, midbrain). To elucidate the functions of mRor1 and mRor2, we have established mutant mice (knock-out mice) lacking the expression of mRor1 or mRor2, and analyzed phenotypes of these mutant mice. Both mRor1 and mRor2 mutant mice died after birth within 24 hrs and 6 hrs, respectively, yet their phenotypes were different. mRor1 mutant mice did not exhibit abnormalities in their appearance, but they died due to a progressive pulmonary dysfunction. On the other hand, mRor2 mutant mice exhibited severe cyanosis (due to pulmonary dysfunction and VSD) with abnormal appearances in their skeletal system, and died within 6 hrs after birth. In mRor2 mutant mice, there were dysfunctions of osteogenesis (ossification) in their fore- and hind-limbs at distal parts. In addition, the fusion of their ribs and deformity of their vertebrae were also observed. As mentioned above, although mRor1 mutant mice did not exhibit apparent abnormality in their skeletal systems, it was found that the skeletal abnormalities in mRor1/mRor2 mutant mice (mRor1/mRor2 double knock-out mice) were severer than those observed in mRor2 mutant mice. Taken together, our findings indicate that mRor2 as well as mRor1 play crucial roles in the formation of the skeletal system during development.

  • Functional analyses of roles of tyrosine kinases/phosphatases in lymhpcyte signaling
    MINAMI Yasuhiro, KOSUGI Atsushi, OGATA Masato, OTANI Hiroki, UMEHARA Hisanori, TANAKA Yosiya
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A)., Kobe University, 1998 - 1999
    In this study, we have found that the proto-oncogene products, H-Ras and c-Myc, act co-operatively to induce homophilic cell adhesion of lymphocytes through the induction of VLA-4 activation and of VCAM-1 expression (Minami, Tanaka). It was also shown that Syk tyrosine kinase and SHP-2 tyrosine phosphatase play important roles in IL-2-induced signal transduction (O'Shea). It was found that an adaptor molecule, LAT is palmitoylated and sequestered at GEM, and is required for the development and activation of T lymphocytes (Samelson). An importance of GEM in T cell engagement was also elucidated (Kosugi). In this study, we have established an experimental system using exo utero method, aiming to examine the effects of tyrosine kinase/phosphatase inhibitors on lymphocyte development in vivo (Otani). We have also shown that a lymphocyte-specific tyrosine phosphatase, LC-PTP, inhibits ERK that is activated during T cell activation (Ogata). It was reported that topoisomerase II inhibitors induce apoptosis of lymphocytes. In this study, it was found that Lyn tyrosine kinase regulates positively the topoisomerase II inhibitor-induced apoptosis of lymphocytes (Yamamura). We have also examined a possible role of tyrosine phosphatases in the process of lymphocyte-macrophage interaction (Moriyama). It was shown that engagement of LFA-1 and of TCR results in a synergistic tyrosine phosphorylation of Fak tyrosine kinase (Umehara). In this collaborative study, we have exchanged results mutually, and have discussed about the respective results extensively. We have also discussed to plan our future collaborative experiments.

  • 生殖細胞特異的な新規遺伝子mRNAの細胞内局在化及びスプライシング制御の機構解析
    南 康博, 杉山 伸
    日本学術振興会, 科学研究費助成事業, 特定領域研究(A), 神戸大学, 1998 - 1998
    ショウジョウバエの生殖細胞に特異的に発現する新規核内蛋白質キナーゼDmnk(Drosophilamaternal nuclear kinase)は卵形成過程における択一的スラプイシングの結果、Dmnk-L,Dmnk-Sの2種のキナーゼが存在する。本年度の研究においては、まずエピトープタギングを行ったDmnk-L,Dmnk-S蛋白質をCOS細胞に遺伝子導入により強制発現させ、これらキナーゼ蛋白質の細胞内分布を免疫化学的方法により解析した。その結果、Dmnk-Lが殆ど核内においてのみ局在が認められるのに対し、Dmnk-Sは細胞質、核内の両者に局在することが明らかとなった。従って、択一的スプライシングの結果、2つのキナーゼアイソフォームの細胞内分布が異なることが示された。また、Dmnkの機能を解析する目的で、Dmnkと会合する分子の検索をyeast two hybrid法を用いて行ったところ、RRMを有するボディーパターン形成に関わる遺伝子産物と会合することを示唆する知見を得た。さらに、Dmnkが今回同定した遺伝子産物とin vivoにおいても会合するか否か、またこの遺伝子産物の機能をリン酸化により制御するか否か、解析を行った。また、データベース解析を行ったところ、線虫においてもDmnkの相同キナーゼ(Cmnk:C.elegans or tholog of Dmnk)が存在することが明らかとなった。RNAi法による機能解析を行ったところ、Cmnkの発現を抑制すると多くの線虫胚において胚性致死の表現型が認められるが、一部では発生が進行し(エスケーバーと呼ばれる表現型)発生が進行した線虫においては、him(high incidence of male)と呼ばれる表現型が観察された。また、RNAi法を行った線虫においては減数分裂の異常が認められることが明らかとなった。

  • ショウジョウバエの生殖細胞に特異的な新規核内蛋白質キナーゼDmnkの機能解析
    南 康博, 杉山 伸
    日本学術振興会, 科学研究費助成事業, 特定領域研究(A), 神戸大学, 1998 - 1998
    本年度の研究においては、ショウジョウバエの生殖細胞に特異的に発現する新規核内蛋白質キナーゼDmnk(Drosophila maternal nuclear kinase)の細胞レベルにおける詳細な発現解析を行った。Dmnkは卵形成過程における択一的スプライシングの結果、Dmnk-L,Dmnk-Sの2種のキナーゼが存在することが明らかとなっている。そこで、まずエピトープタギングを行ったDmnk-L,Dmnk-S蛋白質をCOS細胞に遺伝子導入により強制発現させ、これらのキナーゼ蛋白質の細胞内局在を免疫化学的方法により解析した。その結果、Dmnk-Lが殆ど核内においてのみ局在が認められるのに対し、Dmnk-Sは細胞質内、核内の両者に局在することが明らかとなった。従って、これらの2つのキナーゼが細胞内において異なる機能を有する可能性が示唆された。現在、Dmnkの機能を明らかにする目的で、Dmnkと会合する分子の検索をyeast twohybrid法を用いて行っているが、既に既存のあるボディーパターン形成に関わる遺伝子産物と会合することを示唆する知見を得ている。また、データベース解析を行ったところ、線虫においてもDmnkの相同キナーゼ(Cmnk:C.elegans ortholog of Dmnk)が存在することが明らかとなった。Cmnkの機能を明らかにする目的で、RNAi法による解析を行ったところ、Cmnkの発現を抑制すると多くの線虫胚において胚性致死の表現型が認められるが、一部では発生が進行し(エスケーパーと呼ばれる表現型)発生が進行した線虫においては、him(high incidence ofmale)と呼ばれる表現型が観察された。また、RNAi法を行った線虫においては減数分裂の異常が認められることが明らかとなった。

  • マウス初期歯胚発生に関わる新規蛋白質キナーゼの検索・同定
    南 康博
    日本学術振興会, 科学研究費助成事業, 萌芽的研究, 神戸大学, 1997 - 1997
    本年度の研究においては、まずマウス初期胚盤胞において特異的に発現する新規蛋白質キナーゼ(以下キナーゼ)の検索・同定を試みた。Jackson Laboratory(USA)より供与された初期胚盤胞特異的cDNA libraryを鋳型とし、キナーゼにおいて良く保存されている亜領域VIB、IXに対応するdegenerate primersを用いてPCR法を行い、キナーゼ亜領域VIB、IX間の塩基配列を増幅後その塩基配列を決定した。その結果、計14種のキナーゼを同定することが出来たが、いずれも既存のキナーゼであった。(その内訳は、PDGF受容体をはじめとする5種の受容体型チロシキナーゼ、Srcをはじめとする5種の非受容体型チロシンキナーゼ、及び4種の細胞周期制御に関わるセリン・スレオニンキナーゼである。)本研究を行っている過程において、我々はショウジョウバエの生殖細胞成立に関わる新規核内セリン・スレオニンキナーゼDmnkの同定に成功した。そこで、Dmnkのマウス相同分子を検索・同定する目的で、熊本大学阿部博士から供与を受けたライブラリーを用い、まず胎生13.5日のマウス胚より単離された始原生殖細胞(PGC)特異的cDNAライブラリーを鋳型とし、上述の手法を用い、PGCにおいて発現する新規キナーゼの検索を行った。その結果現在までに、17種のキナーゼを同定することが出来た。これらのキナーゼの内、15種は既知のキナーゼであったが、2種のキナーゼは新規のキナーゼであることが明らかとなった。今後これら2種のキナーゼ遺伝子のcDNA全長のクローニング、詳細な発現解析を行う一方、さらに新規キナーゼのスクリーニングを継続することでDmnkのマウス相同分子の検索・同定を行いたいと考えている。

  • Analysis of expression and function of regulatory molecules in the whole embryos by new developmetnal engineering system
    OTANI Hiroki, YAMADA Gen, MINAMI Yasuhiro, TAKAHASHI Naoki, SAKAGAMI Hiroyuki, AIBA Atsu
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A), Shimane Medical University, 1996 - 1997
    1. Using exo utero development system, functions of several regulatory molecules in the histogenesis of the organs including brain, adrenal cortex, and joints were elucidated. Introduction of exo utero system to the similar analyzes on the following molecules were designed and have been partially initiated. (Otani) 2. K-ras (-/-) mice are embryonic lethal and the embryonic heart has extremely thin wall, whereas H-ras (-/-) and N-ras (-/-) mice appear normal throughout their life span. H-ras (-/-) N-ras (-/-), and H-ras (+/-) N-ras (+/-) K-ras (+/-) mice are viable, suggesting that biallelic expression of K-ras gene or monoallelic expression of both N-ras and K-ras genes are sufficient for mouse development. (Aiba) 3. We cloned a rat homologue of the human Death-associated protein kinase (DAP kinase). DAP kinase was expressed in both mantle and ventricular zones of the entire neuraxis on E15. The expression decreased markedly after birth in the brain, but was maintained in several restricted mature neuronal populations, suggesting that DAP kinase is involved partially in the programd neuronal cell death but in other neuronal functions including synaptic plasticity. (Sakagami) 4. We identified several candidate Hox gene targets, including a mouse homologue of the C.elegans gene mab21 (mmb). To analyze the function of mmab we generated transgenic mice and prepared antibodies against mmab gene product. (Takahashi) 5. We have identified and characterized novel Drosophila protein kinases, Dnrk and Dmnk, expressed specifically in the developing nervous system and in germline during its establishment, respectively. We have also identified and characterized mouse orthologs of Dnrk, mRor1 and mRor2. We are now investigating their functional roles in the development of the nervous system. (Minami) 6. We showed that homeobox gene Goosecoid mutant mice display abnormalities in the trachea, appendicular skeleton and external genitalia. Given the similar expression pattern and the knock-out phenotypes of the Goosecoid and Msx1 genes, the double ko mice for them were created. The data imply the presence of some genetic interactions involved in the patterning of middle ear bones. (Yamada)

  • T細胞活性化のシグナル伝達
    斉藤 隆, 岸原 健二, 高橋 秀実, 南 康博, 藤原 大美, 上出 利光
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 千葉大学, 1996 - 1996
    T細胞活性化の為のTCRシグナル、Co-stimulationシグナル、IL-2受容体を介する増殖シグナルの各々の解析と相互の制御機構の理解が進んだ。 (1)CD3鎖と会合し、活性化に伴ってリン酸化を受け、IL-2産生に重要な新規分子のCASTをクローニングした。Fyn/Lynダブル欠損マウスを解析し、受容体シグナルには複数のSrcキナーゼが関与することを明らかにした。CD45は、T細胞分化のみならずNK細胞の活性化にも重要であることが欠損マウスの解析から判明した。一方、担癌マウスにおけるTCR複合体の構造異常がマクロファージ由来の酸化ストレスによることが明らかになった。 (2)Co-stimulation受容体CD28/CTLA4に結合する、新しいリガンドACBMをクローニングした。また、CTLA4結合分子としてアダプターAP_2複合体のμ_2をクローニングし、この結合とチロシンリン酸化が、CTLA4の細胞表面発現を調節していることを明らかにした。また、CD40Lがマクロファージを活性化してIL-12を産生させ、それがT細胞からIFN-γを産生させることを明らかにした。更に、B7-1を導入した腫瘍細胞の免疫によって特異的なCTLを誘導することができ、このT細胞を移入することによって腫瘍拒絶に成功した。 (3)IL-2受容体を介する増殖シグナルにbclが重要であることが明らかになった。bclは、サイクリンD3の分解を抑え、安定化し、細胞周期を調節する。またBAG-1と強調的に働くことを見出した。Jak3欠損マウスにおける末梢T細胞の解析から、Jak3は増殖シグナルのみでなく、T細胞のネガティブ選択と機能の維持に重要であることが明かとなった。

  • Molecular basis of pathophysiological role of Syk in blood and immumecells
    YAMAMURA Hirohei, SADA Kiyonao, YANAGI Shigeru, MINAMI Yasuhiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), KOBE UNIVERSITY, 1995 - 1996
    A non-receptor type protein-kinase Syk is expressed in almost all the hematopoietic cells. In this project we tried to found out the physiological role of Syk in signal transduction and also pathophysiological role od Syk. We have obtained the following results. 1)Human leukemic cell line K562 is induced to differentiate into the megakaryocytic lineage by stimulation with TPA.We found that TPA stimulation increases tyrosine phosphorylation of 80-kDa protein at an early stage of megakaryocytic differentiation and that this 80-kDa protein is identical with cortactin. 2)The roles of Syk and Lyn in radiation-induced signal transduction and radiation-induced apoptosis, we have studied using Syk-and Lyn-DT-40 cells. Syk and Lyn are involved in radiation-induced signaling, but inactivation of syk or Lyn alone is not sufficient to prevent radiation-induced apoptosis. 3)We studied the relationship between Syk activity and cAMP.cAMP-dependent protein kinase negatively regulates the activation of Syk in fMLP-receptor signaling in polymorphonuclear neutrophils. 4)To explore the mechanisim by which the Syk participates in B cell antigen receptor signaling, we have studied the function of various Syk mutants in B cells made Syk deficient by homologous recombination knockout. We foynd that both SH2 domains are necessary for Syk binding to tyrosine-phosphorvlated 5)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. 6)Syk is rapidely activated in B cells after hydrogen peroxide treatment (oxidative stress) or increased extracellular NaCl concentration (osmotic stress) as well as in response to B cell receptor activation. We have found that both the calcium increase and Jun-amino-teminal kinase (JNK) activity induced by oxidative stress are partly dependent on syk, whereas those induced by osmotic stress are independent of Syk. 7)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.

  • Analysis of intracellular signal transduction mediated by the cytokine receptor
    MINAMI Yasuhiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), 1994 - 1996
    Interleukin (IL-2) plays a crrucial role in regulating proliferation of activated T cells. IL-2 exerts its biological activities through the binding to its specific receptor (IL-2R) on target cells, although it remained elusive how the functional high-affinity IL-2R (consisting of alpha, beta, and gamma chains) transduce IL-2 signals to cell interior. Previous studies demonstrate that the cytyoplasmic regions of both the IL-2Rbeta and gamma chains play important roles in IL-2-induced proliferative signal transmission, and that the cytoplasmic region of the beta chain couples physically and functionally with the Src-family protein tyrosine kinases (PTKs), Lck and Fyn. In this study we found that the sytoplasmic regions of beta and gamma chains also couple both physically and functionally with a series of non-receptor PTKs, Syk, a member of the Syk/ZAP-70-family PTKs, and Jak1 and Jak3, members of the Jak-family PTKs. In addition, we identified a novel protein serine/threonine kinase(s) that associates physically with the cytoplasmic region of the beta chain, although its functional role in IL-2 signaling is still unclear. Furthermore, it was found that protein tyrosine phosphatase, SHP-2, that possesses an SH2 region, is tyrpsine phosphorylated upon IL-2 stimulation. In this study we also identified target genes of IL-2 signals ; i.e.bcl-2 proto-oncogene, a gene encoding the protein tyrosine phosphatase LC-PTP,and BAG-1 gene. Structure-function analyzes of the beta chain revealed that induction of both bcl-2 and BAG-1 genes requires the cytoplasmic "serine-rich" region of the beta chain. On the other hand, the induction of LC-PTP gene requies both the cytoplasmic "serine-rich" and "acidic" regions of the beta chain. We also obtained the results suggesting potential role of Bcl-2 in IL-2-induced cell cycle progression.

  • T細胞活性化のシグナル伝達
    斉藤 隆, 岸原 健二, 高橋 秀実, 南 康博, 藤原 大美, 上出 利光
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 千葉大学, 1995 - 1995
    癌免疫の中心を担うT細胞の活性化と制御のシグナル伝達系を明らかにするため、TCRを介する認識シグナル、接着分子による副シグナル、サイトカインレセプターによる増殖シグナル、の各々のシグナル伝達系とその相互作用を解析した。TCR-CD3複合体で形成する2つのシグナルユニットの一方CD3ζを介するシグナル伝達分子として90kdを同定した。p90は、活性化早期に、TCR刺激特異的に、ζ鎖構造に依存してチロシンリン酸化を受ける。他方、CD3_<ζε>に結合する分子も新たに2分子をクローニングできた。担癌状態に伴うTCR構造異常、特にζ鎖消失は、細胞内でも実際にマクロファージ様細胞との相互作用によって誘導されることを証明し、細胞内レドックス調節に関与することを示唆した。一方、CD28を介してする-stimulationを実際の抗腫瘍免疫へ応用し、B7導入メラノーマでは顕著に転移がなくなり、肝癌では、B7導入細胞で誘導したキラーT細胞が、元のB7-腫瘍も傷害できることを明らかにし、ワクチン療法への展望を拓いた。また、B7-CD28のシグナルが関与しないT_

    細胞の系でも、IL-12が増殖及びIFNγなどのリンホカイン産生の活性化を誘導できることが判明した。IL-2レセプターを介して増殖シグナルの解析では、変異Jak3を用いた解析から、Jak3が増殖シグナルに不可欠であり、Jak3およびStat5の活性化に必要なIL-2Rの領域を決定した。また、IL-2Rに会合するセリン・スレオニンキナーゼを新たに同定した。さらに、Jak3のin vivoでの役割を明らかにするために、Jak3欠損マウスを樹立した。このマウスでは、B細胞、NK細胞、リンパ節、γδ細胞などがほとんど分化しなかったが、T細胞は数は少ないが分化し、末梢CD4^+T細胞では活性化マーカーを発現しており、増殖シグナルと分化・活性化との関連を解析する上で興味深い。T細胞クローンのTCR刺激による増殖阻害においても、Jak3の減少が観察され、TCRシグナルと増殖シグナルの相互作用の解析をさらに進める必要がある。


  • 細胞の分化増殖における非受容体型チロシンキナーゼSykの関与
    山村 博平, 南 康博
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 神戸大学, 1995 - 1995
    チロシンキナーゼSykは他の非受容体型チロシンキナーゼとは異なり細胞質に存在している。またSrc familyとは異なりSH2を2つもちSH3をもたないという特徴を有している。Sykの発現が血球系全般にそして未分化の細胞に見られることより細胞の増殖分化という血球系に共通する機能を担っている可能性がある。我々はK562細胞を用いてSykのdominat negative mutantを作成しTPA刺激等によるSykの機能を解析した。K562細胞においてはSykは分子量80Kの蛋白質をTPA刺激依存性に活性化する。この80K蛋白質を検討した結果コルタクチンであることを明らかにした。発癌遺伝子産物であるSrcの良い基質であるこの蛋白質の燐酸化の意義についてさらに追及している。さらに我々は放射線照射とチロシン燐酸化についてSyk-negativeやLyn-negativeのプロB細胞(DT40細胞)を用いて解析した。たしかに放射線照射はチロシン燐酸化活性を促進しアポトーシスをきたすが、必ずしもSykのみがこの反応に関与しているのではないことを見い出した。またSykの活性化とCyclic AMPの関係について多核白血球を用いて調べたところ、fMLPによるSykの活性化にはCyclic AMPは阻害的に作用することを明らかにした。このことはCyclic AMP依存性蛋白質燐酸化酵素に依るSykの燐酸化そして不活性化を強く示唆している。最近Syk familyに所属するチロシンキナーゼZap-70の2つのSH2のチロシン燐酸化残基との結合様式が明らかにされたが、我々はSykそのものの2つのSH2についてその作用の違いについて検討した。Sykの活性化に依るカルシウム動員作用等において双方のSH2が必要であることを明らかにするとともに、S末側のSH2がより重要な役割を果たしていることをDT40細胞を用いて明らかにした。

  • Molecular mechanisms of G1/s transition
    TUH-E Akio, MINAMI Yasuhiro, YOSHIDA Minoru, TANAKA Kazuma, ARAKI Hiroyuki, HIYAKAWA Tokichi
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Priority Areas, The University of Tokyo, 1993 - 1995
    Our aims of this research project were to elucidate the molecular mechanisms of G1 progression and G1/S transition. To reach this goal, some prominent investigators devoted to this field were supported to proceed their work. During the course of this program, the following new findings were made. 1. Gene functioning at the end of mitosis were isolated by Tohe's group. They are small G protein gene. (TEM1), protein kinase gene (CDC15), protein phosphatase gene (CDC14) and SPO12. A model of network consisting of these genes are presented. 2. Protein phosphatase 2B (calcineurin) was found to antagonize the function of the cAMP pathway which suppresses the expression of the Na+ pump gene. Interactions between calcineurin and MAP kinase cascade were newly found by analyzing mutants displaying a similar phenotype as that of a calcineurin deletion mutant. These were done by Miyakawa's group. 3. Yoshida's group has been screened inhibitors for cell cycle progression. One of their isolates, trycostatin, were found to inhibit histone deacetylase. Administration of this drug induced gelsolin and histone H1 variant. They also obtained drugs which specifically inhibited the growth of cdc13, cdc25, and wee1 of S.pombe. 4. Minami's group devoted to analyze the IL-2 signal transduction system. They reconstituted this system in fibroblast and found new tyrosin kinases that cooperatively function with IL-2. One of them, Sylc induced expression of c-myc in responding to IL-2, and the other enzyme, Jak2 was found to be needed for G1/S transition. 5. Tanaka's group elucidated that Rho-type GTPase, Rho1, is localized at a bud and colocalized with actin. They also found that PKC is on of the effecters of Rho1. Two regulatory proteins of Rho1 were also identified. 6. The largest subunit of DNA polymerase II is POL1. Araki's group isolated a muticopy suppressor of pol2-18 and found that this is a new essential gene designated MDB11. This gene exerts its function at the checkpoint during S phase.

  • Physiological role of protein-tyrosine kinase p72^
    YAMAMURA Hirohei, KUROSAKI Tomohiro, KINET Jean-pierre, YAMAMOTO Tadashi, SADA Kiyonao, YANAGI Shigeru, MINAMI Yasuhiro
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for international Scientific Research, 1993 - 1995
    With Dr. Kurosaki we have been studying about activation mechanism and physiological role of Syk using B cell (DT-40 cell) systems, following results were obtained. 1. Protein-tyrosine kinases Lyn and Syk regulate the B cell receptor-coupled Ca2+ mobilization through the distinct pathwatys. 2. Protein-tyrosine kkinase Syk is activated by the src-family tyrosine kinase (Lyn) in the B cell receptor signaling. Tyrosine phosphorylation of Shc is mediated through protein-tyrosine kinases Lyn and Syk in B cell receptor signaling. Syk and Lyn are involved in radiation-induced signaling, but inactivation of Syk or Lyn alone is not sufficient to prevent radiation-induced apoptosis. 5. Syk recruitment to Ig-alpha and its phosphorylation are essential for B cell antigen receptor signaling. 6. Cooperation of protein-tyrosine kinases Syk and p53/56 Lyn regulates calcium mobilizatio in chicken B cell by oxidant stress signaling. With Dr. Kinet we have been studying about activation mechanism and physiological role of Syk using cultured mast cell systems, following results were obtained. 1. A requirement for Syk in the activation of the microtubule-associated protein kinase/phosphokipase A2 pathway by FcepsilonR1 is not shared by a G protein-coupled receptor. 2. Interactions between protein-tyrosine kinases and the high affinity IgE receptor which are controlled by receptor clustering are reconstituted. Protein-tyrosine kianse Syk is physical and functional association of cortactin in human leukemic cell line K-562. 1.HS1, GAP-associated p190 and a novel GAP-associated p60 protein are phosphorylated by cross-linking of FcgammaRIIIA. 2. With Dr. Kurosaki we also have been studying about role of Syk using other cell systems, folowing results were obtained.

  • T細胞活性化のシグナル伝達
    斉藤 隆, 南 康博, 岸原 健二, 高橋 秀実, 藤原 大美, 上出 利光
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 千葉大学, 1994 - 1994
    T細胞の活性化に重要な3つのシグナル;TCR複合体を介する認識シグナル、CD28を介するCo-stimulationシグナル、IL-2Rを介する増殖シグナルの解析を進めた。 (1)TCRシグナル: ζ鎖欠損マウスを用い、in vivoでもCD3を介する2つのシグナルモジュールが存在し、ζ特異的シグナルの存在を明らかにした。担癌状態でTCR複合体の構造異常が誘導されたが、特殊なマクロファージとT細胞の相互作用によることが明らかになった。また、ペプチド抗原は細胞外でも最小ペプチドにプロセスされ、これによって特異的T細胞の活性化が抑制されることを発見した。抗原受容体により活性化されるチロシンキナーゼの基質としてHS1とCb1をクローニングした。HS1のリン酸化にはSrc型キナーゼとSyk型キナーゼの協調(Lyn+SykまたはFyn+ZAP70)が重要であり、Cb1の活性化にはFynが重要なことが判明した。一方、フォスファターゼCD45は、欠損マウスの解析より、T細胞の選択、TCRα鎖のallelic exclusionおよび移植片の拒絶などに重要な役割を果たしていることがわかった。 (2)Co-stimulationシグナル: Co-stimulatorとしてのB7のオルタナティブスプライシング産物MB7-2をクローニングした。B7やMB7-2をメラノーマに発現させることにより、転移の阻害に成功した。一方、CD28を介するシグナルが、従来のIL-2産生に重要であるのみならず、IL-2R発現に不可欠であることを正常T細胞のシステムで証明した。更に、CD28、CTLA-4の高発現に成功し、両者がヘテロダイマーは形成しないことを明らかにした。 (3)増殖シグナル: IL2レセプター各鎖とJakおよびSykファミリーキナーゼの機能的会合を調べ、β鎖にはSyk、Jak1が、γ鎖にはJak3が会合していることを明らかにした。Sykは、IL-2によるc-mycの誘導に重要なことや、bc12がIL-2シグナルの標的であることも明らかにした。

  • サイトカインシステムにおけるシグナル伝達と遺伝子発現機構の解析
    谷口 維紹, 南 康博, 田中 信之
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 大阪大学, 1992 - 1993
    IL-2シグナル伝達機構の解析から、IL-2受容体(IL-2R)β鎖とp59^が共役し、この会合がp59^及びp53/56^のチロシンキナーゼ(PTK)活性化に関与することを明かとし、IL-2によるsrc型PTK分子の活性化カスケードの存在を示した。更にNIH 3T3細胞に再構成したIL-2R(IL-2Rαβγ鎖)は高親和性IL-2結合能及びIL-2の細胞内への取り込みがみられ、IL-2刺激に応答してMAPキナーゼのチロシンリン酸化の亢進及びc-jun,c-fos,c-myc遺伝子の発現誘導がおこるが、IL-2依存的な細胞増殖能を示さず、IL-2Rの再構成だけではIL-2依存的な細胞増殖の誘導に不十分であることを明かとした。 一方、インターフェロン(IFN)系の転写制御因子IRF-1,IRF-2のDNA認識配列が、多くのIFN誘導遺伝子、細胞増殖関連遺伝子に存在することを見いだし、更にIRFを中心とした遺伝子制御ネットワークが存在することをヒトIRF-1,IRF-2遺伝子発現の解析からを明かにした。また、IRF-1ないしIRF-2遺伝子欠損マウスの作製に成功し、IRF-1欠損マウスの胎児線維芽細胞で二重鎖RNA刺激でのIFN-α,-βの発現が低下することを見いだした。しかし、ウイルス感染時では変化はなく、IFN-β処理によるIFN誘導遺伝子(PKR,1-8,2'-5'オリゴA合成酵素遺伝子)の発現にも変化が見られなかった。一方、IRF-1欠損マウスのマクロファージでのIFN-γによる一酸化窒素(NO)の産生、誘導型NO合成酵素(iNOS)遺伝子の発現誘導がみられず、iNOS遺伝子の発現は特にIRF-1に依存している事を見いだした。これらの事から、IFNシステムにおけるIRFの重要性と共にredundancyが存在することを明かにした。

  • がんの増殖と分化に関連する遺伝子の発現制御
    長田 重一, 十川 和博, 藤沢 淳子, 審良 静男, 山梨 裕司, 南 康博
    日本学術振興会, 科学研究費助成事業, がん特別研究, (財)大阪バイオサイエンス研究所, 1992 - 1992
    私達は細胞の増殖と分化,特に癌化に関与するタンパク質を介した細胞の増殖機構,およびそれら遺伝子の発現機構を分子レベルで解析している。まず,サイトカイン受容体を介したシグナル伝達機構においては,G-CSF受容体やM-CSF受容体(CSF-1)受容体,IL-2受容体β-鎖の細胞質領域が,少なくとも2コの機能ドメインに分けうることを示した。すなわち,M-CSF,G-CSF受容体に関しては増殖,あるいは分化のシグナル伝達経路であり,IL-2受容体β-鎖に関してはc-fos/c-junへの経路とc-mycへ到る経路である。またエリスロポエチン受容体とEGFやM-CSF受容体とのキメラタンパク質を作製し,これら違った受容体群の間のキメラ分子も機能しうることを示した。一方,FGF受容体の一種であるK-samタンパク質は未分化型胃癌で高頻度に発現されていることを示した。また、細胞ヘアポトーシスの情報を伝達するFas抗原がマウスlpr変異の構造遺伝子であることを示し,この受容体様タンパク質の欠陥はある種のT-細胞の異常増殖をひきおこすことを示唆した。 一方,転写因子に関してはc-mycと会合して,その標的部位に作用するタンパク質のcDNAやP-450のプロモーター領域に結合するAh-受容体,BTE結合タンパク質のcDNAを単離した。また,昨年度の本研究で単離した転写因子NF-IL-6の活性がカルモジェリン依存性キナーゼや,MAP-2キナーゼにより制御されていることを示した。一方,節分化を決定する転写因子myogeninのプロモーター領域をlacZに結合した遺伝子をもつトランスジェニックスマウスを作製し,myogeninの発現組織,発現時期を同定した。さらに,癌違伝子lynのプロモーター領域にtaxによる活性化部位を同定するとともに,HLAクラスII遺伝子はその産物に個体差があるばかりでなく,転写機構にも個体差が存在することを示した。

  • Analysis of signal transduction mediated by the cytokine receptor(s)
    MINAMI Yasuhiro, HARADA Hisashi, TANAKA Nobuyuki
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for General Scientific Research (C), Osaka University, 1991 - 1992
    IL-2Rbeta is a critical subunit required for the intracellular signal transduction induced by IL-2 and contains the two functional cytoplasmic subregions( the "serine-rich" and the "acidic" regions), rich in serine residues and in acidic amino acids, respectively. The "acidic" region of IL-2Rbeta is a primarily important site required for associating with a src-family protein tyrosine kinase(PTK), p56^. Our recent study shows that the association between IL-2Rbeta and p56^ is critical for the IL-2-induced activation of lck PTK. In addition, it was shown that another cytoplasmic region, the "serine-rich" region of IL-2Rbeta, is also required for activating lck PTK. We have also shown that another src-family PTK,fyn PTK can associate with IL-2Rbeta and is activated following IL-2 stimulation of BAF-BO3 cells where expression of lck PTK is not detectable. Futhermore, our recent collaborative study with Dr. Satoh et al. (DNAX Research Institute, USA) has in dicated that IL-2 stimulation induces the activation of the ras protein, presumably mediated by a src-family PTK(s). Interestingly, the IL-2-induced activation of a src-family PTK(s)(as well as the IL-2-induced activation of the ras protein) leads to the induction of the c-fos and c-jun genes. On the other hand, it was shown that an as yet unknown signal(s), mediated by the "serine-rich" region of IL-2Rbeta, leads to the c-myc gene induction. Thus, it became evident that IL-2Rbeta is linked to at least two distinct intracellular signaling path ways, leading to the induction of the two different sets of nuclear proto-oncogenes(c-fos/c-jun and c-myc genes).

  • サイトカインシステムにおけるシグナル伝達と遺伝子発現機構の解析
    谷口 維紹, 南 康博, 田中 信之
    日本学術振興会, 科学研究費助成事業, 重点領域研究, 大阪大学, 1991 - 1991
    サイトカイン系におけるシグナル伝達機構の解明を目的とし、インタ-ロイキン2(ILー2)系をモデルシステムとして用い、ILー2受容体β鎖を介する細胞内情報伝達機構の解析を行った。昨年度にはβ鎖の下流に位置しβ鎖と共役するシグナル伝達分子として、リンパ球特異的に発現しているsrcファミリ-チロシンキナ-ゼp56^を同定し、加えてこれら分子間の相互作用に必須な領域を両分子において同定した。本年度は更に、p56^とβ鎖の会合がILー2による細胞内タンパクチロシンリン酸化亢進に必須であることを明らかにした。しかしながら、β鎖を発現させた細胞に活性型p56^を導入してもILー2依存性を失わないことからILー2による増殖性シグンル伝達にはチロシンキナ-ゼ経路以外のものも重要であることが考えられる。ILー2によって核内プロトオンコジ-ンcーfos,cーjun及びcーmycのmRNA発現が効率良く誘導されるが、“acidic region"を欠失させたβ鎖はcーfos,cーjunのmRNA発現を誘導することが出来なかった。一方、“serineーrich region"を欠失させたβ鎖についてはいずれかのmRNAの誘導もほとんど検出されなかった。このことからβ鎖各細胞内領域と、これら遺伝子の誘導には機能的連関があることが考えられる。サイトカイン遺伝子の発現機構の解明を目的とし、インタ-フェロン系においてその解析を行った。本年度は転写調節因子IRFー1がIFNーβ遺伝子及びINFー誘導遺伝子の発現に果す役割を詳細に検討する為、IRFー1cDNAのアンチセンスまたはセンスRNAを強制発現する細胞株を樹立した。センスRNAを発現する細胞株では、コントロ-ル細胞に比べ、polt(rI):(rc)刺激及びウイルス感染によるIFNーβの誘導ならびにIFNー誘導遺伝子(MHCクラスI分子)の発現は顕著に増加した。一方、アンチセンスRNAを発現する細胞株ではこれらの遺伝子の誘導が抑制された。このことから、IRFー1が実際に細胞内でIFNーβおよびMHCクラスI遺伝子の発現においてポジティブに作用していることが明かとなった。

  • リンフォカインと受容体の発現制御
    畠山 昌則, 南 康博, 山田 源, 藤田 尚志
    日本学術振興会, 科学研究費助成事業, 一般研究(C), 大阪大学, 1989 - 1991
    ヒトILー2受容体β鎖cDNAを用いて染色体遺伝子を単離し、その構造を明らかにした。ヒトβ鎖遺伝子は第22染色体長腕qー12ー13に位置し、24.3kbの染色体DNA上に9個のイントロンと10個のエクソンから構成され存在する。さらに第1エクソンの5′上流域の解析から、RNA転写開始部位の5′上流約850ベ-スにおよびDNA配列内にILー2受容体β鎖遺伝子の発現制御に関与するプロモ-タ/エンハンサ-活性が存在することを明らかにした。またヒトcDNAをプロ-ブとしてマウスILー2受容体β鎖cDNAの単離に成功した。cDNA解析から推定されるマウスβ鎖分子は539アミノ酸からなりアミノ酸レベルでのヒトβ鎖分子との相同性は59%であった。マウスILー2受容体β鎖cDNAを用いた解析から、ある種のTリンパ系腫瘍細胞株においてβ鎖遺伝子プロモ-タ-領域にレトロウィルスプロモ-タ-が挿入され、異常発現を惹起していることが明らかにされた。この結果はTリンパ系腫瘍発症/進展にILー2受容体の異常発現が何らかの役割を果たしている可能性を示唆するものと考えられる。 前年度に確立したILー3依存性細胞株におけるヒトILー2受容体β鎖cDNAの機能的発現系を用い、さらに詳細なβ鎖細胞内機能ドメインの解析を行い、細胞内富ロリン領域に存在する単一のロイシン残基を他のアミノ酸に置換するこにより増殖シグナル伝達能が完全に失われることを見い出した。さらに抗ILー2受容体β鎖抗体を用いた免疫沈降実験からβ鎖分子の細胞内ドメインにリンパ球特異的チロシンキナ-ゼp56^が物理的に会合している可能性を示す結果を得た。ILー2シグナル伝達におけるチロシンリン酸化の重要性が強く示唆される。

■ Industrial Property Rights
  • コンディショナルノックアウト動物
    MINAMI YASUHIRO, NISHITA MICHIRU, 可児 修一
    特願2011-071014, 28 Mar. 2011, 大学長, 特許5867671, 15 Jan. 2016
    Patent right

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