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Physiological Function and Signal Transduction Mechanism of the STAT5-target genes

Research Project

Project/Area Number 09044349
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field Cell biology
Research InstitutionKurume University

Principal Investigator

YOSHIMURA Akihiko  Kurume University, Institute of Life Science, Professor, 分子生命科学研究所, 教授 (90182815)

Co-Investigator(Kenkyū-buntansha) MAYEUX Patri  Institute Cochin de Genetique Moleculair, 主任研究員
IHLE James  St. Jude Children's Hospital生化学部, 部長
YASUKAWA Hideo  Kurume University, Institute of Life Science, Assistant, 分子生命科学研究所, 助手 (60289361)
OHTSUBO Motoaki  Kurume University, Institute of Life Science, Assistant, 分子生命科学研究所, 助手 (10211799)
JAMES Ihle  St.Jude Children's Hospital, Department of Biochemistiry, Professor
PATRICK Mayeux  Institute Cochin de Genetique Moleculaire, Department of Cancer Research, Profes
NEWMANN Dror  TelAviv大学, 医学部, 講師
三澤 宏之  久留米大学, 分子生命科学研究所, 助手 (00289505)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 1998: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1997: ¥4,200,000 (Direct Cost: ¥4,200,000)
KeywordsJAK / STAT / Cytokine / SH2 domain / Tyrosine Kinase / Transgenic mouse / Knockout mouse / Ubiquitin / りん酸化 / 情報伝達 / CISファミリー
Research Abstract

A variety of cytokines utilizes Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) family of transcription factors, to exert their biological functions. The tyrosinephosphorylated STATs form homo- or heterodimers and translocate into the nucleus, then activate target genes. Compared with other kinases, little is known about cellular regulators of the JAKs. The CIS (cytokine-indelible SH2 protein) family of proteins that w found recently has been implicated in regulating signal transduction by a variety of cytokines, The first member of this family, CIS1 was cloned as an immediate early gene responding to a number of cytokines including erythropoietin (EPO), interleukin 2 (1L2), 1L3 and GM-CSF, and is regulated by STAT5. CIS1 binds to the tyrosine phosphorylated IL3 and EPO receptors, and negatively regulates STAT5, The second family member was independently cloned by three groups and is termed JAB, SOCS-1, or SSI-1 (6, 20, 29). JAB is induced by IFNgam … More ma and inhibits lFN as wellas IL6 signaling. JAB and CIS directly bind to the kinase domain of JAKs, thereby inhibiting the kinase activity. In collaboration with Dr. Ihie's group, we already created JAB and CIS3 genes knockout mice and we are analyzing them now. We demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2 whose phosphorylation is required for activation of kinase activity. An additional N-terminal 12 amino acid region (kinase inhibitory region) of JAB also contributes to high affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors, On the other hand, it has not been clear how CIS1 suppresses STAT5 activation. We reported that CIS1 binds to the region of the EPO receptor containing the second tyrosine residue (Y401). One of the mechanisms is simply masking the STAT5 binding sites on the receptor. The other possibility is that CIS1 accelerates degradation of the receptor-CIS1 complex by the ubiquitin-proteaspme pathway. Further study is necessary to elucidate the mechanism of STAT5 inhibition by CIS1. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Yasukawa H, et al.: "The JAK-Binding Protein JAB Inhibits Janus Tyrosine Kinase Activity Through Binding in the Activation Loop." EMBO J.18, 5. 1309-1320 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokouchi M, et AL.: "APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis." Oncogene. 18, 3. 759-767 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Helman D, et al.: "Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 singaling." FEBS lett.441, 2. 287-291 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Verdier F, et al.: "Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated CIS protein." J. Biol. Chem.273,43. 28185-28190 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Lebin I, et al.: "Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization." FEBS Lett.427, 2. 164-170 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakamoto H, et al.: "A Janus kinase inhibitor, JAB, is an interferon-γ-inducible gene and confers resistance to interferons." Blood. 92, 5. 1668-1676 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasukawa H,et al.: "The JAK-Binding Protein JAB Inhibits Janus Tyrosine Kinase Activity Thgough Binding in the Activation Loop" EMBO J. 18 (5). 1309-1320 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokouchi M,et al.: "APS,an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis" Oncogene. 18 (3). 759-767 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Helman D,et al.: "Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 singaling" FEBS lett.441 (2). 287-291 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Verdier F,et al.: "Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation.Possible involvement of the ubiquitinated CIS protein." J.Biol.Chem.273 (43). 28185-28190 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Levin I,et al.: "Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization" FEBS Lett.427 (2). 164-170 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakamoto H,et al.: "A Janus kinase inhibitor, JAB,is an interferon-gamma-inducible gene and confers resistance to interferons" Blood. 92 (5). 1668-1676 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasukawa, H, et al.: "The JAK-Biding Protein JAB Inhibits Janus Tyrosine Kinase Activity Through Binding in the Activation Loop." EMBOJ.18, 5. 1309-1320 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yokouchi, M, et al.: "APS.an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis." Oncogene. 18, 3. 759-767 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Helman D, et al.: "Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor mediated STAT5 singaling." FEBS lett.441, 2. 287-291 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Verdier F, et al.: "Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5(STAT5) activation. Possible involvement of the ubiquitinated CIS protein." J.Biol.Chem.273, 43. 28185-28190 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Levin I, et al.: "Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization." FEBS Lett.427, 2. 164-170 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] sakamoto H, et al.: "A Janus Kinase inhibitor, JAB is an interferon-γ-inducible gene and confers resistance to interferons." Blood. 92, 5. 1668-1676 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Endo, A.T., et al: "A new protein containing an SH2 domain that inhibits JAK kinases." Nature. 387-6636. 921-924 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yokouchi, M., et al: "Cloning and characterization of APS,an adaptor molecule containing PH and SH2 domains that is tyrosine phosphorylated upon B-cell receptor stimulation." Oncogene. 15・1. 7-15 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwatsuki, K., et al: "STAT5 activation correlates.with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line." J.Biol.Chem.272・13. 8149-8152 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsumoto, A., et al: "CIS,a cytokine inducible SH2 protein,is a target of the JAK-STAT5 pathway and modulates STAT5 activation." Blood. 89・9. 3148-3154 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Masuhara, M., et al: "Cloning and Characterization of Novel CIS Family Genes." Biochem.Biophys.Res.Comm.239・1. 439-446 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Misawa, H., et al: "Cloning and characterization of a novel class II Phosphoinositide 3-kinase containing C2 domain." Biochem.Biophys.Res.Comm.(in press). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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