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Growth and differentiation signals of the erythropoietin receptor

Research Project

Project/Area Number 09470036
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKurume university

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) YASUKAWA Hideo  Institute of Life Science, Kurume University, Assistant Professor, 分子生命科学研究所, 助手 (60289361)
OHTSUBO Motoaki  Institute of Life Science, Kurume University, Assiatant Professor, 分子生命科学研究所, 助手 (10211799)
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 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 1999: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1998: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1997: ¥5,000,000 (Direct Cost: ¥5,000,000)
Keywordstyrosine kinase / JAK / STAT / CIS / cytokine / knockout mice / erythropoietin / fetal liver hematopoiesis / エリスポエチン / エリスロポエチン受容体 / シグナル伝達 / 細胞分化 / SH2ドメイン / りん酸化 / 情報伝達 / CISファミリー
Research Abstract

To identify the novel substrate of c-kit which is important for hematopoietic stem cell self-renewal or differentiation, CD34-negative, Sca-1 positive, c-KIT-positive, and Lineage marker-negative (CD34-Sca-1+c-Kit-Lin- )cells were sorted by a fluorescence-activated cell sorter from mouse and two hybrid cDNA library was constructed. By the screening using c-kit as bait, we cloned a novel cDNA, designed STAP-1, encoding an adaptor protein with a Pleckstrin homology domain, Src homology 2 domain, and a number of tyrosine phosphorylation sites. RT-PCR analysis revealed that STAP-1 expression is restricted in bone marrow cell fraction expressing c-kit, and the highest expression was observed in CD34-Sca-1+c-Kit+Lin- hematopietic stem cell enriched fraction. Murine myeloid cell line, M1 expressed high level of STAP-1. However, the expression was strongly repressed in response to leukemia inhibitory factor which induced monocytic differentiation of M1 cells, suggesting that STAP-1 is associat … More ed with undifferentiated cell type. In 293 cells, STAP-1 was tyrosine phosphorylated by activated c-kit. In vitro binding assay suggested that STAP-1 SH2 domain interacted with several tyrosine phosphorylated proteins including c-kit and STAT5.There suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.
CIS3/SOC53 are small SH2 containing proteins that interact with and inhibit JAK tyrosine kinases. During embryonic development, CIS53/SOCS-3 is highly expressed in some but no all erythroid lineage cells of the fetal liver and this expression is independent of erythropoietin (EPO) signaling. Transgene mediated constitutive expression blocks fetal erythropoiesis resulting in an embryonic lethality. Deletion of CIS3/SOCS-3 results in an embryonic lethality at 12-16 days that is associated with a marked erythrocytosis. Moreover, the individual in vitro proliferative capacity of fetal liver progenitors is greatly increased. The results demonstrate that CIS3/SOCS-3 play a critical role in negatively regulating fetal liver hematopoiesis. We also demonstrated that CIS3-SOCS3 bound to the EPO receptor as well as JAK2 in erythroid progenitors from spleen and Ba/F3 cells expressing the EPOR (BF-ER), suggesting a specific negative regulatory effect of CIS3/SOCS3 on EPO signaling. Less

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Ward AC, et al.: "The jak-stat pathway in normal and perturbed hematopoiesis"Blood. 95・1. 19-29 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Marine JC, et al.: "SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality"Cell. 98・5. 609-616 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Marine JC, et al.: "SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis"Cell. 98・5. 617-627 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yokouchi M, et al.: "Ligand-induced Ubiquitination of the EGF Receptor Involves the Interaction of the c-Cb1 RING Finger and UbcH7"J. Biol. Chem.. 274・44. 31707-31712 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Matsumoto A, et al.: "Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice"Mol. Cell. Biol. 19・9. 6396-6407 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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
      1999 Final Research Report Summary
  • [Publications] Ward AC, et al.: "The jak-stat pathway in normal and perturbed hematopoiesis."Blood. 95, 1. 19-29 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Marine JC, et al.: "SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality."Cell. 98, 5. 609-616 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Marine JC, et al.: "SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis."Cell. 98, 5. 617-627 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 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-Cb1, and inhibits PDGF-induced mitogenesis."J. Biol. Chem.. 274, 44. 31707-31712 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Matsumoto A, et al.: "Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice."Mol. Cell. Biol.. 19, 9. 6396-6407 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ward AC,et al.: "The jak-stat pathway in normal and perturbed hematopoiesis."Blood. 95・1. 19-29 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Marine JC,et al.: "SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality."Cell. 98・5. 609-616 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Marine JC,et al.: "SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis."Cell. 98・5. 617-627 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yokouchi M,et al.: "Ligand-induced Ubiquitinaiton of the EGF Receptor Involves the Interaction of the c-Cb1 RING Finger and UbcH7."J.Biol.Chem.. 274・44. 31707-31712 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsumoto A,et al.: "Suppression of STAT5 Functions in Liver,Mammary Glands,and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice."Mol.Cell.Biol.. 19・9. 6396-6407 (1999)

    • Related Report
      1999 Annual Research Report
  • [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)

    • Related Report
      1999 Annual Research Report
  • [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)

    • Related Report
      1998 Annual Research Report
  • [Publications] Wakioka T,et al.: "APS,an Adaptor Protein Containing PH and SH2 Domains Inhibits the JAK-STAT Pathway in Collaboration with c-Chl" Leukemia. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okajima Y,et al.: "Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5" J.Biol.Chem.273,36. 22877-22883 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chida D,et al.: "Transcriptional regulation of the β-casein gene by cytokines : cross-talk between STAT5 and other signaling molecules" Mol.Endocrinol.12,11. 1792-1806 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshimura A,et al.: "Physiology and function of the erythropoietin receptor." Curr.Opin.Hematol.5,3. 171-176 (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] Endo,A.T.,et al: "A new protein containing an SH2 domein 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: "STST5 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・2. 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 domein." 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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