| Project/Area Number |
04044135
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Institution | THE UNIVERSITY OF TOKYO |
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Principal Investigator |
TAKATSU Kiyoshi THE INSTITUTE OF MEDICAL SCIENCE University of Tokyo Professor, 医科学研究所, 教授 (10107055)
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| Co-Investigator(Kenkyū-buntansha) |
テルホルフート コックス ハーバード大学, 教授
キンケード ポール オクラホマ医学研究センター, 部長
メルシャーズ フリッツ バーゼル免疫研究所, 所長
等 泰道 東京大学, 医科学研究所, 助手 (10222241)
KINASHI Tatsuo THE INSTITUTE OF MEDICAL SICENCE Assistant Professor, 医科学研究所, 助手 (30202039)
MELCHERS Friz BASEL INSTITUTE FOR IMMUNOLOGY Director
KINCADE Paul OKLAHOMA MEDICAL RESEARCH INSTITUTION Head
YASUMICHI Hitoshi THE INSTITUTE OF MEDICAL SICENCE Assistant Professor
TERHORS Cox BETH ISRAEL HOSPITAL,HARVARD MEDICAL SCHOOL Professor
COX Terhorst ハーバード大学, 医学部, 教授
PAUL Kincade オクラホマ医学研究センター, 部長
FRITS Melche バーゼル免疫研究所, 所長
高木 智 東京大学, 医科学研究所・免疫学研究部, 助手 (10242116)
片桐 拓也 東京大学, 医科学研究所・免疫学研究部, 助手 (70126100)
コックス テルホルスト ハーバード大学, 医学部, 教授
ポール キンケード オクラホマ医学研究センター, 部長
フリッツ メルシャーズ バーゼル免疫研究所, 所長
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1994: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1993: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1992: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Keywords | IL-5 / B cell differentiation / Cytokine / Immunodeficiency / Tyrosine kinase / Btk / IL-5 Receptor / JAK2 kinase / 好酸球 / 免疫不全 / IL-5受容体 / タンパク質リン酸化 / レセプターのクロストーク / トランスジェニックマウス / IL-3 / GM-CSF |
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| Research Abstract |
Interleukin 5 (IL-5) induces proliferation and differentiation of B cells and eosinophils by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, alpha and beta (betac). IL-5 binds to a specific cell surface receptor (IL-5R) with both high (Kd, 10-150 pM) and low affinity (Kd, 2-10 nM). The IL-5Ralpha alone binds IL-5 with low affinity. The betac does not bind IL-5 by itself, but does form a high affinity IL-5R in combination with IL-5Ralpha. The alpha chain is specific for IL-5 while betac is common to receptors for IL-3 and GM-CSF,as well. Unlike several growth factor receptor families that possess intrinsic kinase domains, the receptors for cytokines have no cytoplasmic domain homology with any known enzymes involved in receptor-mediated signal transduction. However, tyrosine phosphorylation of cellular proteins has been observed in various cytokine/cytokine receptor systems and believed to be crucial in their signaling. A recently discovered fami
… More
ly of nonreceptor-tyrosine kinases, including Tyk2, JAK1 and JAK2, was suggested to be associated with cytokine receptors including GM-CSF and IL-3. We have shown that IL-5 induces distinct tyrosine phosphorylation of proteins migrating at about 130 to 140,92,53,48 and 45 kDa in the IL-5-dependent early B cell line, T88-M.
In this project, we investigated the role of IL-5Ralpha in tyrosine phosphorylation of molecules involved in IL-5 signal transduction, using an IL-5-dependent early B cell line, Y16 and transfectants expressing intact or mutant IL-5Ralpha together with intact betac. The results revealed that the transfectants expressing truncated IL-5Ralpha, which entirely lacks a cytoplasmic domain, together with bc showed neither protein-tyrosine phosphorylation nor proliferation in response to IL-5. This confirms the critical role of IL-5Ralpha in the protein-tyrosine phosphorylation initiates cell growth. IL-5 stimulation results in rapid tyrosine phosphorylation of betac and proteins containing Src-homology 2 (SH2) and/or SH3 domains such as phosphatidyl-inositol-3 (PI-3) kinase, Shc, Vav and HS1, suggesting their involvement in IL-5 mediated signal transduction. IL-5 stimulation significantly enhanced activities of JAK2 kinase and B-cell specific Bruton's tyrosine kinase (Btk) and increased the tyrosine phosphorylation of JAK2 kinase. These results and recent data on signaling of growth factors taken together, multiple biochemical pathways driven by tyrosine kinases such as JAK2 and Btk are involved in IL-5 signal transduction. Less
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