Novel mechanisms of Src-family kinase regulation by CD45
| Project/Area Number |
14570292
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Tokyo Metropolitan Organization for Medical Research |
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Principal Investigator |
YAKURA Hidetaka Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Director of Molecular Research Division, 東京都神経科学総合研究所, 参事研究員 (60166486)
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| Co-Investigator(Kenkyū-buntansha) |
OGIMOTO Mami Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 研究員 (80158609)
MIZUNO Kazuya Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Director of Department, 東京都神経科学総合研究所, 副参事研究員 (00219643)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | CD45 / Src-family kinases / GEM / lipid raft / tyrosine phosphatase / tyrosine phosphorylation / GEM(ラフト) / B細胞 / マスト細胞 / 基質 |
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| Research Abstract |
CD45 is a key tyrosine phosphatase regulating Src-family kinases (Src-PTKs) in lymphocytes ; precisely how it exerts its effect remains controversial, however. We previously demonstrated that CD45 negatively regulates Lyn in WEHI-231 B cell line. In this project we obtained the results showing that negative regulation by CD45 was observed in all B cells tested (WEHI-231,BAL-17,and splenic B cells) and that about 5% of total CD45 was constitutively associated with glycolipid-enriched microdomains (GEMs), where it inhibited Src-PTKs by dephosphorylating both the negative and the positive regulatory sites. Upon BCR ligation, however, CD45 dissociated from GEMs within 1 min, inducing phosphorylation of two regulatory sites and activation of Src-PTKs, but subsequently re-associated with the GEMs within 15 min. Disruption of GEMs with methyl-β-cyclodextrin results in abrogation of BCR-induced apoptosis in WEHI-231 cells, suggesting GEMs are critical to signals leading to the fate determination. We thus propose that the primary function of CD45 is inhibition of Src-PTKs and that the level of Src-PTK activation and the B cell fate are determined in part by dynamic behavior of CD45 with respect to GEMs. Further analysis of molecular mechanisms whereby CD45 associated with GEMs and of novel substrates of CD45 should give us a hint as to strategies for prevention of immunological disorders such as autoimmune diseases.
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Report
(3 results)
Research Products
(6 results)
