| Project/Area Number |
11694335
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research |
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Principal Investigator |
YAKURA Hidetaka Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, 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) |
MIZUNO Kazuya Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Director of Department, 東京都神経科学総合研究所, 副参事研究員 (00219643)
KATAGIRI Tatsuo Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Staff Scientist, 東京都神経科学総合研究所, 研究員 (00233742)
OGIMOTO Mami Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Staff Scientist, 東京都神経科学総合研究所, 研究員 (80158609)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 2000: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1999: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | tyrosine phosphatase / adaptor / CD45 / SHP-1 / BLNK / SLP-65 / SLP-76 / Lyn |
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| Research Abstract |
Regulation of lymphocyte activation and inactivation was examined from the perspective of protein tyrosine phosphatases (PTPs), specifically CD45 and SHP-1. The results are shown below.
1. A novel regulatory mechanism of Src-family protein tyrosine kinases (Src-PTKs) by CD45
CD45 negatively regulates Lyn in WEHI-231, by dephosphorylating not only the autophosphorylation site but also the negative regulatory residue. Similarly, in BAL-17 cells, CD45 dephosphorylates both regulatory sites of Fyn and inactivates Fyn. In both cases, BCR ligation induces phosphorylation of both regulatory sites and activates Src-PTKs. Thus the role of CD45 is to inactivate Src-PTKs, and the negative effect of CD45 is somehow attenuated after BCR ligation. Further studies demonstrated that part of CD45 is constitutively present in lipid rafts and inactivates Src-PTKs, but upon BCR ligation, CD45 is sequestered from rafts and Src-PTKs are activated. Thus, CD45 dynamically regulates Src-PTKs by temporally changi
… More
ng its localization with respect to lipid rafts where Src-PTKs reside.
2.Opposing regulation of BCR-induced activation of MAP kinases by CD45
We found that CD45 negatively regulates BCR-induced JNK and p38 activation in WEHI-231, whereas in BAL-17, CD45 positively regulates JNK and p38 activation. Furthermore, cooperative action of JNK and p38 dictated BCR-induced inhibition of growth. Thus, CD45 can exert opposing effects on JNK and p38 in different cellular milieus, controlling the B cell fate.
3. Regulation of lymphocyte signaling by SHP-1 and adaptor proteins
Usin the phosphatase activity-deficient form of SHP-1 (SHP-1-C/S), we determined one of the SHP-1 substrates, the B cell linker protein (BLNK). In vitro kinase assays demonstrated that hyperphosphorylation of BLNK in SHP-1-C/S-expressing cells is not due to enhanced activity of Lyn or Syk. Furthermore, BCR-induced activation of JNK was enhanced in SHP-1-C/S transfectants. Thus, our results suggest that SHP-1 selectively regulates JNK activation by acting on BLNK. Less
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