Regulation of B cell activation and inactivation by the interaction between SHP-1 and adaptor molecules
Project/Area Number |
15590446
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Immunology
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Research Institution | Tokyo Metropolitan Organization for Medical Research |
Principal Investigator |
MIZUNO Kazuya 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, 副参事研究員 (00219643)
|
Project Period (FY) |
2003 – 2004
|
Project Status |
Completed (Fiscal Year 2004)
|
Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
|
Keywords | signal transduction / B cells / protein tyrosine phosphatase / adaptor molecules / c-Jun N terminal kinase / SLP-76 / B細胞抗原受容体 / SHP-1 / CD22 / アポトー |
Research Abstract |
We have examined the molecular mechanisms how SHP-1, a cytosolic protein tyrosine phoshatase, regulates B cell receptor-mediated signaling and obtained the following results. 1)By using substrate trapping approach, we identified SLP-76 as a new substrates of SHP-1 in WEHI-231 cells, a murine immature B cell line. In contrast to the previous reports, our data demonstrated that SLP-76 is expressed in all murine B cell lines tested and in normal splenic B cells. We next examined whether SLP-76 expression in B cell is regulated during differentiation of B cells and found that immature B cells expressed relatively low amount of SLP-76, which showed 〜20% increase in transitional type 1 B cells and 〜40% increase in transitional type 2 and mature B cells, indicating the regulated expression of SLP-76 during B cell development. 2)Dephosphorylation of SLP-76 by SHP-1 inhibits its association with Nck, downregulating JNK activation and exerting positive effect on apoptosis. Knock down of SLP-76 in
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WEHI-231 cells by small interfering RNA attenuated JNK activation but showed little effects on ERK or p38 activation. 3)It has been shown that for T cell activation, SLP-76/Gads complex needs to be translocated to tyrosine-phosphorylated LAT and that both SLP-76 and LAT are required for the restoration of BCR-signaling in BLNK-deficient cells. Contrally, we found the expression of SLP-76 alone is sufficient at least for BCR-induced JNK activation, although WEHI-231 lacks LAT expression. To clarify mechanisms by which SLP-76 functions in the absence of LAT, we first determined the subcellular localization of SLP-76. Although WEHI-231 does not express LAT, SLP-76 localizes in membrane fraction, which increases following B cell receptor (BCR) crosslinking. Further analyses reveals that SLP-76 complexed with Gads is associated with tyrosine-phosphorylated CD22 through the SH2 domains of SLP-76 and Gads. Given that SHP-1 binds to CD22 upon BCR ligation, our findings suggest that dephosphorylation of SLP-76 recruited to CD22 by SHP-1 inhibits BCR-induced JNK activation, dictating apoptosis. Less
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] SLP-76 is recruited to CD22 and dephosphorylated by SHP-1, thereby regulating B cell receptor-induced c-Jun NH2-terminal kinase activation.2005
Author(s)
MIZUNO, K., TAGAWA, Y., WATANABE, N., OGIMOTO, M., YAKURA, H.
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Journal Title
Eur.J.Immunol. 35
Pages: 644-654
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Impairment of B cell receptor-mediated Ca2+ influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells.2004
Author(s)
OGIMOTO, M., ICHINOWATARI, G., QATANABE, N., TADA, N., MIZUNO, K., YAKURA, H.
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Journal Title
Int.Immunol. 16
Pages: 971-982
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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