| Project/Area Number |
13854013
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | RIKEN (2004-2005)
Kansai Medical University (2001-2003) |
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Principal Investigator |
KUROSAKI Tomohiro RIKENE, Laboratory for Lymphocyte Differentiation, Group Director, 分化制御研究グループ, グループディレクター (50178125)
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| Co-Investigator(Kenkyū-buntansha) |
HIKIDA Masaki RIKEN, Laboratory for Lymphocyte Differentiation, 分化制御研究グループ, 上級研究員 (60228715)
大洞 将嗣 関西医科大学, 医学部, 助手 (40351506)
山崎 哲男 関西医科大学, 医学部, 助手 (90330208)
井鍋 一則 関西医科大学, 医学部, 助手 (30309215)
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥123,630,000 (Direct Cost: ¥95,100,000、Indirect Cost: ¥28,530,000)
Fiscal Year 2005: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2004: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2003: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2002: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2001: ¥24,830,000 (Direct Cost: ¥19,100,000、Indirect Cost: ¥5,730,000)
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| Keywords | BCR / adaptor molecules / effector molecules / signal transduction / B lymphocyte development / immune response / BCAP / PI3キナーゼ / B細胞分化 / B細胞活性化 / BANK / CD40 / B細胞活性 / アダプター分化 / 転写因子 / c-Rel / BLNK / PLC-γ2 / ノックアウトマウス / 抗原反応 |
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| Research Abstract |
In BCR signaling, we have clarified mechanisms by which adaptor molecules couple B cell receptors to effector enzymes such as PLC-γ2 and Vav. Particularly, the following five points are novel.
1.BCAP participates in PLC-γ2 activation through distinct mechanisms by which BLNK does.
BLNK brings PLC-γ2 and Btk into close proximity with each other, wherein Btk phosphorylates tyrosine residues on PLC-γ2, being essential for PLC-γ2 activation In BCR signaling context. On the other hand, BCAP participates in PLC-γ2 activation through two mechanisms ; direct PLC-γ2 activation by protein-protein interaction and indirect PLC-γ2 activation through PI3K activation.
2.BCAP regulates B cell differentiation through modulating expression level of c-Rel, one of NF-κB components.
BCAP-deficient mice exhibit B cell developmental arrest from immature to mature B cell phase. This is caused by downregulation of c-Rel by BCAP, because in these mice, expression level of c-Rel is decreased, at least partly, at the trascriptional level. Moreover, overexpression of c-Rel can bypass the developmental defect in BCAP-deficient mice.
3.In contrast to BCAP, BANK plays a negative role in BCR signaling.
BANK is an adptor protein that Is highly expressed in B cells. BANK-deficient mice display enhanced germinal center formation and IgM production in response to T-dependent antigens, whereas this phenotype is blocked In CD40-BANK double knockout mice. Involvement of BANK In CD40 signaling is further demonstrated by in vitro analysis. Thus, these findings suggest that BANK attenuates CD40-mediated Akt activation, thereby preventing hyperactive B cell responses.
4.BLNK regulates two effector enzymes, PLC-γ2 and Vav.
In addition to PLC-γ2 activation, BLNK also regulates Vav and subsequent Rac activation. BLNK functions together with Grb2 to recruit Vav to membrane rafts, thereby bringing Vav to susceptable state to being phosphorylated by Syk.
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