Grant-in-Aid for Scientific Research (S)
|Allocation Type||Single-year Grants |
|Research Institution||RIKEN (2004-2005)|
Kansai Medical University (2001-2003)
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)
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)
|Project Period (FY)
2001 – 2005
Completed (Fiscal Year 2005)
|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)
|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|
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.