Quantitative and qualitative regulation of cellular signaling in immune system

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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.