Quantitative and qualitative regulation of cellular signaling in immune system

在bcr信号转导中，我们已经阐明了接头分子将B细胞受体与效应酶如PLC-γ2和Vav偶联的机制。BLNK通过与BLNK不同的机制参与PLC-γ2的激活。BLNK使PLC-γ2和BTK紧密相连，其中BTK将PLC-γ2上的酪氨酸残基磷酸化，这是BCR信号背景下PLC-γ2激活所必需的。另一方面，BCAP通过两种机制参与PLC-γ2的激活：通过蛋白质相互作用直接激活PLC-γ2和通过PI3K激活间接激活PLC-γ2。2.BCAP通过调节核因子κB组分c-Rel的表达水平来调节B细胞的分化。这是由于BCAP下调了c-Rel的表达，因为在这些小鼠中，c-Rel的表达水平至少部分地在转录水平上降低。与BCAP不同，BANK在BCR信号转导中起负作用。BANK是一种在B细胞中高表达的受体蛋白。BANK缺陷小鼠对T依赖抗原的反应表现为生发中心形成和IgM产生增加，而CD40 BANK双基因敲除小鼠的这一表型被阻断。体外分析进一步证明BANK参与了CD40信号转导。因此，这些发现表明，BANK减弱了CD40介导的Akt激活，从而阻止了B细胞的过度活跃反应。4.BLNK调节两种效应酶，PLC-γ2和VAv。除了PLC-γ2的激活外，BLNK还调节Vav和随后的Rac激活。BLNK与Grb2共同作用，将Vav募集到膜筏上，从而使Vav进入被Syk磷酸化的敏感状态。

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.