Function of CD19 in B-cell Development & Differentiation

描述(申请人提供)：B细胞激活是由近端胞浆和膜结合的接头蛋白的酪氨酸磷酸化启动的，以允许信号通路的分支，例如磷脂酰肌醇3-激酶(PI3K)途径。肌醇磷脂的代谢被认为对B细胞的激活、增殖、分化和存活具有关键作用。PI3K活性是由bcr诱导的，并通过p85pha与CD19或其他胞质接头蛋白的募集而放大。磷脂酰肌醇-3，4，5-三磷酸(PIP3，4，5)是由磷脂酰肌醇-3，4，5-三磷酸(PIP3，4，5)在激活的细胞中产生，导致含有磷脂酰肌醇同源(PH)的蛋白的募集和构象诱导的其他结合伙伴的激活，PIP3，4，5的过量产生导致自身免疫或转化，并受到肌醇磷酸酶PTEN和SHIP的严格调控。本次更新的总体目标是了解PIP3、4、5在B细胞分化和维持中的调控背景。这一目标的核心是详细了解B细胞中磷脂酰肌醇的代谢，特别是PI3-激酶、PTEN和SHIP在调节PIP3、4、5水平方面的相反酶活性，以及它在信号中间体招募和激活中的现有作用。CD19是B细胞中PI3K的主要激活剂，导致PIP3，4和PIP3，4，5的产生，而肌醇磷酸酶PTEN通过转化为PIP4，5来抑制PIP3，4，5的积聚。Fc-Gamma-RIIB1(CD32)也可以通过募集SHIP磷酸酶来降低PIP3，4，5的水平，从而将PIP3，4，5转化为PIP3，4，5。这些发现提示CD19和CD32的相互作用集中在PIP3，4，5的调节产生及其募集和激活下游效应分子的能力。在此，我们探讨了CD19和CD32在调节PIP3，4，4和PIP3，4，5作为影响细胞命运的关键二级信使的产生中的分子基础和生理意义。

DESCRIPTION (provided by applicant): B cell activation is initiated by tyrosine phosphorylation of proximal cytosolic and membrane bound adaptor proteins to allow branching of signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K) pathway. Phosphoinositide metabolism is thought to be of key importance to aspects of B cell activation, proliferation, differentiation and survival. PI3K activity is induced by the BCR and amplified by p85alpha recruitment to CD19 and perhaps other cytosolic adaptor proteins. Phosphatidylinositol-3,4,5-trisphosphate (PIP3,4,5) is generated by PI3K in activated cells, leading to the recruitment of pleckstrin-homology (PH)-containing proteins and conformation induced activation of other binding partners, Excessive production of PIP3,4,5 leads to autoimmunity or transformation and is tightly regulated by the inositol phosphatases PTEN and SHIP. The overall goal of this renewal is to understand the context of PIP3,4,5 regulation in B cell differentiation and maintenance. Central to this goal is a detailed understanding of phosphoinositide metabolism in B cells with a particular focus on the opposing enzymatic activities of PI3-kinase, PTEN and SHIP in regulating levels of PIP3,4, 5 and its incumbent role in the recruitment and activation of signaling intermediates. CD19 is the primary activator of PI3K in B cells, leading to the production of PIP3,4 and PIP3,4,5, while the inositol phosphatase PTEN acts to attenuate PIP3,4,5 accumulation by conversion to PIP4,5. Fc-gamma-RIIB1 (CD32) can also attenuate PIP3,4,5 levels through the recruitment of SHIP phosphatase, which converts PIP3,4,5 to PIP3,4. These findings suggest an interplay of CD19 and CD32 function focused on the regulated production of PIP3,4,5 and its ability to recruit and activate downstream effectors. Herein we explore the molecular basis and physiologic significance of CD19 and CD32 function in the regulated production of PIP3,4, PIP4,5 and PIP3,4,5 as key secondary messengers to effect cell fate.