Function of CD19 in B-cell Development & Differentiation

描述（由申请人提供）：B细胞激活是由近端胞浆和膜结合接头蛋白的酪氨酸磷酸化启动的，以允许信号通路的分支，如磷脂酰肌醇3-激酶（PI3K）通路。磷酸肌肽代谢被认为对B细胞的活化、增殖、分化和存活具有重要意义。PI3K的活性由BCR诱导，并通过p85alpha募集到CD19和其他细胞质衔接蛋白而扩增。磷脂酰肌醇-3,4,5-三磷酸（PIP3,4,5）由活化细胞中的PI3K产生，导致pleckstrin-homology (PH)-containing protein的募集和构象诱导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。这项更新的总体目标是了解PIP3,4,5调控在B细胞分化和维持中的背景。该目标的核心是详细了解B细胞中的磷酸肌苷代谢，特别关注pi3激酶，PTEN和SHIP在调节PIP3, 4,5水平及其在信号中间体募集和激活中的重要作用中的相反酶活性。CD19是B细胞中PI3K的主要激活因子，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来减少PIP3,4,5的积累。fc - γ - riib1 （CD32）也可以通过SHIP磷酸酶的募集降低PIP3,4,5的水平，将PIP3,4,5转化为PIP3,4。这些发现表明，CD19和CD32功能的相互作用集中在PIP3、4,5的调控产生及其招募和激活下游效应物的能力上。本文探讨CD19和CD32在调节PIP3,4, pip4,5和PIP3,4,5作为影响细胞命运的关键次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.