Function of CD19 in B-cell Development & Differentiation

CD19 在 B 细胞发育中的功能

• 批准号: 6730668
• 负责人: ROBERT C RICKERT
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730668
• 关键词: B lymphocyte; CD antigens; CD19 molecule; biological signal transduction; cell differentiation; developmental immunology; enzyme activity; enzyme mechanism; genetically modified animals; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; phosphatidylinositol 3 kinase; phosphatidylinositols; phosphomonoesterases; protein protein interaction

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.

描述（由申请人提供）：B细胞活化由近端胞质和膜结合衔接蛋白的酪氨酸磷酸化引发，以允许信号传导途径分支，如磷脂酰肌醇3-激酶（PI 3 K）途径。磷酸肌醇代谢被认为对B细胞活化、增殖、分化和存活方面具有关键重要性。PI 3 K活性由BCR诱导，并通过p85 α募集至CD 19和可能的其他细胞溶质衔接蛋白而扩增。磷脂酰肌醇-3，4，5-三磷酸（Phosphatidylinositol-3，4，5-trisphosphate，PIP 3，4，5）是由活化细胞中的PI 3 K产生的，导致含有普列克底物蛋白同源性（pleckstrin-homology，PH）的蛋白质的募集和构象诱导的其它结合配偶体的活化。PIP 3，4，5的过量产生导致自身免疫或转化，并且受到肌醇磷酸酶PTEN和SHIP的严格调节。该更新的总体目标是了解PIP 3，4，5在B细胞分化和维持中的调节背景。该目标的核心是详细了解B细胞中的磷酸肌醇代谢，特别关注PI 3-激酶、PTEN和SHIP在调节PIP 3、4、5水平中的相反酶活性及其在信号传导中间体的募集和活化中的现任作用。CD 19是B细胞中PI 3 K的主要激活剂，导致产生PIP 3，4和PIP 3，4，5，而肌醇磷酸酶PTEN通过转化为PIP 4，5而起到减弱PIP 3，4，5积累的作用。Fc-γ-RIIB 1（CD 32）还可通过募集SHIP磷酸酶（将PIP 3，4，5转化为PIP 3，4）来减弱PIP 3，4，5水平。这些发现表明，CD 19和CD 32功能的相互作用集中在PIP 3，4，5的调节产生及其募集和激活下游效应物的能力上。在此，我们探讨了CD 19和CD 32在PIP 3，4，PIP 4，5和PIP 3，4，5作为影响细胞命运的关键第二信使的调节产生中的功能的分子基础和生理意义。