Role of Ab1 Kinases in B and T cell signaling

描述（由申请人提供）：Abl酪氨酸激酶参与细胞增殖、存活、粘附和迁移的调节。小鼠中c-Abl的靶向缺失揭示了该蛋白在B和T细胞发育和功能中的作用。c-Abl缺陷小鼠表现出脾脏和胸腺萎缩和淋巴细胞减少，并且从c-Abl敲除小鼠分离的B淋巴细胞在生长因子撤除后对细胞凋亡的易感性增加。我们已经表明，来自c-Abl敲除小鼠的脾B细胞对B细胞受体（BCR）刺激表现出降低的增殖反应，并且c-Abl结合到BCR辅助受体CD 19并使其磷酸化。在小鼠发育过程中，c-Abl激酶与Arg（一种酪氨酸相关激酶）表现出功能冗余。c-Abl或Arg的单一损失产生存活的小鼠，但是两种激酶的纯合损失导致胚胎死亡，胚胎在多个组织中显示细胞骨架异常和凋亡。Arg酪氨酸激酶在胸腺和脾脏中高度表达，并且可以补偿这些组织中c-Abl的损失。Abl激酶在淋巴细胞信号传导中的作用进一步得到我们最近的发现的支持，即抑制T细胞中Abl激酶的活性显著抑制T细胞受体（TCR）依赖性增殖、IL-2产生、IL-2启动子的转录和对TCR信号传导至关重要的蛋白质亚群的酪氨酸磷酸化。我们假设Abl家族激酶调节B和T细胞中免疫受体下游的增殖、存活和细胞骨架反应。提出了两个具体目标：1）确定Abl激酶用于调节增殖、存活、细胞骨架重组和TCR接合下游的整合素介导的粘附的机制，并鉴定这些过程中的关键Abl靶标，和2）通过鉴定关键Abl靶标和上游调节剂来确定c-Abl调节对BCR刺激的增殖应答的机制，以及检测Arg的缺失是否加重c-Abl依赖性B细胞表型。从拟议的实验结果将提供机制解释的缺陷B和T细胞表型诱导的损失Abl激酶在小鼠中，并将揭示新的信号通路调节这些激酶在正常淋巴细胞和病理条件下引起的损失或失调Abl激酶功能。

DESCRIPTION (provided by applicant): The Abl tyrosine kinases have been implicated in the regulation of cell proliferation, survival, adhesion, and migration. Targeted deletion of c-Abl in mice has revealed a role for this protein in B and T cell development and function. The c-Abl-deficient mice exhibit splenic and thymic atrophy and lymphopenia, and B lymphocytes isolated from c-Abl knockout mice have increased susceptibility to apoptosis following growth factor withdrawal. We have shown that splenic B cells from c-Abl knockout mice exhibit a reduced proliferative response to B cell receptor (BCR) stimulation, and that c-Abl binds to and phosphorylates the BCR co-receptor CD19. The c-Abl kinase exhibits functional redundancy during mouse development with Arg, an Abl-related tyrosine kinase. Single loss of c-Abl or Arg produces viable mice, but homozygous loss of both kinases results in embryonic lethality with the embryos displaying cytoskeletal abnormalities and apoptosis in multiple tissues. The Arg tyrosine kinase is highly expressed in thymus and spleen, and may compensate for loss of c-Abl in these tissues. A role for Abl kinases in lymphocyte signaling is further supported by our recent finding that inhibiting the activities of the Abl kinases in T cells markedly inhibits T cell receptor (TCR)-dependent proliferation, IL-2 production, transcription of the IL-2 promoter, and tyrosine phosphorylation of a subset of proteins critical for TCR signaling. We hypothesize that Abl family kinases regulate proliferative, survival, and cytoskeletal responses downstream of immunoreceptors in B and T cells. Two specific aims are proposed: 1) to define the mechanisms employed by the Abl kinases to regulate proliferation, survival, cytoskeletal reorganization, and integrin-mediated adhesion downstream of TCR engagement, and identify the critical Abl targets in these processes, and 2) to define the mechanisms whereby c-Abl regulates the proliferative response to BCR stimulation through identification of critical Abl targets and upstream regulators, as well as to examine whether loss of Arg exacerbates the c-Abl dependent B cell phenotypes. Results from the proposed experiments will provide mechanistic explanations for the defective B and T cell phenotypes induced by loss of Abl kinases in mice, and wilt reveal novel signaling pathways modulated by these kinases in normal lymphocytes and under pathological conditions elicited by loss or deregulation of Abl kinase function.