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c-Abl的靶向缺失揭示了该蛋白在B细胞和T细胞发育和功能中的作用。c-Abl缺失小鼠表现出脾脏和胸腺萎缩和淋巴细胞减少，从c-Abl敲除小鼠分离的B淋巴细胞在生长因子停用后对凋亡的易感性增加。我们已经证明，来自c-Abl基因敲除小鼠的脾B细胞对B细胞受体（BCR）刺激的增殖反应降低，并且c-Abl结合并磷酸化BCR共受体CD19。在小鼠发育过程中，c-Abl激酶与Arg（一种abl相关的酪氨酸激酶）表现出功能冗余。c-Abl或Arg的单一缺失可以产生存活的小鼠，但这两种激酶的纯合缺失会导致胚胎死亡，胚胎在多个组织中表现出细胞骨架异常和细胞凋亡。精氨酸酪氨酸激酶在胸腺和脾脏中高度表达，可以弥补这些组织中c-Abl的缺失。我们最近的发现进一步支持了Abl激酶在淋巴细胞信号传导中的作用，抑制T细胞中Abl激酶的活性可显著抑制T细胞受体（TCR）依赖的增殖、IL-2的产生、IL-2启动子的转录以及对TCR信号传导至关重要的一组蛋白质的酪氨酸磷酸化。我们假设Abl家族激酶调节B细胞和T细胞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激酶调节增殖、存活、细胞骨架重组和整合素介导的TCR下游粘附的机制，并确定这些过程中的关键Abl靶点；2)通过确定关键Abl靶点和上游调节因子，确定c-Abl调节BCR刺激下的增殖反应的机制。以及检查Arg的丢失是否会加剧c-Abl依赖性B细胞表型。本实验的结果将为Abl激酶缺失引起的小鼠B细胞和T细胞表型缺陷提供机制解释，并揭示正常淋巴细胞中由这些激酶调控的新信号通路，以及Abl激酶功能缺失或失调引起的病理条件下的信号通路。

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.