Role of Ab1 Kinases in B and T cell signaling

Ab1 激酶在 B 和 T 细胞信号传导中的作用

• 批准号: 7407364
• 负责人: Ann Marie Pendergast
• 金额: $ 32.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407364
• 关键词: ABL1 gene; Actins; Adhesions; Apoptosis; Atrophic; B-Lymphocytes; Binding; CD19 gene; CD28 gene; Cell Proliferation Regulation; Cells; Condition; Cytoskeletal Modeling; Development; Embryo; Exhibits; Family; Feedback; Genetic Transcription; Goals; Growth Factor; Integrins; Interleukin-2; Knockout Mice; Lymphocyte; Lymphocyte Function; Lymphopenia; Mediating; Molecular; Mus; Phenotype; Phosphotransferases; Predisposition; Process; Production; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Role; Signal Pathway; Signal Transduction; Spleen; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transcriptional Activation; Tyrosine Phosphorylation; Withdrawal; c-abl Proto-Oncogenes; kinase inhibitor; migration; novel; polymerization; promoter; receptor; research study; response; src-Family Kinases; synaptogenesis

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.

描述（由申请人提供）：ABL酪氨酸激酶与细胞增殖，生存，粘附和迁移有关。在小鼠中，靶向缺失的c-ABL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缺乏的小鼠表现出脾和胸腺萎缩和淋巴细胞减少症，并且从C-ABL敲除小鼠中分离出的B淋巴细胞具有增加生长因子后对凋亡的敏感性。我们已经表明，来自C-ABL敲除小鼠的脾B细胞表现出对B细胞受体（BCR）刺激的增殖反应降低，并且C-ABL与BCR共受体CD19结合并磷酸化。 C-ABL激酶在小鼠发育过程中具有与ABL相关的酪氨酸激酶ARG发育过程中的功能冗余。 C-ABL或ARG的单个丧失会产生可行的小鼠，但两种激酶的纯合损失导致胚胎致死性，胚胎在多个组织中表现出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，可以补偿这些组织中C-ABL的损失。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，即我们最近的发现抑制T细胞中ABL激酶的活性显着抑制了T细胞受体（TCR）依赖性增殖，IL-2产生，IL-2启动子的转录，IL-2启动子的转录和TCR信号的酪氨酸磷酸化磷酸化。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。提出了两个具体的目的：1）定义ABL激酶在调节TCR参与下游下游的增殖，生存，细胞骨架重组和整合素介导的粘附方面所采用的机制，并确定在这些过程中识别构建的机制，并确定构建的机制，并确定b的刺激量，并确定b的刺激性刺激，并确定b的构建机制，以确定b的刺激性刺激，并确定b的刺激性和刺激。上游调节剂，以及检查ARG的丢失是否加剧了依赖C-ABL的B细胞表型。提出的实验的结果将为小鼠中ABL激酶的丧失引起的有缺陷的B和T细胞表型提供机械解释，而Wilt揭示了这些激酶在正常淋巴细胞中调节的新型信号通路，并且在正常淋巴细胞中，在病理条件下通过ABL激酶功能的损失或解析引起的病理条件。