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: 7054127
• 负责人: Ann Marie Pendergast
• 金额: $ 33.84万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054127
• 关键词: B cell receptor; B lymphocyte; SDS polyacrylamide gel electrophoresis; T cell receptor; T lymphocyte; actins; antibody; biological signal transduction; developmental immunology; enzyme activity; enzyme biosynthesis; enzyme mechanism; immune response; immunogenetics; immunologic receptors; immunoprecipitation; immunoregulation; integrins; laboratory mouse; laboratory rabbit; leukocyte adhesion molecules; lymphocyte proliferation; phenotype; polymerization; protein tyrosine kinase; transcription factor; western blottings

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酪氨酸激酶涉及细胞增殖、存活、粘附和迁移的调节。小鼠体内 c-Abl 的靶向删除揭示了该蛋白在 B 细胞和 T 细胞发育和功能中的作用。 c-Abl 缺陷小鼠表现出脾脏和胸腺萎缩以及淋巴细胞减少，从 c-Abl 敲除小鼠中分离的 B 淋巴细胞在生长因子撤除后对细胞凋亡的敏感性增加。我们已经证明，c-Abl 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 与 BCR 辅助受体 CD19 结合并使其磷酸化。 c-Abl 激酶在小鼠发育过程中与 Arg（一种 Abl 相关酪氨酸激酶）表现出功能冗余。 c-Abl 或 Arg 的单一缺失可产生存活的小鼠，但两种激酶的纯合缺失会导致胚胎致死，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，并且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，即抑制 T 细胞中 Abl 激酶的活性可显着抑制 T 细胞受体 (TCR) 依赖性增殖、IL-2 产生以及 IL-2 启动子的转录，以及对 TCR 信号转导至关重要的蛋白质子集的酪氨酸磷酸化。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) 定义 Abl 激酶用于调节增殖、存活、细胞骨架重组和 TCR 参与下游整合素介导的粘附的机制，并确定这些过程中的关键 Abl 靶点，2)通过识别关键 Abl 靶点和上游调节因子，定义 c-Abl 调节对 BCR 刺激的增殖反应的机制，并检查 Arg 的丢失是否会加剧 c-Abl 依赖性B 细胞表型。拟议实验的结果将为小鼠中 Abl 激酶缺失引起的 B 细胞和 T 细胞表型缺陷提供机制解释，并将揭示正常淋巴细胞中以及 Abl 缺失或失调引起的病理条件下由这些激酶调节的新信号传导途径激酶功能。