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.
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