The proto-oncogene, Vav, was first identified from esophageal carcinoma DNA in a screen for oncogenes that could transform fibroblasts. However, its oncogenic potential in fibroblasts probably does not reflect its true function since Vav is exclusively expressed in cells of hematopoietic lineage and in trophoblasts. Recent studies suggest that Vav plays an important role in antigen receptor signal transduction within T lymphocytes and B lymphocytes. These cells play critical roles in immune functions responsible for protection against pathogens. However, these cells also represent the major barriers to organ and tissue transplantation and their abnormal regulation can result in autoimmunity. Although Vav is inducibly tyrosine phosphorylated following T (TCR) and B cell antigen receptor (BCR) stimulation, the specific function of Vav in regulating lymphocyte responses is not known. Vav has numerous protein structural domains that suggest that it is involved in signal transduction functions and multiple protein-protein interactions. The overall goal of this proposal is to define the biochemical basis for the function of Vav in the antigen receptor signaling pathway. By understanding its normal function, it may be possible to develop novel strategies for the development of immunomodulating drugs. Two systems will be used to study Vav function: In the first system, it has been possible, by overexpressing Vav, to activate TCR signaling pathways leading to interleukin-2 gene expression. In the second system, Vav-deficient embryonic stem cells will be used to define its function in T cell development. These two systems will be used to : 1) identify the protein tyrosine kinase(s) responsible for Vav phosphorylation; 2) identify the tyrosine phosphorylation sites of Vav following antigen receptor stimulation; 3) characterize the functional domains of Vav that participate in antigen receptor signal transduction; 4) identify the cellular molecules that interact with the functionally important domains of Vav; and 5) establish an inducible system of Vav expression to study the role of Vav in TCR signal transduction and in T cell development.
These specific aims will provide important insights into the biochemical basis for Vav function in antigen receptor signal transduction.
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