Recently, adapter proteins have been shown to play a critical role in the regulation of signal transduction mediated by numerous cell surface receptors. For the past six years our laboratory has been investigating the role of adapter proteins in the control of T cell activation. During the previous two periods of support with this proposal, we identified and began the characterization of two hematopoietic specific adapter molecules: SH2 domain containing leukocyte phosphoprotein of 76kDa (SLP-76) and SLP-76 associated protein of l30kDa (SLAP-130 also known as Fyb). Evidence is accumulating supporting the notion that both of these proteins play important roles in the regulation of T cell function. The experiments described in this proposal will focus on SLAP-130/Fyb, making extensive use of a mouse we recently generated that is deficient in expression of this protein. Our preliminary data indicate that in the absence of SLAP-130/Fyb there are significant alterations in T cell function, most notably a failure of purified T cells to proliferate ex vivo and an uncoupling of the T cell antigen receptor with upregulation of integrin function. The goals of this proposal are to understand better the role of SLAP-130/Fyb in immune cell function and to investigate the structural features of this adapter protein that are critical for its function. To achieve these goals, three specific aims will be pursued. The first is to characterize thoroughly the phenotype of the SLAP-l30/Fyb deficient mice. Once the defects are clear, the second aim will investigate the structural features of SLAP-130/Fyb that are important for its function using two complementary in vivo approaches. Recognizing that, as an adapter protein, SLAP- 130/Fyb likely exerts its effects by nucleating intermolecular complexes, the third aim of this proposal will investigate the temporal and spatial organization of these complexes in cells, which appear to require SLAP-130/Fyb for their normal function. We anticipate that collectively these studies will provide new insights into how this protein (and by extension other proteins with similar functional domains) may function in the regulation of cellular activation.
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