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* Signal Transduction Program, Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and
Department of Pathology and Laboratory Medicine and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a central role in T cell activation and T cell development. SLP-76 has three functional modules: an acidic domain with three key tyrosines, a central proline-rich domain, and a C-terminal Src homology 2 domain. Of these, mutation of the three N-terminal tyrosines (Y112, Y128, and Y145) results in the most profound effects on T cell development and function. Y112 and Y128 associate with Vav and Nck, two proteins shown to be important for TCR-induced phosphorylation of proximal signaling substrates, Ca2+ flux, and actin reorganization. Y145 has been shown to be important for optimal association of SLP-76 with inducible tyrosine kinase, a key regulator of T cell function. To investigate further the role of the phosphorylatable tyrosines of SLP-76 in TCR signaling, cell lines and primary T cells expressing SLP-76 with mutations in individual or paired tyrosine residues were analyzed. These studies show that Tyr145 of SLP-76 is the most critical tyrosine for both T cell function in vitro and T cell development in vivo.
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