This application describes studies to investigate the mechanism underlying the regulation of cell growth by the protein tyrosine phosphatase SHP-1. SHP-1 is a SH2-domain containing tyrosine phosphatase that has been shown in a number of systems to negatively regulate receptor-mediated cell signaling pathways and therefore negatively regulate cell growth. It has been most extensively studied in the context of hematopoietic/cytokine receptors, FCgRIIB and MCH class I receptors expressed on NK cells, where SHP-1 is recruited to the tyrosine phosphorylated receptor and activated. The investigator has identified nuclear proteins that are associated with SHP-1 and has demonstrated that SHP-1 is found in the nucleus. Dr. Yi proposes to investigate: 1) the role of two C-terminal tyrosine residues in the nuclear localization of SHP-1; 2) the cell cycle dependence on the interaction of SHP-1 with its nuclear binding partners; and 3) the role of these binding partners in activating the phosphatase activity of SHP-1. Through these studies the investigator proposes to identify a nuclear function for SHP-1 that contributes to its role as a negative regulator of cell growth.
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