EXCEED THE SPACE PROVIDED. The broad, long-term objectives of the project are to characterize the structure, regulation and function of the protein tyrosine phosphatase (FTP) family of enzymes. It is now apparent that the coordinated and competing actions of both protein tyrosine kinases {PTKs) and PTPs are integrated in vivo to control such fundamental processes as growth and proliferation, differentiation, survival, motility andmetabolism. Furthermore, disruption of the delicate balance between the action of PTPs and PTKs has been implicatedin the etiology of human diseases. Therefore, characterization of the PTPs is a prerequisite to gaininga complete understanding of the physiological consequences of tyrosine phosphorylaticn under normal diseased conditions. This research program is focused primarily on two nontransmembrane PTPs, PTP1B and TCPTP, which have been shown to be critical regulators of growth factor and hormone-induced signal transduction pathways in vivo, with links to major human diseases including cancer and diabetes.The four Specific Aims are;1) To conduct a structure:function analysis of PTP1B that will define mechanismsof substrate recognition and regulation of enzymatic activity, 2} To characterize the PTP 1Bpromoter and elucidate mechanims by which expression of the PTP is alteredin human diseases, 3) To characterize the regulation and function of TCPTP and 4) To develop proteomics-based strategies for profiling theexpression of members of the PTP family. Both PTP1B and TCPTP are regulated by reversible oxidation in vivo, which induces inhibitory conformational changes of the PTP active site. Strategies have been developedto test whether trapping the oxidized, inactive conformation can be pursued to exploit the PTPs astherapeutic targets. Furthermore, proteomics-based strategies are being developed for PTP identification in biological samples, to define novel therapeutic targets for human disease.
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