Structure and function of protein tyrosine phosphatases

Protein tyrosine phosphorylation is an important post-translational event that is involved at multiple levels of cellular regulation. Protein tyrosine phosphatases (PTPases) working in concert with protein tyrosine kinases, control the tyrosine phosphorylation state of target molecules in various signal transduction pathways. Kinetic and structural studies have been used to explore the catalytic mechanism of both protein tyrosine phosphatases (PTPases) and the dual-specific phosphatases (DS-PTPases). The general features of the mechanism demonstrates that phosphate monoesters are hydrolyzed via a covalent phosphoenzyme intermediate. Evidence suggests that the covalent intermediate involves a thiol phosphate bond. Site-directed mutagenesis was employed to identify a general acid which participates in catalysis. Other residues which play key roles in the breakdown of the intermediate have also been identified. These kinetic studies are supported by x-ray structure analysis of both the PTPases and the DS-PTPases. [Research supported by the NIH (AI34095 to M.A.S.; DK18024 and DK18849 to J.E.D.), an NRSA fellowship to J.M.D. (GM17789), the University of Michigan Multipurpose Arthritis Center. J.Y. is the DPST Scholar from Thailand. M.A.S. is a Pew Scholar in the Biomedical Sciences.].