The central goal of the proposed investigation is the study the structure and function of a family of protein tyrosine phosphatases termed STEP (""""""""striatal-enriched"""""""" phosphatases). STEP members are brain-specific and highly enriched within neurons of the basal ganglia. A striking feature is that some members contain transmembrane domains, PEST sequences and polyproline-rich sequences. The hypotheses to be tested is that some of these domains provide a mechanism for subcellular targeting of these different isoforms, determine substrate specificity for the different STEP isoforms and regulate their activity. Preliminary data suggest that STEP participates in signal transduction pathways through the formation of protein-protein complexes. The proposed experiments would use biochemical, electron microscopic, and molecular techniques to address these hypotheses. Abnormalities in basal ganglia underlie the pathogenesis of many neurological disorders including Huntington's and Parkinson's disease and are also involved in neuropsychiatric disorders such as Tourrette's Syndrome and obsessive-compulsive disorder. This collection of nuclei is also the site of action of many of the unwanted side effects of neuroleptic drugs. Disruption of the neural signaling mechanisms within the basal ganglia is a common component of all of these disorders and further knowledge is needed of the normal signaling pathways that occur in this region of the CNS.
