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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035989-02
Application #
2655555
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Oliver, Eugene J
Project Start
1997-02-01
Project End
2000-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Paul, S; Snyder, G L; Yokakura, H et al. (2000) The Dopamine/D1 receptor mediates the phosphorylation and inactivation of the protein tyrosine phosphatase STEP via a PKA-dependent pathway. J Neurosci 20:5630-8
Gurd, J W; Bissoon, N; Nguyen, T H et al. (1999) Hypoxia-ischemia in perinatal rat brain induces the formation of a low molecular weight isoform of striatal enriched tyrosine phosphatase (STEP). J Neurochem 73:1990-4
Nguyen, T H; Paul, S; Xu, Y et al. (1999) Calcium-dependent cleavage of striatal enriched tyrosine phosphatase (STEP). J Neurochem 73:1995-2001
Brodsky, M; Lombroso, P J (1998) Molecular mechanisms of developmental disorders. Dev Psychopathol 10:1-20
Bult, A; Zhao, F; Dirkx Jr, R et al. (1997) STEP: a family of brain-enriched PTPs. Alternative splicing produces transmembrane, cytosolic and truncated isoforms. Eur J Cell Biol 72:337-44
Bult, A; Zhao, F; Dirkx Jr, R et al. (1996) STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum. J Neurosci 16:7821-31