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Current Research:
My research examines the function of atypical phosphatases involved in phosphorylation-mediated signaling and disease. Each of the proteins under study can be classified within the large superfamily of protein tyrosine phosphatases (PTPs). However, we have discovered a phospho-serine, -threonine or -tyrosine interaction protein, STYX, as the archetype of a new class of so-called, dead-phosphatases. These proteins structurally mimic PTPs except for the endogenous substitution of catalytically essential amino acids. Rather than simply being the non-catalytic relic of an active phosphatase, STYX serves as an adapter to phosphorylated protein targets and plays an essential role in spermatogenesis. Our knockout model of Styx function in mouse leads to male infertility due to the disruption of the differentiation of spermatids into spermatozoa. Endogenous expression of Styx in round spermatids and its coimmunoprecipitation with a multiply phosphorylated spermatid RNA-binding protein suggests that together they form a translational checkpoint governing germ cell differentiation.
Our work with Styx has led to the identification of another dead-phosphatase, Sbf-1, whose loss of expression in mouse results in Sertoli cell dysfunction and azoospermia. We can show that Sbf-1 physically interacts with a catalytically active lipid phosphatase found in Sertoli cells, through which Sbf-1 likely modulates intracellular phosphoinositide signaling and vesicular trafficking. Finally, we have also discovered a new egg-derived lipid phosphatase, EDP, which is involved in vesicular sorting of lysosomes and autophagic vesicles. Recent work to phenotype EDP null mice and ongoing characterization of Styx and Sbf-1 function in our lab, will provide a basic understanding of the regulatory mechanisms of cellular signaling through phosphoproteins and phospholipids, as well as reveal functions for dead-phosphatases in normal reproduction and reproductive pathophysiology.
Recent Publications:
Wishart, M. J., Taylor, G. S., Slama, J. T., and Dixon, J. E., PTEN and myotubularin phosphoinositide phosphatases: bringing bioinformatics to the lab bench. Curr. Opin. Cell Biol. 13, 172-181, 2001.
Wishart, M. J., Taylor, G. S., and Dixon, J. E., Phoxy lipids: revealing PX domains as phosphoinositide binding modules. Cell 105, 817-820, 2001.
Wishart, M. J., and Dixon, J. E., The archetype STYX / dead-phosphatase complexes with a spermatid mRNA binding protein and is essential for normal sperm production. Proc. Natl. Acad. Sci. USA 99, 2112-2117, 2002.
Wishart, M. J., “Chapter 121: Styx / Dead-Phosphatases” in Handbook of Cell Signaling, Volume 1, Bradshaw, R. and Dennis, E., Eds., Academic Press, San Diego, 2003, 741-748, in press.
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