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J. Biol. Chem., Vol. 277, Issue 27, 24274-24279, July 5, 2002

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Striatal Enriched Phosphatase 61 Dephosphorylates Fyn at Phosphotyrosine 420^*

Tri-Hung Nguyen, Jian Liu, and Paul J. Lombroso

From the Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520

A family of protein tyrosine phosphatases enriched within the central nervous system called striatal enriched phosphatase (STEP) has been implicated in the regulation of the N-methyl-D-aspartate receptor. STEP₆₁, a membrane-associated isoform located in the postsynaptic densities (PSDs) of striatal neurons, contains two transmembrane domains, two proline-rich domains, and a kinase-interacting motif. This study demonstrates that STEP₆₁ associates with Fyn, a member of the Src family kinases that is also enriched in PSDs. By using human embryonic kidney 293 cells for co-transfection, we determined that a substrate-trapping variant (STEP₆₁ CS) binds to Fyn but not to other members of the Src family present in PSDs. In a complementary experiment, myc-tagged Fyn immunoprecipitates STEP₆₁ CS. STEP₆₁ binds to Fyn through one of its proline-rich domains and the kinase-interacting motif domain, whereas Fyn binds to STEP₆₁ through its Src homology 2 domain and the unique N-terminal domain. STEP₆₁ CS pulls down Fyn when the Tyr⁴²⁰ site is phosphorylated. In vitro, wild-type STEP₆₁ dephosphorylates Fyn at Tyr⁴²⁰ but not at Tyr⁵³¹. These results suggest that STEP regulates the activity of Fyn by specifically dephosphorylating the regulatory Tyr⁴²⁰ and may be one mechanism by which Fyn activity is decreased within PSDs.

We dedicate this work to the memory of Dr. Akira Okamura.

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