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Abstract
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. STEP(61), 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 STEP(61) 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 (STEP(61) CS) binds to Fyn but not to other members of the Src family present in PSDs. In a complementary experiment, myc-tagged Fyn immunoprecipitates STEP(61) CS. STEP(61) binds to Fyn through one of its proline-rich domains and the kinase-interacting motif domain, whereas Fyn binds to STEP(61) through its Src homology 2 domain and the unique N-terminal domain. STEP(61) CS pulls down Fyn when the Tyr(420) site is phosphorylated. In vitro, wild-type STEP(61) dephosphorylates Fyn at Tyr(420) but not at Tyr(531). These results suggest that STEP regulates the activity of Fyn by specifically dephosphorylating the regulatory Tyr(420) and may be one mechanism by which Fyn activity is decreased within PSDs.
Highlights
Src and Fyn are present within postsynaptic densities of central nervous system neurons (2, 3)
This study demonstrates that STEP61 associates with Fyn, a member of the Src family kinases that is enriched in postsynaptic densities (PSDs)
Similar strategies have been used to identify proteins that associate with a number of protein tyrosine phosphatases (PTPs) after critical amino acids are mutated in order to make the PTP enzymatically inactive (23, 24)
Summary
Src and Fyn are present within postsynaptic densities of central nervous system neurons (2, 3). We looked for the association of STEP with members of the Src kinase family, including Fyn, Src, and Lyn. Western blot analysis determined that, of these proteins, only Fyn was present in the eluate.
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