Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity

Abstract

Background: Proline-rich tyrosine kinase 2 (Pyk2) is implicated in synaptic plasticity; however, it remains unclear how Pyk2 is inactivated within neurons. Results: Striatal-enriched protein-tyrosine phosphatase (STEP) directly binds to and dephosphorylates Pyk2 at Tyr 402 . Conclusion: STEP inactivates Pyk2 and its downstream signaling pathways. Significance: These results identify an important regulatory mechanism for Pyk2 signaling that is critical for understanding the molecular mechanisms underlying synaptic plasticity.

STEP61is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

“…STEP dephosphorylates a number of substrates that can directly and indirectly influence synaptic plasticity. These include Fyn, Pyk2, and ERK1/2, where STEP dephosphorylation inactivates these enzymes (13)(14)(15)(16). Other STEP substrates include the GluN2B subunit of the NMDA receptor and the GluA2 subunit of the AMPA receptor, and STEP dephosphorylation results in internalization of both GluN1/GluN2B and GluA1/GluA2 receptors (18,58).…”

“…The current model of STEP 61 function is that it opposes the development of synaptic strengthening by dephosphorylating regulatory tyrosines on these substrates. In the case of the kinases, STEP 61 -mediated dephosphorylation of the regulatory Tyr within the activation loop inactivates these enzymes (13)(14)(15)(16). STEP-mediated dephosphorylation of Tyr residues in the glutamate receptor subunits results in internalization of GluN1/GluN2B and GluA1/GluA2 receptor complexes (17)(18)(19)(20).…”

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

“…As well, STEP co-immunoprecipitates with the GluN1 subunit [181], directly dephosphorylates Y1472 [216], and, when deleted from the mouse genome, causes hyperphosphorylation of Y1472 in synaptosomal membranes prepared from the hippocampus [277]. Along with a direct effect upon Y1472, STEP may also act indirectly by dephosphorylating regulatory residues in the catalytic domains of Fyn, which is the principal SFK acting at Y1472 [165], and proline-rich tyrosine kinase 2 (Pyk2), which is an upstream activator of SFKs [262]. …”

Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders

“…The PP domains are required for the interactions of STEP 61 with Fyn and Pyk2, indicating that these domains (in addition to the KIM domain) contribute to the substrate specificity of STEP 61 (Nguyen et al, 2002; Xu et al, 2012). The PEST sequences mediate proteolytic processes in several proteins, although their function in STEP 61 remains less clear (Shumway et al, 1999; Spencer et al, 2004).…”