Abstract
Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family and is highly expressed in brain and hematopoietic cells. Pyk2 plays diverse functions in cells, including the regulation of cell adhesion, migration, and cytoskeletal reorganization. In the brain, it is involved in the induction of long term potentiation through regulation of N-methyl-d-aspartate receptor trafficking. This occurs through the phosphorylation and activation of Src family tyrosine kinase members, such as Fyn, that phosphorylate GluN2B at Tyr(1472). Phosphorylation at this site leads to exocytosis of GluN1-GluN2B receptors to synaptic membranes. Pyk2 activity is modulated by phosphorylation at several critical tyrosine sites, including Tyr(402). In this study, we report that Pyk2 is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP). STEP binds to and dephosphorylates Pyk2 at Tyr(402). STEP KO mice showed enhanced phosphorylation of Pyk2 at Tyr(402) and of the Pyk2 substrates paxillin and ASAP1. Functional studies indicated that STEP opposes Pyk2 activation after KCl depolarization of cortical slices and blocks Pyk2 translocation to postsynaptic densities, a key step required for Pyk2 activation and function. This is the first study to identify Pyk2 as a substrate for STEP.
Highlights
Proline-rich tyrosine kinase 2 (Pyk2) is implicated in synaptic plasticity; it remains unclear how Pyk2 is inactivated within neurons
We report that Pyk2 is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP)
Inhibition of Tyrosine Phosphatases Leads to Activation of Pyk2—Our previous study showed that resin-bound anti-Pyk2 antibody facilitated Pyk2 dimerization and activation [15]
Summary
Proline-rich tyrosine kinase 2 (Pyk2) is implicated in synaptic plasticity; it remains unclear how Pyk is inactivated within neurons. Results: Striatal-enriched protein-tyrosine phosphatase (STEP) directly binds to and dephosphorylates Pyk at Tyr402. Pyk plays diverse functions in cells, including the regulation of cell adhesion, migration, and cytoskeletal reorganization In the brain, it is involved in the induction of long term potentiation through regulation of N-methylD-aspartate receptor trafficking. It is involved in the induction of long term potentiation through regulation of N-methylD-aspartate receptor trafficking This occurs through the phosphorylation and activation of Src family tyrosine kinase members, such as Fyn, that phosphorylate GluN2B at Tyr1472. Phosphorylation at this site leads to exocytosis of GluN1GluN2B receptors to synaptic membranes. We report that Pyk is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP). We identify Pyk as a novel substrate for STEP using biochemical, molecular, and immunocytochemical techniques in wild type (WT) and STEP knock-out (KO) mice
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