title: Striatal-enriched protein-tyrosine phosphatase (STEP) regulates Pyk2 kinase activity.
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.
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bartos
authors.forename: Tommaso
authors.initials: T
authors.lastname: Patriarchi
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Hell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology*; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D057907:Post-Synaptic Density / Q000201:enzymology*; D011485:Protein Binding / Q000502:physiology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485546:Asap1 protein, mouse; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D051419:Paxillin; C496062:Pxn protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse