Postsynaptic Clustering and Activation of Pyk2 by PSD-95

Abstract

The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca 2ϩ influx to tyrosine phosphorylation, but the molecular mechanism of Pyk2 activation is unknown. We report that Pyk2 oligomerization by antibodies in vitro or overexpression of PSD-95 in PC6-3 cells induces trans-autophosphorylation of Tyr402, the first step in Pyk2 activation. In neurons, Ca 2ϩ influx through NMDA-type glutamate receptors causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca 2ϩ -and calmodulin-stimulated binding to PSD-95. Accordingly, Ca 2ϩ influx promotes oligomerization and thereby autoactivation of Pyk2 by stimulating its interaction with PSD-95. We show that this mechanism of Pyk2 activation is critical for long-term potentiation in the hippocampus CA1 region, which is thought to underlie learning and memory.

Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

“…Pathway-TKs are expressed in neurons and are particularly enriched in synapses (21)(22)(23)(24) where they phosphorylate and activate a range of substrates (25). A first set of experiments investigated the overall activation of tyrosine kinases after exposure of hippocampal neurons to CORT.…”

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

“…-activated non-receptor tyrosine kinase closely related to focal adhesion kinase (FAK) [1]. Pyk2 is enriched in adult neurons and plays an important role in neuronal plasticity [2][3][4][5][6]. In non-neuronal cells, Pyk2 is involved in osteoclast function [7], macrophage migration [8], and focal adhesion disassembly [9].…”

“…The functional differences between these isoforms are not known. Although the precise mechanism of Pyk2 activation remains unclear, increase in intracellular free Ca 2? can directly or indirectly induce Pyk2 dimerization and transautophosphorylation at Y402 creating a Src-homology-2 binding site that recruits Src family kinases and activates various signaling pathways [1,5,[13][14][15].…”

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

“…Pyk2 phosphorylates and activates Src and Fyn (10 -12), either one of which then phosphorylates Pyk2 at Tyr 579/580 within its activation loop (13,14). Pyk2 activation results in postsynaptic translocation and association of Pyk2 with the SH3 domain of postsynaptic density (PSD)-95 (15), which is essential for Pyk2 activation and the induction of long term potentiation (LTP) (15). Src also phosphorylates Pyk2 at Tyr 881 , leading to recruitment of the Grb2-SOS complex and subsequent activation of mitogen-activated protein kinase (MAPK) (1,16).…”

“…Thus, Pyk2 activates the Src family kinase and MAPK signaling pathways, both of which are required for the induction and maintenance of LTP (17,18). Overexpression of a catalytically inactive mutant of Pyk2 (K457A) or disruption of Pyk2/PSD-95 interactions disrupts LTP, underscoring the importance of Pyk2 in regulating synaptic plasticity (15,17).…”