Postsynaptic clustering and activation of Pyk2 by PSD-95.
The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca(2+) 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(2+) influx through NMDA-type glutamate receptors causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca(2+)- and calmodulin-stimulated binding to PSD-95. Accordingly, Ca(2+) 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.
Bartos
Jason A
JA
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, USA.
Ulrich
Jason D
JD
Li
Hongbin
H
Beazely
Michael A
MA
Chen
Yucui
Y
Macdonald
John F
JF
Hell
Johannes W
JW
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000494:pharmacology; D002461:Cell Line, Transformed; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051418:Focal Adhesion Kinase 2 / Q000276:immunology / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D054731:PDZ Domains / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014443:Tyrosine / Q000378:metabolism
D000906:Antibodies; D002147:Calmodulin; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D013779:Tetrodotoxin; D015759:Ionomycin; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D016202:N-Methylaspartate; D051418:Focal Adhesion Kinase 2; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium