Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Antibodies / pharmacology
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Brain / cytology*
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Brain / metabolism
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Calcium / metabolism
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Calmodulin / pharmacology
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Cell Line, Transformed
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Disks Large Homolog 4 Protein
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Focal Adhesion Kinase 2 / immunology
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Focal Adhesion Kinase 2 / metabolism*
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Green Fluorescent Proteins / genetics
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Immunoprecipitation / methods
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / metabolism*
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Ionomycin / pharmacology
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Ionophores / pharmacology
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Male
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Membrane Proteins / metabolism*
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N-Methylaspartate / pharmacology
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Neurons / drug effects
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Neurons / physiology
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PDZ Domains / physiology
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Patch-Clamp Techniques / methods
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Protein Binding / physiology
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / physiology
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Sodium Channel Blockers / pharmacology
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Synapses / metabolism*
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Tetradecanoylphorbol Acetate / analogs & derivatives
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Tetradecanoylphorbol Acetate / pharmacology
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Tetrodotoxin / pharmacology
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Transfection / methods
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Tyrosine / metabolism
Substances
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Antibodies
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Calmodulin
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Intracellular Signaling Peptides and Proteins
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Ionophores
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Membrane Proteins
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Receptors, N-Methyl-D-Aspartate
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Sodium Channel Blockers
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Green Fluorescent Proteins
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Tyrosine
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Tetrodotoxin
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Ionomycin
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4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
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N-Methylaspartate
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Focal Adhesion Kinase 2
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Tetradecanoylphorbol Acetate
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Calcium