Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102.
The protein-tyrosine kinase Pyk2/CAKbeta/CADTK is a key activator of Src in many cells. At hippocampal synapses, induction of long term potentiation requires the Pyk2/Src signaling pathway, which up-regulates the activity of N-methyl-d-aspartate-type glutamate receptors. Because localization of protein kinases close to their substrates is crucial for effective phosphorylation, we investigated how Pyk2 might be recruited to the N-methyl-d-aspartate receptor complex. This interaction is mediated by PSD-95 and its homolog SAP102. Both proteins colocalize with Pyk2 at postsynaptic dendritic spines in the cerebral cortex. The proline-rich regions in the C-terminal half of Pyk2 bind to the SH3 domain of PSD-95 and SAP102. The SH3 and guanylate kinase homology (GK) domain of PSD-95 and SAP102 interact intramolecularly, but the physiological significance of this interaction has been unclear. We show that Pyk2 effectively binds to the Src homology 3 (SH3) domain of SAP102 only when the GK domain is removed from the SH3 domain. Characterization of PSD-95 and SAP102 as adaptor proteins for Pyk2 fills a critical gap in the understanding of the spatial organization of the Pyk2-Src signaling pathway at the postsynaptic site and reveals a physiological function of the intramolecular SH3-GK domain interaction in SAP102.
Seabold
Gail K
GK
Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706-1532, USA.
Burette
Alain
A
Lim
Indra A
IA
Weinberg
Richard J
RJ
Hell
Johannes W
JW
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D051418:Focal Adhesion Kinase 2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D011233:Precipitin Tests; D016548:Prosencephalon / Q000737:chemistry / Q000648:ultrastructure; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000737:chemistry; D018909:src Homology Domains
D000076122:Disks Large Homolog 4 Protein; C101195:Dlg3 protein, rat; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat