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*
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*
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DOI：
10.1074/jbc.m212825200
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发表时间：
2003-04
期刊：
影响因子：
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通讯作者：
Gail K. Seabold;A. Burette;I. A. Lim;R. Weinberg;J. Hell
中科院分区：
文献类型：
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作者：
Gail K. Seabold;A. Burette;I. A. Lim;R. Weinberg;J. Hell
蛋白酪氨酸激酶Pyk2/CAKβ/CADTK在许多细胞中是Src的关键激活因子。在海马突触，长期增强的诱导需要Pyk2/Src信号通路，该通路上调n -甲基-d-天冬氨酸型谷氨酸受体的活性。由于蛋白激酶在其底物附近的定位对于有效磷酸化至关重要，因此我们研究了Pyk2如何被募集到n -甲基-d-天冬氨酸受体复合物中。这种相互作用是由PSD-95及其同源物SAP102介导的。这两种蛋白在大脑皮层突触后树突棘与Pyk2共定位。Pyk2的c端一半富含脯氨酸的区域与PSD-95和SAP102的SH3结构域结合。PSD-95和SAP102的SH3和鸟苷酸激酶同源（GK）结构域在分子内相互作用，但这种相互作用的生理意义尚不清楚。我们发现，只有当GK结构域从SH3结构域移除时，Pyk2才能有效地与SAP102的Src同源3 （SH3）结构域结合。PSD-95和SAP102作为Pyk2的接头蛋白的特性填补了理解Pyk2- src信号通路在突触后位点的空间组织的关键空白，并揭示了SAP102分子内SH3-GK结构域相互作用的生理功能。
The protein-tyrosine kinase Pyk2/CAKβ/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 ofN-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.