Postsynaptic clustering and activation of Pyk2 by PSD-95.
Postsynaptic clustering and activation of Pyk2 by PSD-95.
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DOI：
10.1523/jneurosci.4992-08.2010
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发表时间：
2010-01-13
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影响因子：
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通讯作者：
Hell JW
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文献类型：
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作者：
Bartos JA;Ulrich JD;Li H;Beazely MA;Chen Y;Macdonald JF;Hell JW
酪氨酸激酶Pyk 2通过连接Ca 2+内流和酪氨酸磷酸化在细胞内信号转导中起独特作用，但Pyk 2激活的分子机制尚不清楚。我们报告说，Pyk 2寡聚化抗体在体外或PSD-95在PC 6 -3细胞中的过表达诱导Tyr 402的反式自磷酸化，Pyk 2激活的第一步。在神经元中，通过NMDA型谷氨酸受体（NMDAR）的Ca 2+内流通过Ca 2+和钙调素刺激的与PSD-95的结合引起内源性Pyk 2的突触后聚集和自磷酸化。因此，Ca 2+内流通过刺激Pyk 2与PSD-95的相互作用促进Pyk 2的寡聚化，从而促进Pyk 2的自激活。我们发现Pyk 2激活的这种机制对于海马CA 1区的LTP至关重要，这被认为是学习和记忆的基础。
The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca2+ 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, Ca2+ influx through NMDA-type glutamate receptors (NMDAR) causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca2+- and calmodulin-stimulated binding to PSD-95. Accordingly, Ca2+ 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 LTP in the hippocampus CA1 region, which is thought to underlie learning and memory.