Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, USA.
J Neurosci. 2010 Jan 13;30(2):449-63. doi: 10.1523/JNEUROSCI.4992-08.2010.
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.
酪氨酸激酶 Pyk2 通过将 Ca(2+) 内流与酪氨酸磷酸化联系起来，在细胞内信号转导中发挥独特的作用，但 Pyk2 的激活机制尚不清楚。我们报告说，体外用抗体使 Pyk2 寡聚化或在 PC6-3 细胞中过表达 PSD-95 可诱导 Tyr402 的转磷酸化，这是 Pyk2 激活的第一步。在神经元中，通过 NMDA 型谷氨酸受体的 Ca(2+) 内流通过 Ca(2+) 和钙调蛋白刺激与 PSD-95 的结合，导致内源性 Pyk2 的突触后聚集和自身磷酸化。因此，Ca(2+) 内流通过刺激其与 PSD-95 的相互作用，促进 Pyk2 的寡聚化，从而自动激活 Pyk2。我们表明，这种 Pyk2 激活机制对于海马 CA1 区的长时程增强至关重要，长时程增强被认为是学习和记忆的基础。
