Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity*
Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity*
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DOI：
10.1074/jbc.m112.368654
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发表时间：
2012-04
期刊：
影响因子：
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通讯作者：
Jian Xu;P. Kurup;J. Bartos;Tommaso Patriarchi;J. Hell;P. Lombroso
中科院分区：
文献类型：
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作者：
Jian Xu;P. Kurup;J. Bartos;Tommaso Patriarchi;J. Hell;P. Lombroso
背景：富含脯氨酸的酪氨酸激酶 2 (Pyk2) 与突触可塑性有关；然而，目前尚不清楚 Pyk2 如何在神经元内失活。结果：富含纹状体的蛋白酪氨酸磷酸酶 (STEP) 直接结合 Pyk2 的 Tyr402 并使其去磷酸化。结论：STEP 使 Pyk2 及其下游信号通路失活。意义：这些结果确定了 Pyk2 信号传导的重要调节机制，对于理解突触可塑性的分子机制至关重要。富含脯氨酸的酪氨酸激酶 2 (Pyk2) 是粘着斑激酶家族的成员，在脑和造血细胞中高度表达。 Pyk2 在细胞中发挥多种功能，包括调节细胞粘附、迁移和细胞骨架重组。在大脑中，它通过调节 N-甲基-d-天冬氨酸受体运输参与诱导长时程增强。这是通过 Src 家族酪氨酸激酶成员（例如 Fyn）的磷酸化和激活而发生的，该成员会在 Tyr1472 位点磷酸化 GluN2B。该位点的磷酸化导致 GluN1-GluN2B 受体胞吐至突触膜。 Pyk2 活性通过几个关键酪氨酸位点（包括 Tyr402）的磷酸化来调节。在这项研究中，我们报告 Pyk2 是纹状体富含蛋白酪氨酸磷酸酶 (STEP) 的底物。 STEP 与 Pyk2 Tyr402 位点结合并使其去磷酸化。 STEP KO 小鼠表现出 Pyk2 Tyr402 以及 Pyk2 底物桩蛋白和 ASAP1 磷酸化增强。功能研究表明，STEP 在皮质切片 KCl 去极化后反对 Pyk2 激活，并阻止 Pyk2 易位至突触后密度，这是 Pyk2 激活和功能所需的关键步骤。这是第一项确定 Pyk2 作为 STEP 底物的研究。
Background: Proline-rich tyrosine kinase 2 (Pyk2) is implicated in synaptic plasticity; however, it remains unclear how Pyk2 is inactivated within neurons. Results: Striatal-enriched protein-tyrosine phosphatase (STEP) directly binds to and dephosphorylates Pyk2 at Tyr402. Conclusion: STEP inactivates Pyk2 and its downstream signaling pathways. Significance: These results identify an important regulatory mechanism for Pyk2 signaling that is critical for understanding the molecular mechanisms underlying synaptic plasticity. Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family and is highly expressed in brain and hematopoietic cells. Pyk2 plays diverse functions in cells, including the regulation of cell adhesion, migration, and cytoskeletal reorganization. In the brain, it is involved in the induction of long term potentiation through regulation of N-methyl-d-aspartate receptor trafficking. This occurs through the phosphorylation and activation of Src family tyrosine kinase members, such as Fyn, that phosphorylate GluN2B at Tyr1472. Phosphorylation at this site leads to exocytosis of GluN1-GluN2B receptors to synaptic membranes. Pyk2 activity is modulated by phosphorylation at several critical tyrosine sites, including Tyr402. In this study, we report that Pyk2 is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP). STEP binds to and dephosphorylates Pyk2 at Tyr402. STEP KO mice showed enhanced phosphorylation of Pyk2 at Tyr402 and of the Pyk2 substrates paxillin and ASAP1. Functional studies indicated that STEP opposes Pyk2 activation after KCl depolarization of cortical slices and blocks Pyk2 translocation to postsynaptic densities, a key step required for Pyk2 activation and function. This is the first study to identify Pyk2 as a substrate for STEP.