FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST.
FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST.
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DOI：
10.1016/j.molcel.2009.06.013
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发表时间：
2009-07-10
期刊：
影响因子：
16
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
--
作者：
Zheng, Yanhua;Xia, Yan;Hawke, David;Halle, Maxime;Tremblay, Michel L.;Gao, Xiang;Zhou, Xiao Zhen;Aldape, Kenneth;Cobb, Melanie H.;Xie, Keping;He, Jie;Lu, Zhimin
活化的Ras在许多类型的癌症中被发现。然而，Ras促进肿瘤转移的机制仍不清楚。我们在这里证明，激活Ras诱导酪氨酸去磷酸化和抑制FAK介导的Ras下游Fgd 1-Cdc 42-PAK 1-MEK-ERK信号级联。ERK磷酸化FAK S910并募集PIN 1和PTP-PEST，其与FAK共定位于迁移细胞的板状伪足。PIN 1结合和FAK的脯氨酰异构化导致PTP-PEST与FAK Y397相互作用并使FAK Y397去磷酸化。抑制FAK介导的这种信号中继促进Ras诱导的细胞迁移，侵袭和转移。这些发现揭示了FAK的丝氨酸磷酸化，异构化和酪氨酸去磷酸化的顺序修饰的重要性，在FAK活性的调节，从而在Ras相关的肿瘤转移。
Activated Ras has been found in many types of cancer. However, the mechanism underlying Ras-promoted tumor metastasis remains unclear. We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade. ERK phosphorylates FAK S910 and recruits PIN1 and PTP-PEST, which co-localize with FAK at the lamellipodia of migrating cells. PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis. These findings uncover the importance of sequential modification of FAK—by serine phosphorylation, isomerization, and tyrosine dephosphorylation—in the regulation of FAK activity and, thereby, in Ras-related tumor metastasis.
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作者：
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