FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST

Yanhua Zheng, Yan Xia, David Hawke, Maxime Halle, Michel L. Tremblay, Xiang Gao, Xiao Zhen Zhou, Kenneth Aldape, Melanie H. Cobb, Keping Xie, Jie He, Zhimin Lu

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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 colocalize 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.

Original languageEnglish (US)
Pages (from-to)11-25
Number of pages15
JournalMolecular cell
Volume35
Issue number1
DOIs
StatePublished - Jul 10 2009

Keywords

  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Zheng, Y., Xia, Y., Hawke, D., Halle, M., Tremblay, M. L., Gao, X., Zhou, X. Z., Aldape, K., Cobb, M. H., Xie, K., He, J., & Lu, Z. (2009). FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST. Molecular cell, 35(1), 11-25. https://doi.org/10.1016/j.molcel.2009.06.013