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

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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

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Non-Receptor Type 12 Protein Tyrosine Phosphatase
Tyrosine
Phosphorylation
Neoplasm Metastasis
Neoplasms
Pseudopodia
Mitogen-Activated Protein Kinase Kinases
Serine
Cell Movement

Keywords

  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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

In: Molecular Cell, Vol. 35, No. 1, 10.07.2009, p. 11-25.

Research output: Contribution to journalArticle

Zheng, Y, Xia, Y, Hawke, D, Halle, M, Tremblay, ML, Gao, X, Zhou, XZ, Aldape, K, Cobb, MH, 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, vol. 35, no. 1, pp. 11-25. https://doi.org/10.1016/j.molcel.2009.06.013
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. / FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST. In: Molecular Cell. 2009 ; Vol. 35, No. 1. pp. 11-25.
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