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Mol Cell. 2009 Jul 10;35(1):11-25. doi: 10.1016/j.molcel.2009.06.013.

FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST.

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Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.


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.

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