@article{0c3dde941d524f3cb25bb8f41569d5a1,
title = "FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST",
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.",
keywords = "SIGNALING",
author = "Yanhua Zheng and Yan Xia and David Hawke and Maxime Halle and Tremblay, {Michel L.} and Xiang Gao and Zhou, {Xiao Zhen} and Kenneth Aldape and Cobb, {Melanie H.} and Keping Xie and Jie He and Zhimin Lu",
note = "Funding Information: We thank Drs. Tony Hunter, Lynda Chin, Ronald DePinho, Nicholas Tonks, David Foster, Anthony Means, Steven Hanks, David Schlaepfer, Steven Reed, Makoto Noda, Gerald R. Crabtree, Rakesh Kumar, Jeffrey Field, Bill Davis, Len Stephens, Richard Cerione, Giancarlo Vecchio, Zhizuang Joe Zhao, Kevin Pumiglia, Maria-Magdalena Georgescu, Seth Corey, Jean-Guy LeHoux, Alan Hall, Martin Alexander Schwartz, Yan Chen, Joseph Kissil, Kent Rossman, Jerome Gorski, Roberto Buccione, Michiyuki Matsuda, and Tetsu Akiyam for useful reagents. We thank Stephanie Deming for editing of this manuscript. This work was supported by the Pediatric Brain Tumor Foundation (Z.L.), a Brain Tumor Society research grant (Z.L.), a Phi Beta Psi Sorority research grant (Z.L.), an institutional research grant from The University of Texas M.D. Anderson Cancer Center (Z.L.), National Cancer Institute grant 5R01CA109035 (Z.L.), and a grant from MOST of China (2009CB918703 [Y.X.]). ",
year = "2009",
month = jul,
day = "10",
doi = "10.1016/j.molcel.2009.06.013",
language = "English (US)",
volume = "35",
pages = "11--25",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",
}