FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST.
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.
Zheng
Yanhua
Y
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Xia
Yan
Y
Hawke
David
D
Halle
Maxime
M
Tremblay
Michel L
ML
Gao
Xiang
X
Zhou
Xiao Zhen
XZ
Aldape
Kenneth
K
Cobb
Melanie H
MH
Xie
Keping
K
He
Jie
J
Lu
Zhimin
Z
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D014443:Tyrosine; D012694:Serine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D018631:ras Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse