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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Focal Adhesion Protein-Tyrosine Kinases / genetics
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • NIH 3T3 Cells
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism*
  • Serine / metabolism
  • Transfection
  • Tyrosine / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • NIMA-Interacting Peptidylprolyl Isomerase
  • Tyrosine
  • Serine
  • Focal Adhesion Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12
  • ras Proteins
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse