ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility

Cancer Cell. 2003 Jul;4(1):67-79. doi: 10.1016/s1535-6108(03)00162-4.


We describe two signaling events downstream of ERK-MAP kinase contributing to cell motility in colon carcinoma cells. The Fos family member Fra-1 is expressed in an ERK-dependent manner. Silencing of Fra-1 expression with short interfering RNAs leads to losses of cell polarization, motility, and invasiveness in vitro. These effects of ablating Fra-1 are a consequence of activation of a RhoA-ROCK pathway by beta1-integrin, leading to an increase in the amount of stress fibers and stabilization of focal adhesions. We propose that Fra-1 promotes cell motility by inactivating beta1-integrin and keeping RhoA activity low. This depression of RhoA activity is necessary to permit a second ERK-dependent signaling event via uPAR, the receptor for urokinase-type plasminogen activator, to activate Rac and to drive motility through polarized lamellipodia extension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement*
  • Cell Polarity
  • Collagen / metabolism
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Drug Combinations
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Integrin beta1 / metabolism
  • Laminin / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Neoplasm Invasiveness
  • Proteoglycans / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-fos / pharmacology
  • Pseudopodia / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / metabolism
  • Receptors, Urokinase Plasminogen Activator
  • Signal Transduction*
  • Tumor Cells, Cultured
  • rac1 GTP-Binding Protein / metabolism*
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / metabolism*


  • Drug Combinations
  • Integrin beta1
  • Laminin
  • Proteoglycans
  • Proto-Oncogene Proteins c-fos
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • fos-related antigen 1
  • matrigel
  • Collagen
  • Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein