ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility.
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.
Vial
Emmanuel
E
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, United Kingdom.
Sahai
Erik
E
Marshall
Christopher J
CJ
D002465:Cell Movement; D016764:Cell Polarity; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D019012:Integrin beta1 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
D003094:Collagen; D004338:Drug Combinations; D019012:Integrin beta1; D007797:Laminin; D020928:Mitogen-Activated Protein Kinases; D011509:Proteoglycans; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000099169:Fos-Related Antigen 1; C059485:matrigel