Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Movement*
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Cell Polarity
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Collagen / metabolism
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology*
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Drug Combinations
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Gene Expression Regulation, Neoplastic
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Gene Silencing
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Integrin beta1 / metabolism
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Laminin / metabolism
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Mitogen-Activated Protein Kinases / physiology*
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Neoplasm Invasiveness
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Proteoglycans / metabolism
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-fos / pharmacology
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Pseudopodia / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Cell Surface / metabolism
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Receptors, Urokinase Plasminogen Activator
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Signal Transduction*
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Tumor Cells, Cultured
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rac1 GTP-Binding Protein / metabolism*
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rhoA GTP-Binding Protein / antagonists & inhibitors
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rhoA GTP-Binding Protein / metabolism*
Substances
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Drug Combinations
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Integrin beta1
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Laminin
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Proteoglycans
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Proto-Oncogene Proteins c-fos
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RNA, Small Interfering
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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fos-related antigen 1
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matrigel
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Collagen
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Mitogen-Activated Protein Kinases
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein