Abstract
Adherent cells assemble fibronectin into a fibrillar matrix on their apical surface. The fibril formation is initiated by fibronectin binding to the integrins alpha5 beta1 and alphav beta3, and is completed by a process that includes fibronectin self-assembly. We found that a 76- amino acid fragment of fibronectin (III1-C) that forms one of the self-assembly sites caused disassembly of preformed fibronectin matrix without affecting cell adhesion. Treating attached fibroblasts or endothelial cells with III1-C inhibited cell migration and proliferation. Rho-dependent stress fiber formation and Rho-dependent focal contact protein phosphorylation were also inhibited, whereas Cdc42 was activated, leading to actin polymerization into filopodia. ACK (activated Cdc42-binding kinase) and p38 MAPK (mitogen-activated protein kinase), two downstream effectors of Cdc42, were activated, whereas PAK (p21-activated kinase) and JNK/SAPK (c-Jun NH2-terminal kinase/ stress-activated protein kinase) were inhibited. III1-C treatment also modulated activation of JNK and ERK (extracellular signal-regulated kinases) in response to growth factors, and reduced the activity of the cyclin E-cdk2 complex. These results indicate that the absence of fibronectin matrix causes activation of Cdc42, and that fibronectin matrix is required for Rho activation and cell cycle progression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / drug effects
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Actins / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Cycle / drug effects
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Cell Cycle / physiology*
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Cell Cycle Proteins / metabolism*
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Cytoskeleton / physiology
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology*
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Enzyme Activation
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Extracellular Matrix / physiology*
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Fibroblasts / cytology
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Fibroblasts / physiology
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Fibronectins / pharmacology
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Fibronectins / physiology*
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GTP Phosphohydrolases / metabolism*
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GTP-Binding Proteins / metabolism*
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Humans
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JNK Mitogen-Activated Protein Kinases
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Laminin / pharmacology
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Laminin / physiology
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases*
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Peptide Fragments / pharmacology
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Protein-Tyrosine Kinases / metabolism
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Recombinant Proteins / metabolism
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Umbilical Veins
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Vitronectin / pharmacology
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Vitronectin / physiology
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cdc42 GTP-Binding Protein, Saccharomyces cerevisiae
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p38 Mitogen-Activated Protein Kinases
Substances
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Actins
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Cell Cycle Proteins
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Fibronectins
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Laminin
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Peptide Fragments
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Recombinant Proteins
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Vitronectin
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Protein-Tyrosine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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GTP Phosphohydrolases
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GTP-Binding Proteins
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cdc42 GTP-Binding Protein, Saccharomyces cerevisiae