Abstract
The extracellular matrix exerts a stringent control on the proliferation of normal cells, suggesting the existence of a mitogenic signaling pathway activated by integrins, but not significantly by growth factor receptors. Herein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors cause more modest or no activation of this enzyme. Integrin-mediated stimulation of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130(CAS), the phosphorylation of p130(CAS), and subsequently, the recruitment of Crk. Ras and PI-3K were not required. FAK-JNK signaling was necessary for proper progression through the G1 phase of the cell cycle. These findings establish a role for FAK in both the activation of JNK and the control of the cell cycle, and identify a physiological stimulus for JNK signaling that is consistent with the role of Jun in both proliferation and transformation.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Adhesion / physiology
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Cell Adhesion Molecules / chemistry
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Line
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Crk-Associated Substrate Protein
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Enzyme Activation / drug effects
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Fibronectins / metabolism
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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G1 Phase*
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Gene Expression Regulation / drug effects
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Growth Substances / pharmacology
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Growth Substances / physiology
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Humans
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Integrins / physiology*
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4*
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Mice
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Mutation
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proteins*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-crk
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Retinoblastoma-Like Protein p130
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Signal Transduction* / drug effects
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src Homology Domains / genetics
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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BCAR1 protein, human
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Bcar1 protein, mouse
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Cell Adhesion Molecules
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Crk-Associated Substrate Protein
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Fibronectins
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Growth Substances
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Integrins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-crk
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Retinoblastoma-Like Protein p130
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Ptk2 protein, mouse
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src-Family Kinases
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Protein Serine-Threonine 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 Kinases
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MAP Kinase Kinase 4
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MAP2K4 protein, human
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Map2k4 protein, mouse
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Mitogen-Activated Protein Kinase Kinases