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PMID: 10385525 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle.

The Journal of cell biology ·Vol. 145 ·No. 7 ·1999-06-28 ·Pages 1461-9

Oktay M, Wary KK, Dans M, Birge RB, Giancotti FG

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.

MeSH Terms
Animals Binding Sites Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Adhesion/physiology Cell Adhesion Molecules/chemistry,genetics,metabolism Cell Line Crk-Associated Substrate Protein Endothelium, Vascular/cytology,drug effects,enzymology Enzyme Activation/drug effects Fibronectins/metabolism Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases G1 Phase Gene Expression Regulation/drug effects Growth Substances/pharmacology,physiology Humans Integrins/physiology JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 Mice Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mutation Phosphoproteins/genetics,metabolism Phosphorylation/drug effects Protein Serine-Threonine Kinases/genetics,metabolism Protein-Tyrosine Kinases/chemistry,genetics,metabolism Proteins Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-crk Retinoblastoma-Like Protein p130 Signal Transduction/drug effects src Homology Domains/genetics src-Family Kinases/genetics,metabolism
Chemicals
BCAR1 protein, human Bcar1 protein, mouse Cell Adhesion Molecules Crk-Associated Substrate Protein Fibronectins Growth Substances Integrins Phosphoproteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-crk Retinoblastoma-Like Protein p130 Protein-Tyrosine Kinases Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases PTK2 protein, human Ptk2 protein, mouse src-Family Kinases Protein Serine-Threonine Kinases Calcium-Calmodulin-Dependent Protein Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 MAP2K4 protein, human Map2k4 protein, mouse Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Oktay M
Laboratory of Cell Adhesion and Signaling, Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Wary K K
Dans M
Birge R B
Giancotti F G
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.145.7.1461
Published
1999-06-28
Pages
1461-9
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2133163
Subset
IM
Grants
NCI NIH HHS · P30 CA08748 · United States
NCI NIH HHS · R01 CA78901 · United States
External Links
PubMed source DOI: 10.1083/jcb.145.7.1461 PMC Full Text View journal details
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