Focal Adhesion Kinase Mediates the Integrin Signaling Requirement for Growth Factor Activation of MAP Kinase

• Published in: The Journal of cell biology Vol. 147; no. 3; pp. 611 - 618
• Main Authors: Renshaw, Mark W., Price, Leo S., Schwartz, Martin Alexander
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01-11-1999; The Rockefeller University Press
• Subjects: 3T3 Cells; Animals; Cell adhesion; Cell Adhesion - drug effects; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Division - drug effects; Cell growth; Cell Line, Transformed; Cell Transformation, Neoplastic - metabolism; Cells; Cellular biology; Enzyme Activation - drug effects; Enzyme Activation - genetics; Epithelial cells; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - metabolism; focal adhesion kinase; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Focal adhesions; Gene Deletion; Genes, Dominant - genetics; Growth Substances - pharmacology; Integrin beta1 - genetics; Integrin beta1 - metabolism; Integrins; MAP kinase; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; NIH 3T3 cells; Oncogene Protein pp60(v-src) - physiology; Original; Phosphorylation; Physical growth; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Ras protein; ras Proteins - physiology; Recombinant Fusion Proteins - metabolism; Signal Transduction - drug effects; Transfection; v-src gene
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.147.3.611

The mitogen-activated protein (MAP) kinase pathway is a critical regulator of cell growth, migration, and differentiation. Growth factor activation of MAP kinase in NIH 3T3 cells is strongly dependent upon integrin-mediated adhesion, an effect that contributes to the anchorage dependence of normal cell growth. We now show that expression of constructs that constitutively activate focal adhesion kinase (FAK) rescued the defect in serum activation of MAP kinase in suspended cells without directly activating MAP kinase. Dominant negative FAK blocked both the rescue of suspended cells by the activated construct and the serum activation of MAP kinase in adherent cells. MAP kinase in FAK-/-mouse embryo fibroblasts was adhesion-insensitive, and reexpression of FAK restored its adhesion dependence. MAP kinase activity in ras-transformed cells is still decreased in suspension, but expression of constructs that constitutively activate FAK enhanced their anchorage-independent growth without increasing adherent growth. V-src, which activates both Ras and FAK, induced MAP kinase activation that was insensitive to loss of adhesion, and that was blocked by a dominant negative FAK. These results demonstrate that FAK mediates the integrin requirement for serum activation of MAP kinase in normal cells, and that bypassing this mechanism contributes to anchorage-independent growth in transformed cells.