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© The Rockefeller University Press,
0021-9525/1999//611 $5.00
The Journal of Cell Biology, Volume 147, Number 3,
, 1999 611-618
Original Article |
Focal Adhesion Kinase Mediates the Integrin Signaling Requirement for Growth Factor Activation of Map Kinase
schwartz{at}scripps.edu
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.
Key Words: growth factor regulation • signal transduction • anchorage independence • src transformation • cancer
© 1999 The Rockefeller University Press
1.used in this paper: ECM, extracellular matrix; Erk, extracellular regulated kinase; FAK, focal adhesion kinase; FN, fibronectin; HA, hemagglutinin; MAP, mitogen-activated protein
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