RAS ACTIVATION IS NECESSARY FOR INTEGRIN-MEDIATED ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE 2 AND CYTOSOLIC PHOSPHOLIPASE A(2) BUT NOT FOR CYTOSKELETAL ORGANIZATION

Cell adhesion to the extracellular matrix triggers a cascade of intrac ellular biochemical signals regulated by the integrin family of recept ors, Recent evidence suggests that integrin engagement may activate a mitogen-activated protein (MAP) kinase cascade that may cooperate with more clearly defined mitogenic signaling pathways to regulate cell pr oliferation, adhesion, and migration. Here we report that the adhesion -dependent activation of the MAP kinase Erk2 (extracellular signal-reg ulated kinase 2) occurs in serum-starved NIH3T3 cells, and that this a ctivation of Erk2 is preceded by the activation of the small GTP-bindi ng protein Ras in fibronectin adherent cells, Inhibition of Ras signal ing by expression of a dominant inhibitory mutant of Ras (N17Ras) in N IH3T3 cells blocked adhesion-dependent activation of Erk2, although th e focal adhesion kinase (FAK) was still activated in these cells, Furt hermore, activation of this Ras-MAP kinase pathway activated cytosolic phospholipase A(2), leading to the release of arachidonic acid metabo lites, and N17Ras also inhibited these events, However, N17Ras express ion does not inhibit cell adhesion, spreading, or focal contact and st ress fiber formation, These results suggest that, while integrin-depen dent activation of this MAP kinase pathway is Ras-dependent, the integ rin-dependent activation of FAK and several morphological events are R as independent, Thus, integrin-mediated signals involved in regulating cell morphology appear to diverge from those regulating MAP kinase ac tivation at a level upstream of Ras activation.