RELATIONSHIP BETWEEN THE MAP KINASE-ACTIVITY AND THE DUAL EFFECT OF EGF ON A431 CELL-PROLIFERATION

EGF is involved in the regulation of cell proliferation in normal as w ell as in neoplastic tissues. The A431 cells that over-express EGFR, d isplay in vitro ambivalent growth properties in response to EGF, since stimulation induced by low concentrations (10(-12) M-10(-10) M) is re versed with increasing concentrations (10(-9) M-10(-8) M). To assess d ifferential mechanisms of signal transduction that determine growth st imulatory and inhibitory activity, we have studied the MAP kinase acti vation induced by mitotic and antimitotic concentrations of EGF. We de monstrate that the presence of a growth stimulatory concentration of E GF (10(-12) M) leads to a moderate but persistent activation of p42 MA P kinase during all the time of the EGF treatment. Conversely, an earl y peak of kinase activation that rapidly falls down below the basal le vel, is observed when a growth inhibitory concentration of EGF(10(-8) M) is used, Moreover, the addition of Na-orthovanadate in 10(-8) M EGF -treated cells leads to the rescue of the MAP kinase activity, suggest ing that the loss of kinase activity induced by growth inhibitory EGF concentrations involves the dephosphorylation of the MAP kinase. In co nclusion, our data demonstrate that the dual effect ( stimulator/ inhi bitor) of EGF on the proliferation of A431 cells is associated to diff erential mechanisms of p42 MAP kinase regulation. (C) 1994 Academic Pr ess, Inc.