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 well as in neoplastic tissues. The A431 cells that over-express EGFR, display in vitro ambivalent growth properties in response to EGF, since stimulation induced by low concentrations (10(-12) M-10(-10) M) is reversed with increasing concentrations (10(-9) M-10(-8) M). To assess differential mechanisms of signal transduction that determine growth stimulatory and inhibitory activity, we have studied the MAP kinase activation induced by mitotic and antimitotic concentrations of EGF. We demonstrate that the presence of a growth stimulatory concentration of EGF (10(-12) M) leads to a moderate but persistent activation of p42 MAP kinase during all the time of the EGF treatment. Conversely, an early peak of kinase activation that rapidly falls down below the basal level, 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, suggesting that the loss of kinase activity induced by growth inhibitory EGF concentrations involves the dephosphorylation of the MAP kinase. In conclusion, our data demonstrate that the dual effect (stimulator/inhibitor) of EGF on the proliferation of A431 cells is associated to differential mechanisms of p42 MAP kinase regulation.