INHIBITION OR DOWN-REGULATION OF PROTEIN-KINASE-C ATTENUATES LATE PHASE P70(S6K) ACTIVATION INDUCED BY EPIDERMAL GROWTH-FACTOR BUT NOT BY PLATELET-DERIVED GROWTH-FACTOR OR INSULIN

The late phase of the time-dependent epidermal growth factor (EGF)-ind uced biphasic activation of the p70s6k is selectively attenuated by th e specific PKC inhibitor, CGP 41 251, a staurosporine derivative. At a 40-fold lower concentration than CGP 41 251, staurosporine inhibits b oth phases of S6 kinase activation to the same extent, whereas the ina ctive staurosporine derivative CGP 42 700 shows no effect on either ph ase. Platelet-derived growth factor (PDGF) and insulin also induce bip hasic S6 kinase activation, but in neither case is either phase of act ivation affected by the presence of CGP 41 251. This finding was unexp ected in the case of PDGF, which is a potent activator of PKC and whos e receptor directly interacts with phospholipase C(gamma)1. However, s imilar results were obtained following down-regulation of PKC by prolo nged 12-O-tetradecanoylphorbol-13-acetate treatment. Therefore, even t hough EGF and PDGF induce PKC activation, PDGF, unlike EGF, does not a ppear to use this signaling pathway for late phase p70s6k activation.