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  • Title: Evidence for discrete diacylglycerol and phorbol ester activator sites on protein kinase C. Differences in effects of 1-alkanol inhibition, activation by phosphatidylethanolamine and calcium chelation.
    Author: Slater SJ, Kelly MB, Taddeo FJ, Rubin E, Stubbs CD.
    Journal: J Biol Chem; 1994 Jun 24; 269(25):17160-5. PubMed ID: 8006023.
    Abstract:
    Stimulation of protein kinase C (PKC) activity is achieved in vivo by diacylglycerol but can also be obtained with tumor-promoting phorbol esters. Evidence is presented indicating that these two classes of activator may interact at different regions of the enzyme. The activity of a calcium-dependent PKC isoform (PKC-I) preparation was determined using 1,2-dioleoylglycerol (DOG) together with the phorbol ester 4 beta-12-O-tetradecanoylphorbol-13-acetate (TPA). The resulting PKC activity was in excess of that attained with either activator alone, each being at a maximum concentration for activation. A similar result was obtained with purified PKC-alpha and -epsilon isoforms, indicating that the additive effect was not due to sites being on distinct enzyme molecules. Support for two dissimilar activator sites came from the observation that the inactive phorbol ester 4 alpha-TPA competed for TPA but not for DOG in PKC activation. Other differences were observed between TPA- and DOG-activated PKC. It was found that 1-butanol inhibited DOG-activated PKC-I, while being without effect on stimulation by TPA. Also, the inclusion of phosphatidylethanolamine in the lipid vesicles led to a potentiation of PKC-I activity which was greater when activation was achieved by DOG compared to TPA. Further, the calcium- and DOG-dependent active conformational change of PKC was fully reversible upon calcium chelation, while that stimulated by TPA was only partially reversible. These experiments taken together suggest that diacylglycerols and phorbol esters bind with different affinities and at different sites on PKC, and induce distinct activated conformational forms of the enzyme.
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