Phorbol Esters and Diacylglycerol: The PKC Activators

Abstract

Protein kinase C ({PKC}) represents the most prominent of the families of signaling proteins integrating response to the ubiquitous lipophilic second messenger sn-1,2-diacylglycerol and to its ultrapotent analogs, the tumor-promoting phorbol esters. Response is mediated through twin conserved zinc finger structures, the C1 domains. The C1 domains function as hydrophobic switches, for which ligand binding completes a hydrophobic surface on the face of the C1 domain, driving membrane association of {PKC} and enzymatic activation. Since the lipid bilayer provides critical contacts for ligand binding, along with the C1 domain, membrane heterogeneity provides an important mechanism for diversity, as do the differential functions of the twin C1 domains. Consistent with such mechanistic diversity, {PKC} ligands can differ dramatically in biological consequences. Thus, whereas {PKC} ligands have provided the paradigm for tumor promoters, some {PKC} ligands in fact function as inhibitors of tumor promotion. Reflecting the central role of {PKC} in cellular signaling, {PKC} has emerged as a promising therapeutic target for cancer with several {PKC} ligands currently in clinical trials.