Nestled at the tip of a branch of the kinome, protein kinase C (PKC) family members are poised to transduce signals emanating from the cell surface. Cell membranes provide the platform for PKC function, supporting the maturation of PKC through phosphorylation, its allosteric activation by binding specific lipids, and, ultimately, promoting the downregulation of the enzyme. These regulatory mechanisms precisely control the level of signalingcompetent PKC in the cell. Disruption of this regulation results in pathophysiological states, most notably cancer, where PKC levels are often grossly altered. This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members.calcium; diacylglycerol; phorbol esters THE FAMILY OF PKC ISOZYMES transduces the myriad of signals resulting from receptor-mediated hydrolysis of phospholipids, playing critical roles in diverse cellular functions. The discovery in the 1980s that they are the receptors for the potent tumor promoting phorbol esters, coupled with the discovery that they mediate signaling by the lipid second messenger diacylglycerol, secured a center stage position for this family of enzymes in cellular regulation (6, 66). Family members, themselves, are regulated by precise mechanisms that control their structure, function, and subcellular localization. This review discusses our current understanding of the mechanisms controlling protein kinase C signaling.
The PKC FamilyThe PKC family occupies the tip of a branch of the AGC kinases from which the related kinases protein kinase N (PKN), Akt/PKB, p70 S6 kinase, and the phosphoinositidedependent kinase-1 (PDK-1) diverge (Fig. 1A). The 10 members that populate the mammalian family evolved from the single PKC in saccharomyces cerivisiae, PKC1 (57, 98), and are grouped into three classes based on their domain composition (Fig. 1B) (71). This domain composition, in turn, dictates the cofactor regulation of the classes (Fig. 1C). At the very tip of the branch are the four conventional isozymes: PKC␣, the first isozyme cloned (76); the alternatively spliced PKCI and PKCII (which differ in the last 43 amino acids) and PKC␥; next are the four novel isozymes, PKC␦, -ε, -, and -; closest to the point of divergence are the atypical isozymes PKC and PKC (human; murine isozyme is PKC).All family members share the same architecture: a carboxylterminal kinase domain linked by a flexible hinge segment to an amino-terminal region containing regulatory modules (Fig. 1B) (69, 77). These regulatory modules confer sensitivity to the second messengers diacylglycerol (C1 domain) or Ca 2ϩ (C2 domain), although, importantly, some isozymes have variants of these modules that do not bind ligand (8,20).Conventional isozymes contain tandem C1 domains that bind diacylglycerol and a C2 domain that binds anionic lipids in a Ca 2ϩ -dependent manner. The small globular C1 domain is also the binding site for the potent tumor-promoting phorbol esters (43, 100), which bi...