Protein kinase C: poised to signal

Abstract

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 PKC␤I and PKC␤II (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...

Feeling the hidden mechanical forces in lipid bilayer is an original sense

“…Nonetheless they house many signal-transduction pathways that deploy receptors, G proteins, PLC, and TRPs. Such pathways are commonly explored according to the current dominant paradigm, with the ultimate explanation being protein phosphorylations due to PLC's activation of protein kinase C (PKC) (71). One wonders how much the PLC-induced changes in bilayer tension discussed here in fact participate in these pathways (72).…”

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

“…These are known as the conventional PKCs (cPKCs; comprised of PKC , I / II and isoforms), the novel PKCs (nPKCs; comprised of , , and ) and the atypical PKCs (aPKCs; comprised of PKC and ). The structural features and mechanism of activation of these isoforms has been reviewed elsewhere [1,2,14]. Spatial and temporal control of PKC signalling is also influenced via interaction with adaptor/scaffolding proteins that anchor the PKCs to various intracellular locations in the cell.…”

“…Protein Kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases that play key roles in many of the signalling pathways that control cellular growth, proliferation, differentiation and cell death [1,2]. To date, nine different PKC isoforms that are transcribed from separate genes have been cloned and characterised.…”

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

“…1) and cytoskeletal reorganization (10) after infection, we hypothesized that the Ca 2+ -dependent kinase PKCα might contribute to the process because it can modulate the actin cytoskeleton (13,14). Cytosolic Ca 2+ induces the translocation of Ca 2+ -bound PKCα to the plasma membrane, where the kinase is activated although its interaction with diacylglycerol (15). To test whether HCMV induces the translocation of PKCα, we transfected fibroblasts with a plasmid expressing PKCα fused to GFP (16,17), and then mock-infected or infected the cultures.…”