Structural Basis of Protein Kinase C Isoform Function

Abstract

Protein kinase C (PKC) isoforms comprise a family of lipid-activated enzymes that have been implicated in a wide range of cellular functions. PKCs are modular enzymes comprised of a regulatory domain (that contains the membrane-targeting motifs that respond to lipid cofactors, and in the case of some PKCs calcium) and a relatively conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed and respond to similar stimulatory agonists in many cell types. However, there is growing evidence that individual PKC isoforms subserve unique (and in some cases opposing) functions in cells, at least in part as a result of isoform-specific subcellular compartmentalization patterns, protein-protein interactions, and posttranslational modifications that influence catalytic function. This review focuses on the structural basis for differences in lipid cofactor responsiveness for individual PKC isoforms, the regulatory phosphorylations that control the normal maturation, activation, signaling function, and downregulation of these enzymes, and the intra-/intermolecular interactions that control PKC isoform activation and subcellular targeting in cells. A detailed understanding of the unique molecular features that underlie isoform-specific posttranslational modification patterns, protein-protein interactions, and subcellular targeting (i.e., that impart functional specificity) should provide the basis for the design of novel PKC isoform-specific activator or inhibitor compounds that can achieve therapeutically useful changes in PKC signaling in cells.

Differential Regulation of RasGAPs in Cancer

“…In this context, it should be noted that the localization of protein kinases such as PKC and PKA is regulated by scaffold proteins, including RACKs, A kinase anchoring proteins (AKAPs), and annexins, [79][80][81][82][83] all of which facilitate the complex and spatiotemporal targeting of PKC and PKA to unique subcellular localization to be part of specialized signaling complexes. The complex interplay of protein kinases with their specific scaffolds could therefore determine NF1 and, as outlined below, p120GAP activity and localization.…”

Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood–Brain Barrier Permeability and Tight Junction Protein Expression during Hypoxia and Posthypoxic Reoxygenation

“…Several factors have been identified, including TJ protein phosphorylation. The protein kinase C (PKC) family of serine/ threonine protein kinases includes at least 12 known isozymes divided into three groups depending on the enzymes' cofactor requirements: (1) conventional (cPKC; PKC-a, PKC-bI, PKC-bII, and PKC-g), (2) novel (nPKC; PKC-d, PKC-e, PKC-Z, and PKC-y), and (3) atypical (aPKC; PKC-l and PKC-z) (Steinberg, 2008). These isozymes differ in their mechanism of activation, subcellular distribution, substrate type, and expression, suggesting that each of these PKC isozymes can perform unique biological tasks (Banan et al, 2003(Banan et al, , 2004(Banan et al, , 2007.…”

Molecular mechanisms of mechanosensing in muscle development

“…Vertebrate PKC isoforms are divided into three subgroups: the conventional PKCs ␣, ␤I, ␤II, and ␥; novel PKCs ␦, ⑀, , and , which require diacylglycerol, but not Ca 2ϩ for activation; and atypical PKCs , , and protein kinase N, which are dependent on phosphatidylinositol trisphosphate, but are not affected by diacylglycerol and phorbol esters (Steinberg, 2008). The large repertoire of PKC isoforms, therefore, ensures diversity in the temporal activation, subcellular localization, and amplitude of expression of PKCs, which will result in efficient activation of a multitude of different PKC targets.…”