Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Abstract

Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

“…PKCa is one of the classical (cPKC) Ca 2C -dependent members of the PKC family that regulate a wide variety of biological events within the cell, regulating multiple biological processes, including cell proliferation, apoptosis, differentiation, migration, and adhesion (for recent reviews, see (33,34,35)). Its expression in our patient's TCBs and skin fibroblasts was higher compared with control cells, and it is therefore tempting to speculate that elevated expression of PRKCA may be involved in the GH insensitivity and possibly other clinical and laboratory features of this syndrome.…”

Protein Kinase C Function in Muscle, Liver, and β-Cells and Its Therapeutic Implications for Type 2 Diabetes

“…Insulin has also been reported to stimulate the activity of cPKC and nPKC isoforms to promote glucose disposal (7). Putative mechanisms of activation include tyrosine phosphorylation of PKC␦ and alternative splicing of PKC␤ to increase PKC␤II levels, but these have not been widely substantiated, and the positive effects of these kinases need to be reconciled with the negative regulation of insulin action detailed below.…”

eEF1A Phosphorylation in the Nucleus of Insulin-stimulated C2C12 Myoblasts

“…Insulin provokes rapid changes in phospholipid metabolism and, thereby, generates biologically active lipids that serve as intracellular signaling factors. Conventional protein kinase Cs (cPKCs), 1 novel PKCs, and atypical PKCs that are activated by this insulin signaling cascade have key roles in the regulation of the metabolic effects of insulin (4). Deregulated protein phosphorylation is associated with many disease states, including cancer and diabetes.…”