Insight into intra- and inter-molecular interactions of PKC: Design of specific modulators of kinase function

Abstract

Protein kinase C (PKC) is a family of kinases that are critical in many cellular events. These enzymes are activated by lipid-derived second messengers, are dependent on binding to negatively charged phospholipids and some members also require calcium to attain full activation. The interaction with lipids and calcium activators is mediated by binding to the regulatory domains C1 and C2. In addition, many protein-protein interactions between PKC and other proteins have been described. These include interactions with adaptor proteins, substrates and cytoskeletal elements. Regulation of the interactions between PKC, small molecules and other proteins is essential for signal transduction to occur. Finally, a number of auto-inhibitory intramolecular protein-protein interactions have also been identified in PKC. This chapter focuses on mapping the sites for many of these inter and intramolecular interactions and how this information may be used to generate selective inhibitors and activators of PKC signaling.

Copine-III interacts with ErbB2 and promotes tumor cell migration

“…It is tempting to speculate that in cells with low Copine-III, ErbB2 loses its ability to couple to proteins and pathways involved in motility. Considering these and other proteins that interact with ErbB2, we propose the following model: in response to ligand activation, ErbB2 binds and activates PLCg1 (Meira et al, 2009), which causes an increase in diacylglycerol levels and initiates Ca 2 þ influx from the endoplasmic reticulum and through store-operated channels into the cytoplasm (Patterson et al, 2005;Kheifets and Mochly-Rosen, 2007). Interestingly, specific residues that have been mapped in the C2D of PKCa as being essential for RACK1 binding (McCahill et al, 2002) are conserved in Copine-III C2D-B.…”

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.…”

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice

“…The PKC superfamily comprises homologous serine/threonine kinases that are involved in many signalling events [11,[13][14][15]. In mammals, a gene family of nine independent loci are distributed over the whole genome [12].…”

“…As more information becomes available regarding the activation of PKC isoforms, it is likely that other mechanisms of phosphorylation and activation of specific isoforms will be elucidated. The activation and degradation of the PKC isoforms is controlled spatially and temporally, since all cells and/or tissues produce more than one PKC isoform that can act in a functionally redundant manner while targeting the same or overlapping sets of substrates [11,12,15]. There is now ample evidence that the wide spectrum of PKC-mediated signalling is organised by isotype specificity that, despite the broad overlapping substrate specificities, is defined via unique expression patterns, intracellular localisation and adaptor proteins [13,17].…”

“…The following summary is not intended to be comprehensive but instead focuses on some of the more recent research developments in this field, with particular focus on knockout (KO) mouse studies. For further information, we would like to refer the reader to other recent reviews [6,7,[10][11][12].…”