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Protein Kinase C ? Interacts with a Novel Binding Region of G?q to Act as a Functional Effector.

ABSTRACT: Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between G?q and protein kinase C ? (PKC?), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLC?. We report herein that the activation-dependent G?q/PKC? complex involves the basic PB1-type II domain of PKC? and a novel interaction module in G?q different from the classical effector-binding site. Point mutations in this G?q region completely abrogate ERK5 phosphorylation, indicating that G?q/PKC? association is required for the activation of the pathway. Indeed, PKC? was demonstrated to directly bind ERK5 thus acting as a scaffold between G?q and ERK5 upon GPCR activation. The inhibition of these protein complexes by G protein-coupled receptor kinase 2, a known G?q modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that G?q/PKC? complexes link G?q to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in G?q and the effector PKC? is a key event in G?q signaling.

SUBMITTER: Sanchez-Fernandez G

PROVIDER: S-EPMC4850291 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector.

Sánchez-Fernández Guzmán G Cabezudo Sofía S Caballero Álvaro Á García-Hoz Carlota C Tall Gregory G GG Klett Javier J Michnick Stephen W SW Mayor Federico F Ribas Catalina C

The Journal of biological chemistry 20160217 18

Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between Gαq and protein kinase C ζ (PKCζ), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLCβ. We report herein that the activation-dependent Gαq/PKCζ complex involves the basic PB1-type II domain of PK ...[more]

PMID: 26887939

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Project description:Class I phosphoinositide 3-kinases exert important cellular effects through their two primary lipid products, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P(2)). As few molecular targets for PtdIns(3,4)P(2) have yet been identified, a screen for PI 3-kinase-responsive proteins that is selective for these is described. This features a tertiary approach incorporating a unique, primary recruitment of target proteins in intact cells to membranes selectively enriched in PtdIns(3,4)P(2). A secondary purification of these proteins, optimized using tandem pleckstrin homology domain containing protein-1 (TAPP-1), an established PtdIns(3,4)P(2) selective ligand, yields a fraction enriched in proteins of potentially similar lipid binding character that are identified by liquid chromatography-tandem MS. Thirdly, this approach is coupled to stable isotope labeling with amino acids in cell culture using differential isotope labeling of cells stimulated in the absence and presence of the PI 3-kinase inhibitor wortmannin. This provides a ratio-metric readout that distinguishes authentically responsive components from copurifying background proteins. Enriched fractions thus obtained from astrocytoma cells revealed a subset of proteins that exhibited ratios indicative of their initial, cellular responsiveness to PI 3-kinase activation. The inclusion among these of tandem pleckstrin homology domain containing protein-1, three isoforms of Akt, switch associated protein-70, early endosome antigen-1 and of additional proteins expressing recognized lipid binding domains demonstrates the utility of this strategy and lends credibility to the novel candidate proteins identified. The latter encompass a broad set of proteins that include the gene product of TBC1D2A, a putative Rab guanine nucleotide triphosphatase activating protein (GAP) and IQ motif containing GAP1, a potential tumor promoter. A sequence comparison of the former protein indicates the presence of a pleckstrin homology domain whose lipid binding character remains to be established. IQ motif containing GAP1 lacks known lipid interacting components and a preliminary analysis here indicates that this may exemplify a novel class of atypical phosphoinositide (aPI) binding domain.

Dataset Information

Protein Kinase C ? Interacts with a Novel Binding Region of G?q to Act as a Functional Effector.

Publications

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector.

Similar Datasets

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