Translocation Inhibitors Define Specificity of Protein Kinase C Isoenzymes in Pancreatic β-Cells*

The protein kinase C (PKC) family consists of 11 isoenzymes. Following activation, each isoenzyme translocates and binds to a specific eceptor for ctivated inase (RACK) (Mochly-Rosen, D. (1995) Science 268, 247-251) that provides an anchoring site in close proximity to the isoenzyme's specific substrate. Pancreatic islet cells contain at least six PKC isoenzymes (Knutson, K. L., and Hoenig, M. (1994) Endocrinology 135, 881-886). Although PKC activation enhances insulin release, the specific function of each isoenzyme is unknown. Here we show that following stimulation with glucose, αPKC and εPKC translocate to the cell's periphery, while δPKC and ζPKC translocate to perinuclear sites. βC2-4, a peptide derived from the RACK1-binding site in the C2 domain of βPKC, inhibits translocation of αPKC and reduces insulin response to glucose. Likewise, εV1-2, an εPKC-derived peptide containing the site for its specific RACK, inhibits translocation of εPKC and reduces insulin response to glucose. Inhibition of islet-glucose metabolism with mannoheptulose blocks translocation of both αPKC and εPKC and diminishes insulin response to glucose while calcium-free buffer inhibits translocation of αPKC but not εPKC and lowers insulin response by 50%. These findings illustrate the unique ability of specific translocation inhibitors to elucidate the isoenzyme-specific functions of PKC in complex signal transduction pathways.

• Publication year

  1997

• Venue

  Journal of Biological Chemistry

• Publication date

  1997-01-17

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.272.3.1417PMID 8999804
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A Protein Kinase C Translocation Inhibitor as an Isozyme-selective Antagonist of Cardiac Function*

  1996cited by this paper
• C2 Region-derived Peptides Inhibit Translocation and Function of β Protein Kinase C in Vivo(*)

  1995cited by this paper
• Localization of protein kinases by anchoring proteins: a theme in signal transduction.

  1995cited by this paper
• Analysis of the Role of Protein Kinase C-α, -ϵ, and -ζ in T Cell Activation (*)

  1995cited by this paper
• Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets.

  1995cited by this paper
• Identification and subcellular characterization of protein kinase-C isoforms in insulinoma beta-cells and whole islets.

  1994cited by this paper
• Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels.

  1994cited by this paper
• Protein kinase C--a question of specificity.

  1994cited by this paper
• Distinct responses of protein kinase C isozymes to c-erbB-2 activation in SKBR-3 human breast carcinoma cells.

  1994cited by this paper
• Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins.

  1994cited by this paper
• Localization of protein kinase C isozymes in cardiac myocytes.

  1994cited by this paper
• Activation of protein kinases and inhibition of protein phosphatases play a central role in the regulation of exocytosis in mouse pancreatic beta cells.

  1994cited by this paper
• Arachidonic acid as a second messenger in glucose-induced insulin secretion from pancreatic beta-cells.

  1993cited by this paper
• Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells

  1993cited by this paper
• Molecular cloning and characterization of PKC iota, an atypical isoform of protein kinase C derived from insulin-secreting cells.

  1993cited by this paper
• Immunocytochemical Localization of a-Protein Kinase C in Rat Pancreatic/ -Cells during Glucose-induced Insulin Secretion

  1992cited by this paper
• Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.

  1992cited by this paper
• Translocation of protein kinase C isozymes in thrombin-stimulated human platelets. Correlation with 1,2-diacylglycerol levels.

  1992cited by this paper
• Immunocytochemical localization of alpha-protein kinase C in rat pancreatic beta-cells during glucose-induced insulin secretion

  1992cited by this paper
• Influence of staurosporine on glucose-mediated and glucose-conditioned insulin secretion.

  1991cited by this paper
• Identification of intracellular receptor proteins for activated protein kinase C.

  1991cited by this paper
• A protein kinase C isozyme is translocated to cytoskeletal elements on activation.

  1990cited by this paper
• Control of insulin secretion: a model involving Ca2+, cAMP and diacylglycerol.

  1990cited by this paper
• Activation of alpha-protein kinase C leads to association with detergent-insoluble components of GH4C1 cells.

  1990cited by this paper
• Protein kinase C--a family affair.

  1989cited by this paper
• Protein kinase C in mouse kidney: subcellular distribution and endogenous substrates.

  1988cited by this paper
• Monolayer culture of adult rat pancreatic islets on extracellular matrix: long term maintenance of differentiated B-cell function.

  1988cited by this paper
• Protein kinase C binding to isolated nuclei and its activation by a Ca2+/phospholipid-independent mechanism.

  1987cited by this paper
• The role of phospholipid-derived mediators including arachidonic acid, its metabolites, and inositoltrisphosphate and of intracellular Ca2+ in glucose-induced insulin secretion by pancreatic islets.

  1987cited by this paper
• Immunocytochemical evidence for phorbol ester-induced protein kinase C translocation in HL60 cells.

  1986cited by this paper
• Correction of diabetic pattern of insulin release from islets of the spiny mouse (Acomys cahirinus) by glucose priming in vitro

  1985cited by this paper

• Cell-penetrant peptides as novel inhibitors of the interaction of coatomer protein COPB2/RACK2 with protein kinase Cε and cargo proteins.

  2025cites this paper
• Protein kinase C-θ knockout decreases serum IL-10 levels and inhibits insulin secretion from islet β cells

  2021cites this paper
• Targeting PKC in microglia to promote remyelination and repair in the CNS.

  2021cites this paper
• Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review

  2020cites this paper
• A PKCβ-LYN-PYK2 Signaling Axis Is Critical for MCP-1-Dependent Migration and Adhesion of Monocytes.

  2020cites this paper
• G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells

  2019cites this paper
• Characterisation of peptide interactions that regulate PKCε activation

  2018cites this paper
• Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells.

  2017cites this paper
• Platelet Signaling: Protein Phosphorylation

  2017cites this paper
• The Roles of Free Fatty Acids and Inflammation in β-Cell Dysfunction

  2017cites this paper
• The tumor promoter‐activated protein kinase Cs are a system for regulating filopodia

  2017influential citation
• Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in β Cells*

  2016cites this paper
• Lipid signalling dynamics at the β-cell plasma membrane.

  2015cites this paper
• Expression of Protein Kinase C Isoforms in Pancreatic Islets and Liver of Male Goto-Kakizaki Rats, a Model of Type 2 Diabetes

  2015cites this paper
• Orexin a phosphorylates the γ‐Aminobutyric acid type A receptor β2 subunit on a serine residue and changes the surface expression of the receptor in SH‐SY5Y cells exposed to propofol

  2015cites this paper
• Sox17 Regulates Insulin Secretion in the Normal and Pathologic Mouse β Cell

  2014cites this paper
• Clostridium perfringens Phospholipase C Induced ROS Production and Cytotoxicity Require PKC, MEK1 and NFκB Activation

  2014cites this paper
• Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase Cε-Dependent Mechanism in Neurons

  2014cites this paper
• Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D / Protein Kinase C-epsilon-Dependent Mechanism in Neurons

  2014cites this paper
• Contribution of protein kinase Cα in the stimulation of insulin by the down-regulation of Cavβ subunits

  2014cites this paper
• Single-Molecule Studies Reveal a Hidden Key Step in the Activation Mechanism of Membrane-Bound Protein Kinase C-α

  2014cites this paper
• A Preconditioning Regimen with a PKCε Activator Improves Islet Graft Function in a Mouse Transplant Model

  2014cites this paper
• Depression of type I diacylglycerol kinases in pancreatic β-cells from male mice results in impaired insulin secretion.

  2013cites this paper
• Lipid Signalling Dynamics in Insulin-secreting β-cells

  2013influential citation
• P2Y1 receptor‐dependent diacylglycerol signaling microdomains in β cells promote insulin secretion

  2013cites this paper
• Functional and genetic studies in Type 2 diabetes and obesity

  2013cites this paper
• Untersuchungen zur Regulation der Genexpression des diabetes-assoziierten Autoantigens ZnT-8 in INS-1- Insulinomazellen

  2012cites this paper
• Effect of Bothrops alternatus snake venom on macrophage phagocytosis and superoxide production: participation of protein kinase C

  2011cites this paper
• Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling

  2011cites this paper
• Identification of a small molecule activator of novel PKCs for promoting glucose-dependent insulin secretion

  2011cites this paper
• Mecanismos de ação do palmitato como modulador da NADPH oxidase em ilhotas pancreáticas e linhagem INS-1 E.

  2011cites this paper
• Sublethal concentrations of the platinum(II) complex [Pt(O,O′‐acac)(γ‐acac)(DMS)] alter the motility and induce anoikis in MCF‐7 cells

  2010cites this paper
• Enhancement of glucagon secretion in mouse and human pancreatic alpha cells by protein kinase C (PKC) involves intracellular trafficking of PKCα and PKCδ

  2010cites this paper
• Targeting triglyceride/fatty acid cycling in β-cells as a therapy for augmenting glucose-stimulated insulin secretion

  2010cites this paper
• Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets.

  2010cites this paper
• Role of iduronate-2-sulfatase in glucose-stimulated insulin secretion by activation of exocytosis.

  2009cites this paper
• The incretin hormones GIP and GLP‐1 in diabetic rats: effects on insulin secretion and small bowel motility

  2009cites this paper
• Rationally designed peptide regulators of protein kinase C.

  2009cites this paper
• Protein kinase C-Fyn kinase cascade mediates the oleic acid-induced disassembly of neonatal rat cardiomyocyte adherens junctions.

  2009cites this paper
• Anti‐apoptotic effects of protein kinase C‐δ and c‐fos in cisplatin‐treated thyroid cells

  2009cites this paper
• RESEARCH PAPER Anti-apoptotic effects of protein kinase C-d and c-fos in cisplatin-treated thyroid cells

  2009cites this paper
• Functions of epidermal growth factor receptor in cisplatin response of thyroid cells.

  2009cites this paper
• Unraveling the intricacies of spatial organization of the ErbB receptors and downstream signaling pathways

  2009cites this paper
• Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer.

  2009cites this paper
• Dual regulation of the cardiac L-type calcium channel in L6 cells by protein kinase C.

  2008cites this paper
• Novel Chimeric Peptide Inhibits Protein Kinase C and Induces Apoptosis in Human Immune Cells

  2008cites this paper
• Cell Surface Levels of Organellar Na+/H+ Exchanger Isoform 6 Are Regulated by Interaction with RACK1*

  2008cites this paper
• The Major Chemical-detoxifying System of UDP-glucuronosyltransferases Requires Regulated Phosphorylation Supported by Protein Kinase C*

  2008cites this paper
• PDE4 associates with different scaffolding proteins: modulating interactions as treatment for certain diseases.

  2008cites this paper
• The diverse roles of protein kinase C in pancreatic beta-cell function.

  2008cites this paper
• PKCepsilon mediates glucose-regulated insulin production in pancreatic beta-cells.

  2008cites this paper
• Protein Kinase C Function in Muscle, Liver, and β-Cells and Its Therapeutic Implications for Type 2 Diabetes

  2008influential citation
• Targeting protein kinase C (PKC) in physiology and cancer of the gastric cell system.

  2008cites this paper
• Genetic variants in protein kinase C zeta gene and type 2 diabetes risk: a case‐control study of a Chinese Han population

  2008cites this paper
• PKC‐ε‐dependent cytosol‐to‐membrane translocation of pendrin in rat thyroid PC Cl3 cells

  2008cites this paper
• Protein kinase Czeta is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells.

  2007cites this paper
• Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells.

  2007cites this paper
• Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I

  2007influential citation
• Inhibition of PKCɛ Improves Glucose-Stimulated Insulin Secretion and Reduces Insulin Clearance

  2007cites this paper
• Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance.

  2007cites this paper
• Peptides derived from the C2 domain of protein kinase C epsilon (epsilon PKC) modulate epsilon PKC activity and identify potential protein-protein interaction surfaces.

  2007cites this paper
• Modulation of LPS stimulated NF-kappaB mediated Nitric Oxide production by PKCε and JAK2 in RAW macrophages

  2007cites this paper
• Protein Kinase Cδ Plays a Non-redundant Role in Insulin Secretion in Pancreatic β Cells*

  2007cites this paper
• The linoleic acid derivative DCP-LA selectively activates PKC-epsilon, possibly binding to the phosphatidylserine binding site.

  2006cites this paper
• Selective Regulation of IL-10 Signaling and Function by Zymosan

  2006cites this paper
• FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2.

  2006cites this paper
• FGF‐2 protects small cell lung cancer cells from apoptosis through a complex involving PKCε, B‐Raf and S6K2

  2006cites this paper
• Ezrin/Radixin/Moesin Proteins Are Phosphorylated by TNF-α and Modulate Permeability Increases in Human Pulmonary Microvascular Endothelial Cells1

  2006cites this paper
• Protein Kinase C Family Members as a Target for Regulation of Blood–Brain Barrier Na,K,2Cl-Cotransporter During In Vitro Stroke Conditions and Nicotine Exposure

  2006cites this paper
• Dynamics of glucose-induced localization of PKC isoenzymes in pancreatic beta-cells: diabetes-related changes in the GK rat.

  2006cites this paper
• New Insights into Fatty Acid Modulation of Pancreatic β‐Cell Function

  2006cites this paper
• Nuclear protein kinase C.

  2006cites this paper
• The linoleic acid derivative DCP-LA selectively activates PKC-ϵ, possibly binding to the phosphatidylserine binding site Published, JLR Papers in Press, March 6, 2006.

  2006cites this paper
• Glucagon-like Peptide 1 Activates Protein Kinase C through Ca2+-dependent Activation of Phospholipase C in Insulin-secreting Cells*

  2006cites this paper
• New insights into fatty acid modulation of pancreatic beta-cell function.

  2006cites this paper
• Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C beta (PKC-beta)-mediated cardiac troponin I phosphorylation.

  2005cites this paper
• Peptide inhibitors of protein kinases-discovery, characterisation and use.

  2005cites this paper
• Effects of Selective Protein Kinase C Isozymes in Prostaglandin2α-Induced Ca2+ Signaling and Luteinizing Hormone-Induced Progesterone Accumulation in the Mid-Phase Bovine Corpus Luteum1

  2005cites this paper
• Protein profiling of human pancreatic islets by two-dimensional gel electrophoresis and mass spectrometry.

  2005cites this paper
• Microvascular Endothelial Cells Permeability Increases in Human Pulmonary and Modulate α Phosphorylated by TNF-Ezrin / Radixin / Moesin Proteins Are

  2005cites this paper
• Inhibitors of protein kinase C

  2005cites this paper
• Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity.

  2005cites this paper
• Effect of protein kinase C activation on intracellular Ca2+ signaling and integrity of intestinal epithelial cells.

  2005cites this paper
• Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Localization Acts in Concert with Substrate Targeting to Create Spatial Restriction for Phosphorylation*

  2005cites this paper
• Involvement of novel protein kinase C isoforms in carbachol-stimulated insulin secretion from rat pancreatic islets.

  2005cites this paper
• Control of mammalian glycogen synthase by PAS kinase.

  2005cites this paper
• Role of p90 Ribosomal S6 Kinase (p90RSK) in Reactive Oxygen Species and Protein Kinase C β (PKC-β)-mediated Cardiac Troponin I Phosphorylation*

  2005cites this paper
• The Influence of Spermine on the Activity of a Protein Kinase C-like Enzyme in Marchantia polymorpha Thalli During Programmed Cell Death

  2005cites this paper
• Bimodal role of conventional protein kinase C in insulin secretion from rat pancreatic β cells

  2004influential citation
• Genetic approaches to the study of anxiety.

  2004cites this paper
• Cytochrome c oxidase subunit IV as a marker of protein kinase Cepsilon function in neonatal cardiac myocytes: implications for cytochrome c oxidase activity.

  2004cites this paper
• PTPmu signaling via PKCdelta is instructive for retinal ganglion cell guidance.

  2004cites this paper
• PKCα Is Activated But Not Required During Glucose-Induced Insulin Secretion From Rat Pancreatic Islets

  2004cites this paper
• PKC alpha is activated but not required during glucose-induced insulin secretion from rat pancreatic islets.

  2004cites this paper
• Scaffold proteins and assembly of multiprotein signaling complexes.

  2004cites this paper
• G Protein-coupled Receptor-mediated Phosphorylation of the Activation Loop of Protein Kinase D

  2004cites this paper
• Epsilon protein kinase C lengthens the quiescent period between spontaneous contractions in rat ventricular cardiac myocytes and trabecula

  2004cites this paper
• PTPμ signaling via PKCδ is instructive for retinal ganglion cell guidance

  2004cites this paper
• G protein-coupled receptor-mediated phosphorylation of the activation loop of protein kinase D: dependence on plasma membrane translocation and protein kinase Cepsilon.

  2004cites this paper
• PAR1-type thrombin receptor stimulates migration and matrix adhesion of human colon carcinoma cells by a PKCepsilon-dependent mechanism.

  2004cites this paper