Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic β-Cells.

Jones, Peter M.; Persaud, Shanta J.

doi:10.1210/edrv.19.4.0339

Cited by 102 publications

(73 citation statements)

References 333 publications

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“…Real-time imaging studies in isolated insulinoma cells and intact islets (Thore et al, 2004;Tamarina et al, 2005;Thore et al, 2007) have recently confirmed that glucose stimulates PLC activity secondary to the elevation of [Ca 2+ ] i and that membrane depolarization alone (Gromada et al, 1996;Liu et al, 1996) or increase of [Ca 2+ ] i (Mathias et al, 1985;Best et al, 1987;Biden et al, 1987) In addition to contributing to the generation and shaping of Ca 2+ signals, PLC activation can be anticipated to regulate insulin secretion kinetics via generation of DAG and activation of PKC. Several conventional, novel and atypical PKC isoforms are expressed in islets and insulin-secreting cells (Jones and Persaud, 1998;Warwar et al, 2006). Activation of the PLC-PKC signalling pathway has been proposed to account for the second phase of glucoseinduced insulin secretion (Zawalich and Zawalich, 1996).…”

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

“…Rapid changes in DAG formation have been detected in rat islets following stimulation with glucose or carbachol (Peter-Riesch et al, 1988;Wolf et al, 1989). Although DAG analogues and phorbol esters have been found to stimulate insulin secretion (Virji et al, 1978;Malaisse et al, 1980;Jones et al, 1985) by sensitizing the secretory machinery to Ca 2+ (Jones et al, 1985;Tamagawa et al, 1985), it is debated whether PKC is involved in nutrient-induced insulin secretion (Metz, 1988;Jones and Persaud, 1998). The use of PKC inhibitors has resulted in conflicting conclusions (Jones and Persaud, 1998).…”

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

“…Although DAG analogues and phorbol esters have been found to stimulate insulin secretion (Virji et al, 1978;Malaisse et al, 1980;Jones et al, 1985) by sensitizing the secretory machinery to Ca 2+ (Jones et al, 1985;Tamagawa et al, 1985), it is debated whether PKC is involved in nutrient-induced insulin secretion (Metz, 1988;Jones and Persaud, 1998). The use of PKC inhibitors has resulted in conflicting conclusions (Jones and Persaud, 1998). Recent studies of PKC isoform-selective knock-out mice have indicated important roles for PKCδ and -λ in insulin secretion (Hashimoto et al, 2005;Uchida et al, 2007).…”

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

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Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

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Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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“…Although various protein kinases have been identified in pancreatic ␤-cells, few have been identified in a single cell simultaneously (46). We confirmed the presence of four intact MAPK modules (Raf1/B 3 Mek1/2 3 ERK1/2, Cot/Tpl-2 3 Mek4/7 3 SAPK, PAK␣ 3 Mek63 p38␣, and ERK3) in rGIP-15, ␤TC-3, and INS-1 (832/ 13) cells (Tables I-III).…”

Section: Gip Activates Erk Via Rap1 Independently Of G␤␥ and Src-mentioning

confidence: 99%

Glucose-dependent Insulinotropic Polypeptide Activates the Raf-Mek1/2-ERK1/2 Module via a Cyclic AMP/cAMP-dependent Protein Kinase/Rap1-mediated Pathway

Ehses

Pelech

Pederson

et al. 2002

Journal of Biological Chemistry

115

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The gastrointestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is one of the most important regulators of insulin secretion following ingestion of a meal. GIP stimulates insulin secretion from the pancreatic ␤-cell via its G protein-coupled receptor activation of adenylyl cyclase and other signal transduction pathways, but there is little known regarding subsequent protein kinase pathways that are activated. A screening technique was used to determine the relative abundance of 75 protein kinases in CHO-K1 cells expressing the GIP receptor and in two pancreatic ␤-cell lines (␤TC-3 and INS-1 (832/13) cells). This information was used to identify kinases that are potentially regulated following GIP stimulation, with a focus on GIP regulation of the ERK1/2 MAPK pathway. In CHO-K1 cells, GIP induced phosphorylation of Raf-1 (Ser-259), Mek1/2 (Ser-217/Ser-221), ERK1/2 (Thr-202 and Tyr-204), and p90 RSK (Ser-380) in a concentration-dependent manner. Activation of ERK1/2 was maximal at 4 min and was cAMP-dependent protein kinase-dependent and protein kinase C-independent. Studies using a ␤-cell line (INS-1 clone 832/13) corroborated these findings, and it was also demonstrated that the ERK1/2 module could be activated by GIP in the absence of glucose. Finally, we have shown that GIP regulation of the ERK1/2 module is via Rap1 but does not involve G␤␥ subunits nor Src tyrosine kinase, and we propose that cAMP-based regulation occurs via B-Raf in both CHO-K1 and ␤-cells. These results establish the importance of GIP in the cellular regulation of the ERK1/2 module and identify a role for cAMP in coupling its G protein-coupled receptors to ERK1/2 activity in pancreatic ␤-cells.

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“…One important feature of these pathways is the phosphorylation cascade of a wide range of cellular substrates. Many different kinases such as protein kinase C, cAMP-dependent protein kinase (protein kinase A), Ca 2ϩ /calmodulin-dependent kinase II, mitogen-activated protein kinases, and protein-tyrosine kinases are present in the islets (14). From neuronal systems it is known that protein phosphorylation of synaptic proteins plays significant roles in modulating different steps during exocytosis and synaptic vesicle recycling (15).…”

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confidence: 99%

Cyclin-dependent Kinase 5 Promotes Insulin Exocytosis

Lilja

Yang

Webb

et al. 2001

Journal of Biological Chemistry

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Cyclin-dependent kinase 5 (Cdk5) is widely expressed although kinase activity has been described preferentially in neuronal systems. Cdk5 has an impact on actin polymerization during neuronal migration and neurite outgrowth and deregulation of the kinase has been implicated in the promotion of neurodegeneration. Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function. In addition, Cdk5 phosphorylates munc-18 and synapsin I, two essential components of the exocytotic machinery. We have shown by reverse transcriptase-polymerase chain reaction, immunocytochemistry, and Western blotting that Cdk5 is present in the insulin-secreting pancreatic ␤-cell. Subcellular fractionation of isolated ␤-cells revealed a glucose-induced translocation of membrane-bound Cdk5 protein to lower density fractions. Inhibition of Cdk5 with roscovitine reduced insulin secretion with ϳ35% compared with control after glucose stimulation and with ϳ65% after depolarization with glucose and KCl. Capacitance measurements performed on single ␤-cells that expressed a dominantnegative Cdk5 mutant showed impaired exocytosis. The effect on exocytosis by Cdk5 appeared to be independent of changes in free cytoplasmic Ca 2؉ concentration. Taken together these results show that Cdk5 is present in ␤-cells and acts as a positive regulator of insulin exocytosis.Insulin is stored in secretory granules in pancreatic ␤-cells and upon stimulation with secretagogues insulin is released by exocytosis. Exocytosis has been suggested to be mediated by the same core fusion machinery that traverses intracellular membrane traffic in all cells (1-3). It was reported that the membrane fusion event required the N-ethylmaleimide sensitive factor (NSF), 1 and soluble NSF Attachment Proteins, ␣-, ␤-, and ␥-SNAP (1, 2). In addition to NSF and SNAPs, a 7 S core complex with SNAp receptors or "SNARE" proteins corresponding to the vesicle component synaptobrevin/vesicular-associated membrane protein, as well as the plasma membrane proteins SNAP-25 (synaptosomal-associated protein of 25 kDa) and syntaxin were necessary for neuronal exocytosis (3). The SNARE hypothesis proposes that the SNARE proteins form trans-complexes between adjacent membranes, thereby forcing them to proximity. After association of ␣-SNAP, the ATPase NSF completes the reaction by disassembling the SNARE complex leading to membrane bilayer mixing (3). More recently, trans-SNARE pairing and NSF activity has been suggested to act either prior to docking of vesicles or after membrane bilayer mixing (4 -9). Initially the SNARE proteins were regarded as neuron-specific. However, syntaxin, SNAP-25, synaptobrevin/ vesicular-associated membrane protein, and other synaptic proteins regulating neuronal exocytosis have also been identified in pancreatic ␤-cells, suggesting that the mechanism for insulin secretion is similar to that of neurotransmitter release from synaptic vesicles in neurons (10 -13). Regulated secretion of insulin from pancreatic ␤-cells has to be tightl...

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Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic β-Cells.

Cited by 102 publications

References 333 publications

Oscillatory control of insulin secretion

Oscillatory control of insulin secretion

Glucose-dependent Insulinotropic Polypeptide Activates the Raf-Mek1/2-ERK1/2 Module via a Cyclic AMP/cAMP-dependent Protein Kinase/Rap1-mediated Pathway

Cyclin-dependent Kinase 5 Promotes Insulin Exocytosis

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