Regulation of ERK1 and ERK2 by Glucose and Peptide Hormones in Pancreatic β Cells

Arnette, Don; Gibson, Tara Beers; Lawrence, Michael C.; January, Bridgette; Khoo, Shih; McGlynn, Kathleen; Vanderbilt, Colleen A.; Cobb, Melanie H.

doi:10.1074/jbc.m301174200

Cited by 122 publications

(143 citation statements)

References 72 publications

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“…A rise in intracellular Ca 2+ is secondary to glucose metabolism and cell depolarisation. Moreover, activation of ERK1/2 by glucose is sensitive to inhibitors of calmodulin and the class 2B Ca 2+ /calmodulin-dependent phosphatase, calcineurin [44]. Hence, calcineurin is an upstream regulator of the ERK1/2 pathway in pancreatic beta cells.…”

Section: Discussionmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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“…Glucose, the major regulator of insulin production and release, activates nutrient-sensing and signal transduction pathways, including the mitogenactivated protein (MAP) kinases and extracellular signalregulated protein kinases 1 and 2 (ERK1/2), in islets and ␤-cell lines (1)(2)(3)(4). ERK1/2 act in many signal transduction pathways (5,6).…”

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confidence: 99%

Inhibition of Glucose-Stimulated Activation of Extracellular Signal–Regulated Protein Kinases 1 and 2 by Epinephrine in Pancreatic β-Cells

et al. 2006

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Glucose sensing is essential for the ability of pancreatic ␤-cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signalregulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic ␤-cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the ␣ 2 -adrenergic receptor. Epinephrine and the selective ␣ 2 -adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin-sensitive manner, implicating the ␣ subunit of a Gi family member. ␣ 2 -adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that ␣ 2 -adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand.

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“…During the course of our study, we noted that in differentiated rodent beta cell lines, specifically, certain INS-1 cell lines and RinM5F cells (D. Hörsch, unpublished results), Rap and B-Raf are not always activated by glucose and GLP-1. This may be due to the altered glucose responsiveness of these cells, and may explain some of the conflicting results obtained with respect to the activation of GTPases and Raf kinases in beta cells [3][4][5].…”

Section: Discussionmentioning

confidence: 99%

“…How-ever, the published results are inconsistent with respect to whether this activation is dependent on [3] or independent of [4,5] Ras and Raf kinases. These discrepancies may be attributed to the different beta cell lines used in the different studies.…”

Section: Introductionmentioning

confidence: 94%

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The Rap–B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells

et al. 2005

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Aims/hypothesis: Glucose and glucagon-like peptide-1 have been shown to activate extracellular signalregulated kinase (ERK) and phosphoinositide 3-kinase in beta cells. We examined the contributions of the small GTPases Rap and Ras and the serine-threonine kinases BRaf and Raf-1 to the activation of these kinases in human islet cells. Methods: The expression of Rap, Ras, B-Raf and Raf-1 in human islets was examined by immunohistochemistry and immunoblotting. Human islets were incubated in glucose at concentrations of 2.5 and 15 mmol/l and were stimulated with 10 nmol/l glucagon-like peptide-1. The activation of ERK and Raf kinases was examined by phosphorylation-specific antibodies and immuno-complexed kinase assays. The activation of Rap and Ras was determined by pull-down assays. Stimulation of phosphoinositide 3-kinase was detected by immuno-complexed lipid kinase assays. Results: Extracellular-regulated kinase and protein kinase B (a downstream target of phosphoinositide 3-kinase) were activated in islets stimulated with glucose and glucagon-like peptide-1. In these islets, the Rap-B-Raf signalling pathway was activated preferentially compared with Ras and Raf-1, and activated Rap and B-Raf mediated ERK stimulation in kinase assays in vitro. In addition, Rap rather than Ras mediated activation of phosphoinositide 3-kinase in islets stimulated with glucose and glucagon-like peptide-1. Conclusions/interpretation: In human islet cells, glucose and glucagon-like peptide-1 activate the Rap and BRaf signalling module, which mediates ERK activation in assays in vitro. Rap also activates phosphoinositide 3-kinase, delineating central roles for Rap and B-Raf as therapeutic targets for beta cell growth in diabetes mellitus.

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Regulation of ERK1 and ERK2 by Glucose and Peptide Hormones in Pancreatic β Cells

Cited by 122 publications

References 72 publications

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Inhibition of Glucose-Stimulated Activation of Extracellular Signal–Regulated Protein Kinases 1 and 2 by Epinephrine in Pancreatic β-Cells

The Rap–B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells

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