Protein Farnesylation–Dependent Raf/Extracellular Signal–Related Kinase Signaling Links to Cytoskeletal Remodeling to Facilitate Glucose-Induced Insulin Secretion in Pancreatic β-Cells

Kowluru, Anjaneyulu; Veluthakal, Rajakrishnan; Rhodes, Christopher J.; Kamath, Vasudeva; Syed, Ismail; Koch, Brandon J.

doi:10.2337/db09-1334

Cited by 47 publications

(70 citation statements)

References 51 publications

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“…Our data secure the placement of PAK1 upstream of ERK1/2 activation, which fits well with prior studies that have implicated ERK1/2 in the later phase of insulin release (39 -42). In addition, Raf kinase may be a missing link between PAK1 and ERK1/2 activations, since Raf kinases (B-Raf in human islets and Raf-1 in mouse islets) are implicated in insulin release (40,43,44). The PAK1 KO islets will be invaluable to test this putative step in the pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Wang¹,

Oh²,

Clapp³

et al. 2011

Journal of Biological Chemistry

115

166

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Background: P21-activated kinase (PAK1) is a downstream effector of the GTPase Cdc42. Results: Inhibition of Cdc42-PAK1 signaling in human islets inhibited insulin secretion. PAK1 knock-out mice showed defects in insulin release and skeletal muscle insulin action, underlying impaired whole body glucose homeostasis. Conclusion: Attenuated PAK1 abundance/activation may contribute to type 2 diabetes susceptibility. Significance: Cdc42-PAK1 signaling is crucial for regulating glucose homeostasis in vivo.

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Section: Discussionmentioning

confidence: 99%

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Wang¹,

Oh²,

Clapp³

et al. 2011

Journal of Biological Chemistry

115

166

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“…This was accomplished using a pull-down assay that our laboratory described recently (18). Briefly, INS 832/13 cells were starved overnight in low-serum, low-glucose-containing medium in either the presence or absence of MPA (10 M).…”

Section: Methodsmentioning

confidence: 99%

“…2 and 3. In this context, our laboratory recently reported that coprovision of FTI-277 or FTI-2628 or siRNA-mediated knockdown of farnesyltransferase ␤-subunit resulted in a significant inhibition of glucose-stimulated activation of ERK1/2, Rac1, and insulin secretion, further ruling out the potential involvement of Ras in these signaling steps (18). Based on …”

Section: Selective Inhibitors Of Protein Prenylation Markedly Attenuamentioning

confidence: 99%

“…Additional studies are needed to conclusively determine the identity of this protein. However, based on our laboratory's recently published evidence (18), it is unlikely that the farnesylated protein is Ras, since inhibition of Ras (a farnesylated protein) had no effects on glucose-induced ERK1/2 phosphorylation, Rac1 activation, and insulin secretion.…”

Section: R759 G-protein-dependent Rosmentioning

confidence: 99%

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Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: role of protein prenylation

Syed

Kyathanahalli

Kowluru

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Syed I, Kyathanahalli CN, Kowluru A. Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: role of protein prenylation. Am J Physiol Regul Integr Comp Physiol 300: R756-R762, 2011. First published January 12, 2011 doi:10.1152/ajpregu.00786.2010.-Recent evidence suggests that an acute increase in the generation of phagocyte-like NADPH-oxidase (Nox)-mediated reactive oxygen species (ROS) may be necessary for glucose-stimulated insulin secretion. Using rat islets and INS 832/13 cells, we tested the hypothesis that activation of specific G proteins is necessary for nutrient-mediated intracellular generation of ROS. Stimulation of ␤-cells with glucose or a mixture of mitochondrial fuels (mono-methylsuccinate plus ␣-ketoisocaproic acid) markedly elevated intracellular accumulation of ROS, which was attenuated by selective inhibitors of Nox (e.g., apocynin or diphenyleneiodonium chloride) or short interfering RNA-mediated knockdown of p47 phox , one of the subunits of Nox. Selective inhibitors of protein prenylation (FTI-277 or GGTI-2147) markedly inhibited nutrient-induced ROS generation, suggesting that activation of one (or more) prenylated small G proteins and/or ␥-subunits of trimeric G proteins is involved in this signaling axis. Depletion of endogenous GTP levels with mycophenolic acid significantly reduced glucose-induced activation of Rac1 and ROS generation in these cells. Other immunosuppressants, like cyclosporine A or rapamycin, which do not deplete endogenous GTP levels, failed to affect glucose-induced ROS generation, suggesting that endogenous GTP is necessary for glucose-induced Nox activation and ROS generation. Treatment of INS 832/13 cells or rat islets with pertussis toxin (Ptx), which ADP ribosylates and inhibits inhibitory class of trimeric G proteins (i.e., G i or Go), significantly attenuated glucoseinduced ROS generation in these cells, implicating activation of a Ptx-sensitive G protein in these signaling cascade. Together, our findings suggest a prenylated Ptx-sensitive signaling step couples Rac1 activation in the signaling steps necessary for glucose-mediated generation of ROS in the pancreatic ␤-cells. G protein; pancreatic islets; Rac1 activation; pertussis toxin; inosine monophosphate dehydrogenase GLUCOSE-INDUCED INSULIN SECRETION (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. It is widely accepted that vesicular transport and fusion involves interplay between signaling proteins, including vesicle-associated membrane proteins on the secretory granule and docking proteins on the plasma membrane (23,28,33). Furthermore, interaction between these proteins is widely felt to require cytoskeletal remodeling, which is under the fine control of small molecular mass G proteins belonging to the Rho subfamily (e.g., Cdc42 and Rac1; see Ref. 17 for a recent review). Several effector proteins for these sm...

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“…Beta cell function and mass in Rkip1 −/− animals Since Raf-1 activity is critical for insulin secretion [16,24,25] and insulin synthesis [25], we examined whether Rkip1 ablation affected these functions. We found that islets isolated from 8-week-old Rkip1 −/− and WT animals exhibited similar basal and glucose-induced insulin secretion and had comparable insulin contents (Fig.…”

Section: Rkip1 Levels In the Mouse Pancreasmentioning

confidence: 99%

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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Protein Farnesylation–Dependent Raf/Extracellular Signal–Related Kinase Signaling Links to Cytoskeletal Remodeling to Facilitate Glucose-Induced Insulin Secretion in Pancreatic β-Cells

Cited by 47 publications

References 51 publications

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: role of protein prenylation

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

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