Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin

Ravichandran, Lingamanaidu V.; Esposito, Diana L.; Chen, Judy; Quon, Michael J.

doi:10.1074/jbc.m007231200

Cited by 211 publications

(171 citation statements)

References 45 publications

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“…Expression of PKCz seems to be regulated by LC-CoA in insulin secretion stimulated by palmitate (Yaney et al, 2000). The isoform PKCz is also activated by insulin and mediates the phosphorylation of IRS proteins (Liu et al, 2001;Ravichandran et al, 2001). As a consequence the IR-IRS complexe dissociates, inhibiting the ability of IRS proteins to induce tyrosine phosphorylation (Liu et al, 2001).…”

Section: Insulin Receptor In Pancreatic B-cellmentioning

confidence: 99%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

148

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Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic b-cells have long been recognized. Acute exposure of the pancreatic b-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for b-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acylCoA (LC-CoA) controls several aspects of the b-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide-and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.

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Section: Insulin Receptor In Pancreatic B-cellmentioning

confidence: 99%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

148

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“…Insulin receptor substrate-1 (IRS-1), one major intracellular substrate of the insulin receptor kinase, interacts with the insulin receptor at sites adjacent to the N-terminus. Recently it was found that during insulin signaling IRS-1 is phosphorylated by protein kinase C (PKC)-, thereby attenuating the insulin signal transduction [2,3]. To disclose these phosphorylation sites, we developed a mass spectrometric strategy combining two independent MS methods.…”

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confidence: 99%

Identification of an in vitro insulin receptor substrate-1 phosphorylation site by negative-ion μLC/ES-API-CID-MS hybrid scan technique

Beck

Moeschel

Deeg

et al. 2003

J. Am. Soc. Mass Spectrom.

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Recently, we reported a fast on-line alkaline micro-liquid chromatography/electrosprayatmospheric pressure ionization/collision-induced dissociation/mass spectrometric approach for sensitive phosphopeptide screening of a tryptic digested protein and subsequent characterization of the identified phosphopeptide. Based on this study, we now applied an improved method for the identification of phosphorylation sites in insulin receptor substrate 1, an important mediator in insulin signal transduction which was phosphorylated in vitro by protein kinase C-. The approach consists of an on-line alkaline negative-ion micro-liquid chromatography/electrospray-atmospheric pressure ionization/collision-induced dissociation/mass spectrometric hybrid scan experiment using a triple-quadrupole mass spectrometer with fractionation and subsequent off-line nanoES-MS (ion trap) analysis of the phosphopeptide-containing fractions. During the liquid chromatography (LC)/ES-MS experiment, the phosphopeptides of the enzymatic digest mixture of the studied insulin receptor substrate 1 fragment were detected under high skimmer potential (API-CID) using phosphorylationspecific m/z 79 marker ions as well as the intact m/z-values of the peptides which were recorded under low skimmer potential. Subsequently, the targeted fractions were analyzed by off-line nanoES-MS/MS and MS 3 . Using this approach, serine 318 was clearly identified as a major in vitro protein kinase C-phosphorylation site in the insulin receptor substrate Ϫ1 fragment. Together, our results indicate that the applied strategy is useful for unequivocal and fast analysis of phosphorylation sites in low abundant signaling proteins. (J Am Soc Mass Spectrom 2003, 14, 401-405)

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“…In fact, atypical PKCs are essential for insulin stimulation of glucose transport in muscle tissue [41]. Although atypical PKCs are located downstream of IRS-1 and PI3-kinase in insulin signalling, IRS-1 is also a novel substrate for atypical PKCs [42]. Moreover, suppressors of cytokine signalling (SOCS) proteins have been implicated in the insulin signalling network [43].…”

Section: Discussionmentioning

confidence: 99%

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Tzeng

Liu²

2005

Diabetologia

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Aims/hypothesis: This study investigated the role of opioid μ-receptor activation in the improvement of insulin resistance. Methods: Myoblast C 2 C 12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulinsignalling pathways were detected by immunoblotting. Results: The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid μ-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals. Conclusions/interpretation: Opioid μ-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.

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Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin

Cited by 211 publications

References 45 publications

Pleiotropic effects of fatty acids on pancreatic β‐cells

Pleiotropic effects of fatty acids on pancreatic β‐cells

Identification of an in vitro insulin receptor substrate-1 phosphorylation site by negative-ion μLC/ES-API-CID-MS hybrid scan technique

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

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