Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases

Gao, Zhan‐Guo; Zuberi, Aamir; Quon, Michael J.; Dong, Zigang; Ye, Jianping

doi:10.1074/jbc.m300423200

Cited by 229 publications

(160 citation statements)

References 65 publications

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“…However, the cellular enzymes that (possibly) mediate the acetyl transfer have not been identified. Interestingly, there are by now numerous reports of cyclooxygenase-independent actions of acetyl salicylic acid that impinge primarily upon MAP kinaseand NF-B-signaling pathways (27,28). In the light of our results, we speculate that some of these effects might be due to the transfer of acetyl groups to the active sites of MAPKKs/IKKs catalyzed by yet uncharacterized serine/threonine acetyl transferases.…”

Section: Discussionsupporting

confidence: 49%

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Mittal

Peak‐Chew²,

McMahon³

2006

Proc. Natl. Acad. Sci. U.S.A.

262

272

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To overcome host defenses, bacterial pathogens of the genus Yersinia inject specific effector proteins into colonized mammalian cells. One such virulence factor, YopJ, inhibits the host inflammatory response and induces apoptosis of immune cells by blocking multiple signaling pathways, including the MAPK and NF-B pathways. In this study, we show that YopJ exerts its deleterious effects by catalyzing the acetylation of two serine residues in the activation loop of the MAP kinase kinase, MEK2. This covalent modification prevents the phosphorylation of these serine residues that is required for activation of MEK2 and downstream signal propagation. We also show that YopJ causes acetylation of a threonine residue in the activation loop of both the ␣ and ␤ subunits of the NF-B pathway kinase, IKK. These results establish a hitherto uncharacterized mode of action for bacterial toxins and suggest the possibility that serine/threonine acetylation may occur even under nonpathogenic conditions and may be a widespread protein modification regulating protein function in eukaryotic cells.inflammation ͉ MEK U nderstanding the mode of action of bacterial toxins has provided insight into the working of mammalian cells especially with regard to signal transduction pathways that impinge upon the activation of the innate immune system (1, 2). Historically, plague has been one of the most devastating diseases to humans, second only to smallpox. The bacillus Yersinia pestis is the causative agent of plague, and two other Yersinia species, Yersinia pseudotuberculosis and Yersinia enterocolitica, cause septicaemic and gastrointestinal disorders (3). These pathogens inject a bouquet of six effector proteins into the mammalian cell cytosol using a type III secretion apparatus (4). These Yersinia outer proteins (Yops) help the pathogen multiply extracellularly in the host by preventing its phagocytosis and by slowing down the onset of the inflammatory response (5). YopE, YopT, and YopO target the Rho family of GTP-binding proteins that control actin cytoskeleton dynamics whereas YopH dephosphorylates focal adhesion proteins, thus inhibiting focal adhesion disassembly. Together, the action of these Yops contributes to the resistance of Yersinia to undergo phagocytosis, a process known to require remodeling of the actin cytoskeleton and of focal adhesions. Suppression of phagocytosis enables Yersinia to evade the macrophage defense network, thereby allowing them to proliferate in Peyer's patches as extracellular microcolonies. The leucine-rich protein, YopM, has been shown to bind to several host cell kinases, resulting in their activation (6). The remaining outer protein, YopJ (also called YopP in Y. enterocolitica) has emerged as an important agent that leads to the reduced host inflammatory response characteristic of Yersinia infections (5). Exposure of macrophages to lipopolysaccharide leads to the activation of NF-B and of several members of the MAPK family that promote the production of proinflammatory cytokines such as TNF-␣. YopJ in...

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Section: Discussionsupporting

confidence: 49%

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Mittal

Peak‐Chew²,

McMahon³

2006

Proc. Natl. Acad. Sci. U.S.A.

262

272

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“…Interestingly, we also have seen how Taurine (10 mM) as an antioxidant was capable of reversing glucose uptake dysfunction and restoring insulin sensitivity in oleate-treated cells. The current finding might carry a substantial interest as a potential therapeutic target for muscle insulin resistance and the treatment of type-2 diabetes [32][33][34].…”

Section: Discussionmentioning

confidence: 81%

“…Consequently, IRS-1 Serine 307 is inducible leading to the inhibition of IRS-1 function by either IKK or c-jun N-terminal kinase (JNK) [32][33][34]. Interestingly, we also have seen how Taurine (10 mM) as an antioxidant was capable of reversing glucose uptake dysfunction and restoring insulin sensitivity in oleate-treated cells.…”

Section: Discussionmentioning

confidence: 86%

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

Ragheb

Shanab

Medhat

et al. 2009

Biochemical and Biophysical Research Communications

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In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine 307 phosphorylation of IRS-1. IRS-1 Serine 307 phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IκB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKα/β, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10 mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms. KeywordsFree fatty acid (FFA); Insulin resistance (IR); Skeletal muscle cell (C2C12); Protein kinase C (PKC); Insulin receptor substrate-1 (IRS-1)

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“…4C) suggests that S6K protein reduction may not be a result of inhibition at the mRNA level. In an early study, we observed that TNF-␣ was able to induce serine phosphorylation of S6K (34). Protein degradation is commonly observed after serine phosphorylation.…”

Section: The P50-ko Mice Are Lean Andmentioning

confidence: 99%

Inactivation of NF-κB p50 Leads to Insulin Sensitization in Liver through Post-translational Inhibition of p70S6K

Gao

Yin

Zhang

et al. 2009

Journal of Biological Chemistry

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In this study, we investigated the metabolic phenotype of the NF-B p50 knock-out (p50-KO) mice. Compared with wild type mice, the p50-KO mice had an increase in food intake, but a decrease in body fat content. On chow diet, their blood glucose dropped much more than the wild type (WT) mice in the insulin tolerance test. Their glucose infusion rate was 30% higher than that of the WT mice in the hyperinsulinemic-euglycemic clamp. Their hepatic glucose production was suppressed more actively by insulin, and their insulin-induced glucose uptake was not altered in skeletal muscle or adipose tissue. In the liver, their p70S6K (S6K1) protein was significantly lower, and tumor necrosis factor-␣ (TNF-␣) expression was much higher. Their S6K1 protein was reduced by TNF-␣ treatment in the primary culture of hepatocytes. S6K1 reduction was blocked by the proteasome inhibitor MG132. In their livers, IKK2 (IKK␤) activity was reduced together with IKK␥. Their S6K1 degradation was dependent on IKK2 deficiency. Reconstitution of the S6K1 protein in their liver blocked the increase in insulin sensitivity. S6K1 degradation was not observed in hepatocytes of the WT mice. The data suggest that inactivation of NF-B p50 leads to suppression of IKK2 activity in the liver. IKK2 deficiency leads to S6K1 inhibition through TNF-induced protein degradation. The S6K1 reduction may contribute to insulin sensitivity in p50-KO mice. This study suggests that hepatic S6K1 may be a drug target in the treatment of insulin resistance.Chronic inflammation occurs in adipose tissue and liver in obesity (1, 2). It is generally believed that inflammation contributes to pathogenesis of insulin resistance through activation of IKK/NF-B and JNK signaling pathways. Serine kinase IKK2 (IKK␤) contributes to insulin resistance by activation of transcription factor NF-B (3-6) or induction of IRS-1 serine phosphorylation (7,8). Data from Ikk2 transgenic mice suggest that NF-B may be involved in the pathogenesis of insulin resistance (4). However, the role of NF-B has not been directly tested by gene knock-out in mice.NF-B contains two subunits, p50 (NF-B1) and p65 (RelA), in most cases. The p50 knock-out (p50-KO) mice were first reported in 1995, in which the p50 gene was globally inactivated by gene deletion (9). The mice are normal in growth, but deficient in B lymphocyte function. The p50-KO mice have been used in the study of many biological systems including the immune system (10, 11), muscle dystrophy (12), liver regeneration (13, 14), aging (15), and brain function (16). However, the metabolic phenotype remains unclear in this line of KO mice. Whole body knock-out of p65 (p65-KO) was reported in 1995 for embryonic lethality (17, 18). S6K1 (p70 ribosomal protein S6 kinase) is a serine kinase in the PI3K/Akt signaling pathway. It mediates nutrient (amino acid and glucose) and insulin signals in the regulation of insulin sensitivity (19,20). Global inactivation of S6K1 in knock-out mice protects the mice against diet-induced insulin resistance (21). An increa...

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Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases

Cited by 229 publications

References 65 publications

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling

Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

Inactivation of NF-κB p50 Leads to Insulin Sensitization in Liver through Post-translational Inhibition of p70S6K

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