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Morris F. White - One of the best experts on this subject based on the ideXlab platform.
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IRS proteins and diabetic complications
Diabetologia, 2016Co-Authors: Deborah P. Lavin, Morris F. White, Derek P BrazilAbstract:IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lipid metabolism and cell proliferation. There are two main IRS proteins in humans (IRS1 and IRS2), both of which are widely expressed. Given their central role in the insulin signalling pathway, it is not surprising that male mice lacking IRS1 or Irs2 present with elevated blood glucose or type 2 diabetes, respectively. For reasons yet to be identified, female Irs2 ^−/− mice do not develop type 2 diabetes. A number of organs are affected by complications of diabetes; macrovascular complications include stroke and coronary artery disease, while nephropathy, neuropathy and retinopathy fall into the category of microvascular complications. Given the serious consequences of these complications on patient morbidity and mortality, it is essential to identify the molecular pathogenesis underlying diabetic complications, with a view to improving therapeutic intervention and patient outcomes. A number of recently published papers have converged on the hypothesis that the loss of insulin signalling and IRS proteins is instrumental to the development and/or progression of diabetic complications. This review will summarise some highlights from the published work in which this hypothesis is discussed.
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serine 302 phosphorylation of mouse insulin receptor substrate 1 IRS1 is dispensable for normal insulin signaling and feedback regulation by hepatic s6 kinase
Journal of Biological Chemistry, 2016Co-Authors: Kyle D Copps, Wei Qiu, Nancy J Hancer, Morris F. WhiteAbstract:Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity.
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insulin and metabolic stress stimulate multisite serine threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation
Journal of Biological Chemistry, 2014Co-Authors: Nancy J Hancer, Wei Qiu, Christine E Cherella, Kyle D Copps, Morris F. WhiteAbstract:IRS1 and IRS2 are key substrates of the insulin receptor tyrosine kinase. Mass spectrometry reveals more than 50 phosphorylated IRS1 serine and threonine residues (Ser(P)/Thr(P) residues) in IRS1 from insulin-stimulated cells or human tissues. We investigated a subset of IRS1 Ser(P)/Thr(P) residues using a newly developed panel of 25 phospho-specific monoclonal antibodies (αpS/TmAbIRS1). CHO cells overexpressing the human insulin receptor and rat IRS1 were stimulated with insulin in the absence or presence of inhibitors of the PI3K → Akt → mechanistic target of rapamycin (mTOR) → S6 kinase or MEK pathways. Nearly all IRS1 Ser(P)/Thr(P) residues were stimulated by insulin and significantly suppressed by PI3K inhibition; fewer were suppressed by Akt or mTOR inhibition, and none were suppressed by MEK inhibition. Insulin-stimulated IRS1 tyrosine phosphorylation (Tyr(P)IRS1) was enhanced by inhibition of the PI3K → Akt → mTOR pathway and correlated with decreased Ser(P)-302IRS1, Ser(P)-307IRS1, Ser(P)-318IRS1, Ser(P)-325IRS1, and Ser(P)-346IRS1. Metabolic stress modeled by anisomycin, thapsigargin, or tunicamycin increased many of the same Ser(P)/Thr(P) residues as insulin, some of which (Ser(P)-302IRS1, Ser(P)-307IRS1, and four others) correlated significantly with impaired insulin-stimulated Tyr(P)IRS1. Thus, IRS1 Ser(P)/Thr(P) is an integrated response to insulin stimulation and metabolic stress, which associates with reduced Tyr(P)IRS1 in CHOIR/IRS1 cells.
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Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
Diabetes, 2013Co-Authors: Qinglei Zhu, Morris F. White, Candice M. Thomas, Rajesh Kumar, Hao Feng, David E. Dostal, Kenneth M. Baker, Shaodong GuoAbstract:Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.
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Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis.
Molecular metabolism, 2013Co-Authors: Marianna Sadagurski, X. Charlie Dong, Martin G. Myers, Morris F. WhiteAbstract:Insulin receptor substrates (IRS1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4(-/y) mice that lacked Irs2 in the CNS (bIrs2(-/-)·Irs4(-/y)) or only in LepRb-neurons (Lepr (∆Irs2) ·Irs4 (-/y) ). bIrs2(-/-)·Irs4(-/y) mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr (∆Irs2) ·Irs4 (-/y) mice were not different from Lepr (∆Irs2) mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.
Kyle D Copps - One of the best experts on this subject based on the ideXlab platform.
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ablation of insulin receptor substrates 1 and 2 suppresses kras driven lung tumorigenesis
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Minsik Lee, Peiyun Tsai, Ashley S Adler, Natasha L Curry, Saketh Challa, Elizaveta Freinkman, Daniel S Hitchcock, Kyle D CoppsAbstract:Non–small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (IRS1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with IRS1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.
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Hepatic Insulin Signaling Regulates Hepatokines to Coordinate Energy Expenditure and Weight Gain through Irs2 in Sim1 Neurons
Diabetes, 2018Co-Authors: Rongya Tao, Kyle D Copps, Oliver Stoehr, Orris F. WhiteAbstract:Insulin resistance is the underlying cause of type 2 diabetes; however, insulin resistance might also be a feed-back mechanism to protect cells and tissues from acute effects of over nutrition. Based upon our results with LDKO (hepatic specific IRS1L/LIrs2L/L CreAlbumin) mice, we found that hepatic insulin resistance elevated systemic oxygen consumption and energy expenditure, which was associated with a dramatic reduction of the RER (respiratory exchange ratio) and resistance to diet-induced obesity. Deletion of hepatic FoxO1 in LDKO-mice restored energy homeostasis and oxygen consumption, and increased the RER into the normal range. Contrary to the progressive peripheral insulin resistance of the LDKO-mice, Irs2 expression and insulin sensitivity increased in the PVH (paraventricular nucleus of hypothalamus). Interestingly, deletion of Irs2 in the PVH (Irs2L/L-mice intercrossed with CreSim1-mice) increased body weight and promoted obesity. To identify the molecular cross-talk between liver and brain, we used a neuronal cell line to screen for the effects of hepatokines that were dysregulated in LDKO-mice—but normalized in LTKO-mice. Among these dysregulated hepatokines, excess circulating NTF3 and GPX3 led to increased Irs2 expression and insulin sensitivity in neurons. Thus, our study suggests that hepatic FoxO1-dependent hepatokines—NTF3 or GPX3—modulate systemic energy expenditure and body weight through Irs2 expression in the PVH. Disclosure R. Tao: None. K.D. Copps: None. O. Stoehr: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.
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serine 302 phosphorylation of mouse insulin receptor substrate 1 IRS1 is dispensable for normal insulin signaling and feedback regulation by hepatic s6 kinase
Journal of Biological Chemistry, 2016Co-Authors: Kyle D Copps, Wei Qiu, Nancy J Hancer, Morris F. WhiteAbstract:Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity.
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insulin and metabolic stress stimulate multisite serine threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation
Journal of Biological Chemistry, 2014Co-Authors: Nancy J Hancer, Wei Qiu, Christine E Cherella, Kyle D Copps, Morris F. WhiteAbstract:IRS1 and IRS2 are key substrates of the insulin receptor tyrosine kinase. Mass spectrometry reveals more than 50 phosphorylated IRS1 serine and threonine residues (Ser(P)/Thr(P) residues) in IRS1 from insulin-stimulated cells or human tissues. We investigated a subset of IRS1 Ser(P)/Thr(P) residues using a newly developed panel of 25 phospho-specific monoclonal antibodies (αpS/TmAbIRS1). CHO cells overexpressing the human insulin receptor and rat IRS1 were stimulated with insulin in the absence or presence of inhibitors of the PI3K → Akt → mechanistic target of rapamycin (mTOR) → S6 kinase or MEK pathways. Nearly all IRS1 Ser(P)/Thr(P) residues were stimulated by insulin and significantly suppressed by PI3K inhibition; fewer were suppressed by Akt or mTOR inhibition, and none were suppressed by MEK inhibition. Insulin-stimulated IRS1 tyrosine phosphorylation (Tyr(P)IRS1) was enhanced by inhibition of the PI3K → Akt → mTOR pathway and correlated with decreased Ser(P)-302IRS1, Ser(P)-307IRS1, Ser(P)-318IRS1, Ser(P)-325IRS1, and Ser(P)-346IRS1. Metabolic stress modeled by anisomycin, thapsigargin, or tunicamycin increased many of the same Ser(P)/Thr(P) residues as insulin, some of which (Ser(P)-302IRS1, Ser(P)-307IRS1, and four others) correlated significantly with impaired insulin-stimulated Tyr(P)IRS1. Thus, IRS1 Ser(P)/Thr(P) is an integrated response to insulin stimulation and metabolic stress, which associates with reduced Tyr(P)IRS1 in CHOIR/IRS1 cells.
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regulation of insulin sensitivity by serine threonine phosphorylation of insulin receptor substrate proteins IRS1 and irs2
Diabetologia, 2012Co-Authors: Kyle D Copps, Morris F. WhiteAbstract:The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
Nancy J Hancer - One of the best experts on this subject based on the ideXlab platform.
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serine 302 phosphorylation of mouse insulin receptor substrate 1 IRS1 is dispensable for normal insulin signaling and feedback regulation by hepatic s6 kinase
Journal of Biological Chemistry, 2016Co-Authors: Kyle D Copps, Wei Qiu, Nancy J Hancer, Morris F. WhiteAbstract:Constitutive activation of the mammalian target of rapamycin complex 1 and S6 kinase (mTORC1→ S6K) attenuates insulin-stimulated Akt activity in certain tumors in part through "feedback" phosphorylation of the upstream insulin receptor substrate 1 (IRS1). However, the significance of this mechanism for regulating insulin sensitivity in normal tissue remains unclear. We investigated the function of Ser-302 in mouse IRS1, the major site of its phosphorylation by S6K in vitro, through genetic knock-in of a serine-to-alanine mutation (A302). Although insulin rapidly stimulated feedback phosphorylation of Ser-302 in mouse liver and muscle, homozygous A302 mice (A/A) and their knock-in controls (S/S) exhibited similar glucose homeostasis and muscle insulin signaling. Furthermore, both A302 and control primary hepatocytes from which Irs2 was deleted showed marked inhibition of insulin-stimulated IRS1 tyrosine phosphorylation and PI3K binding after emetine treatment to raise intracellular amino acids and activate mTORC1 → S6K signaling. To specifically activate mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus. Although it moderately decreased IRS1/PI3K association and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or promote hyperinsulinemia in mixed background A/A or S/S mice. Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or other putative S6K sites within IRS1, whereas ribosomal S6 protein was constitutively phosphorylated. Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but not IRS1/PI3K association, was rapidly restored by treatment with the mTORC1 inhibitor rapamycin. Thus, within the hepatic compartment, mTORC1 → S6K signaling regulates Akt largely through IRS-independent means with little effect upon physiologic insulin sensitivity.
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insulin and metabolic stress stimulate multisite serine threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation
Journal of Biological Chemistry, 2014Co-Authors: Nancy J Hancer, Wei Qiu, Christine E Cherella, Kyle D Copps, Morris F. WhiteAbstract:IRS1 and IRS2 are key substrates of the insulin receptor tyrosine kinase. Mass spectrometry reveals more than 50 phosphorylated IRS1 serine and threonine residues (Ser(P)/Thr(P) residues) in IRS1 from insulin-stimulated cells or human tissues. We investigated a subset of IRS1 Ser(P)/Thr(P) residues using a newly developed panel of 25 phospho-specific monoclonal antibodies (αpS/TmAbIRS1). CHO cells overexpressing the human insulin receptor and rat IRS1 were stimulated with insulin in the absence or presence of inhibitors of the PI3K → Akt → mechanistic target of rapamycin (mTOR) → S6 kinase or MEK pathways. Nearly all IRS1 Ser(P)/Thr(P) residues were stimulated by insulin and significantly suppressed by PI3K inhibition; fewer were suppressed by Akt or mTOR inhibition, and none were suppressed by MEK inhibition. Insulin-stimulated IRS1 tyrosine phosphorylation (Tyr(P)IRS1) was enhanced by inhibition of the PI3K → Akt → mTOR pathway and correlated with decreased Ser(P)-302IRS1, Ser(P)-307IRS1, Ser(P)-318IRS1, Ser(P)-325IRS1, and Ser(P)-346IRS1. Metabolic stress modeled by anisomycin, thapsigargin, or tunicamycin increased many of the same Ser(P)/Thr(P) residues as insulin, some of which (Ser(P)-302IRS1, Ser(P)-307IRS1, and four others) correlated significantly with impaired insulin-stimulated Tyr(P)IRS1. Thus, IRS1 Ser(P)/Thr(P) is an integrated response to insulin stimulation and metabolic stress, which associates with reduced Tyr(P)IRS1 in CHOIR/IRS1 cells.
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IRS1 Serine 307 Promotes Insulin Sensitivity in Mice
Cell metabolism, 2010Co-Authors: Kyle D Copps, Nancy J Hancer, Wei Qiu, Lynn Opare-ado, Cari Walsh, Morris F. WhiteAbstract:Summary Phosphorylation of the insulin receptor substrates (Irs) on serine residues—typified by Ser307 of rodent IRS1—is thought to mediate insulin resistance. To determine whether Ser307 negatively regulates IRS1 in vivo, we generated knockin mice in which Ser307 (human Ser312) was replaced with alanine (A/A). Unexpectedly, A/A mice that were fed a high-fat diet developed more severe insulin resistance than control mice, accompanied by enhanced pancreatic compensation and impaired muscle insulin signaling. Chow-fed mice whose livers lacked Irs2 but retained a single knockin allele (A/lox::LKO2) were profoundly insulin resistant (versus +/lox::LKO2 mice), and their hepatocytes showed impaired insulin signaling ex vivo. Similarly, mutant A307 IRS1 adenovirus only partially restored the response to injected insulin in mice lacking hepatic IRS1 and Irs2. Thus, contrary to the results of cell-based experiments, Ser307 in mice is a positive regulatory site that moderates the severity of insulin resistance by maintaining proximal insulin signaling.
Jeffrey E. Pessin - One of the best experts on this subject based on the ideXlab platform.
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Nexilin, a Cardiomyopathy-Associated F-Actin Binding Protein, Binds and Regulates IRS1 Signaling in Skeletal Muscle Cells
PloS one, 2013Co-Authors: Andrew Lee, Jeffrey E. Pessin, Fumihiko Hakuno, Paul A. Northcott, Maria Rozakis AdcockAbstract:Insulin stimulates glucose uptake through a highly organized and complex process that involves movement of the glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane. Previous studies in L6 skeletal muscle cells have shown that insulin-induced activation and assembly of insulin receptor substrate 1 (IRS1) and p85α the regulatory subunit of the Type 1A phosphatidylinositol-3-kinase (PI3K), within remodeled actin-rich membrane structures is critical for downstream signalling mediating the translocation of GLUT4. The mechanism for localization within actin cytoskeletal scaffolds is not known, as direct interaction of IRS1 or p85α with F-actin has not been demonstrated. Here we show that nexilin, a F-actin binding protein implicated in the pathogenesis of familial dilated cardiomyopathies, preferentially binds to IRS1 over IRS2 to influence glucose transport in skeletal muscle cells. Nexilin stably associates with IRS1 under basal conditions in L6 myotubes and this complex is disassembled by insulin. Exposure of L6 myotubes to Latrunculin B disrupts the spatial patterning of nexilin and its transient association with IRS1. Functional silencing of nexilin has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, however it enhances recruitment of p85α to IRS1 resulting in increased PI-3, 4, 5-P3 formation, coincident with enhanced AKT activation and glucose uptake. By contrast, overexpression of nexilin inhibits transmission of IRS1 signals to AKT. Based on these findings we propose that nexilin may tether IRS1 to actin-rich structures under basal conditions, confining IRS1 signaling to specific subcellular locations in the cell. Insulin-elicited release of this constraint may enhance the efficiency of IRS1/PI3K interaction and PI-3, 4, 5-P3 production at localized sites. Moreover, the selective binding of nexilin to IRS1 and not IRS2 may contribute to the differential specificity of IRS isoforms in the modulation of GLUT4 trafficking in skeletal muscle cells.
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Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave.
Trends in cell biology, 1996Co-Authors: Steven B. Waters, Jeffrey E. PessinAbstract:Abstract The insulin receptor is a transmembrane tyrosine kinase that is essential for mediating multiple intracellular signalling cascades that lead ultimately to the biological actions of insulin Tyrosine phosphorylation o f the cytosolic proteins insulin receptor substrate 1 and 2 (IRS1 and IRS2) produces protein ‘scaffolding' for the assembly of effector proteins containing Src homology 2 (SH2) domains, thereby generating multisubunit signalling complexes. Although IRS1 was originally isolated as a specific insulin receptor substrate, both IRS1 and IRS2 appear to play a broader role, functioning also as proximal substrates in growth hormone and cytokine receptor signalling. Current data establish IRS1 and IRS2 as critical effectors integrating various cell-type-specific signals into distinct, but overlapping, biological responses.
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Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling.
The Journal of biological chemistry, 1994Co-Authors: Keishi Yamauchi, Jeffrey E. PessinAbstract:Abstract Expression of the insulin receptor substrate-1 (IRS1) or Shc cDNA resulted in both increased protein and insulin-stimulated tyrosine phosphorylation of IRS1 and Shc proteins, respectively. Although expression of Shc had no significant effect on insulin-stimulated mitogen-activated protein (MAP) kinase gel shift or c-fos transcriptional activation, expression of IRS1 inhibited these responses. The effect of IRS1 expression on the formation of multisubunit signaling complexes was determined by a series of indirect co-immunoprecipitations. Grb2 immunoprecipitation from IRS1-transfected and insulin-treated cells demonstrated an increased coimmunoprecipitation of Syp and the p85 regulatory subunit of the phosphatidylinositol 3-kinase. Similarly, cell extracts immunoprecipitated with a p85 antibody displayed an increased co-immunoprecipitation of Syp and Grb2. However, expression of IRS1 increased the extent of Grb2 associated with IRS1 with a concomitant reduction in the amount of Grb2 associated with Shc. Furthermore, increased expression of Shc reduced the amount of Grb2 bound to IRS1 with a concomitant increase in Grb2 associated with Shc. Together, these data demonstrate that IRS1 and Shc compete for a limited cellular pool of Grb2, and insulin activation of MAP kinase and c-fos transcription predominantly occur through the Shc-Grb2 signaling pathway.
Yongtao Geng - One of the best experts on this subject based on the ideXlab platform.
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insulin receptor substrate 1 2 IRS1 2 regulates wnt β catenin signaling through blocking autophagic degradation of dishevelled2
Journal of Biological Chemistry, 2014Co-Authors: Yongtao Geng, Fangli Ren, Ying Qiu, Yasuhiko Tomita, Miki Tomoeda, Mioka Kishida, Yinyin Wang, Lian Jin, Chunhong WeiAbstract:Wnt signaling plays a pivotal role in cell proliferation, tissue homeostasis, and tumorigenesis. Dishevelled (Dvl) is a central node of Wnt signaling. Insulin receptor substrates (IRSs), as a critical component of insulin signaling, are involved in cell proliferation, metabolism, and cancer development. In this study, we report that IRS1/2 promotes Wnt/β-catenin signaling by stabilizing Dvl2. We found that IRS1/2 interacts with Dvl2. Overexpression of IRS1/2 increased the protein level of Dvl2 and promoted canonical Wnt signaling, as evidenced by the increased T cell-specific factor 4 transcriptional activity and the up-regulation of expression of CYCLIN D1 and c-MYC, two Wnt target genes critical for cell growth, whereas depletion of IRS1/2 reduced the level of Dvl2 and attenuated Wnt/β-catenin signaling. Biochemical analyses revealed that IRS1/2 decreased Lys-63-linked ubiquitination of Dvl2 and stabilized Dvl2 protein via suppressing its autophagy-mediated degradation. We further revealed that IRS1/2 blocks autophagy-induced formation of the Dvl2-p62/SQSTM1 complex, resulting in disabled association of Dvl2 to autophagosomes. We demonstrated that IRS1/2 promoted the induction of epithelial-mesenchymal transition (EMT) and cell proliferation in response to Wnt stimulation, whereas depletion of Dvl2 impaired the IRS1/2-mediated EMT and cell growth. Our findings revealed that IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2.
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Insulin Receptor Substrate 1/2 (IRS1/2) Regulates Wnt/β-Catenin Signaling through Blocking Autophagic Degradation of Dishevelled2
The Journal of biological chemistry, 2014Co-Authors: Yongtao Geng, Fangli Ren, Ying Qiu, Yasuhiko Tomita, Miki Tomoeda, Mioka Kishida, Yinyin Wang, Lian JinAbstract:Wnt signaling plays a pivotal role in cell proliferation, tissue homeostasis, and tumorigenesis. Dishevelled (Dvl) is a central node of Wnt signaling. Insulin receptor substrates (IRSs), as a critical component of insulin signaling, are involved in cell proliferation, metabolism, and cancer development. In this study, we report that IRS1/2 promotes Wnt/β-catenin signaling by stabilizing Dvl2. We found that IRS1/2 interacts with Dvl2. Overexpression of IRS1/2 increased the protein level of Dvl2 and promoted canonical Wnt signaling, as evidenced by the increased T cell-specific factor 4 transcriptional activity and the up-regulation of expression of CYCLIN D1 and c-MYC, two Wnt target genes critical for cell growth, whereas depletion of IRS1/2 reduced the level of Dvl2 and attenuated Wnt/β-catenin signaling. Biochemical analyses revealed that IRS1/2 decreased Lys-63-linked ubiquitination of Dvl2 and stabilized Dvl2 protein via suppressing its autophagy-mediated degradation. We further revealed that IRS1/2 blocks autophagy-induced formation of the Dvl2-p62/SQSTM1 complex, resulting in disabled association of Dvl2 to autophagosomes. We demonstrated that IRS1/2 promoted the induction of epithelial-mesenchymal transition (EMT) and cell proliferation in response to Wnt stimulation, whereas depletion of Dvl2 impaired the IRS1/2-mediated EMT and cell growth. Our findings revealed that IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2.
