Insulin Receptor Substrate-2 (IRS-2) Can Mediate the Action of Insulin to Stimulate Translocation of GLUT4 to the Cell Surface in Rat Adipose Cells

Zhou, Lixin; Chen, Hui; Lin, Chung Hao; Cong, Li-Na; McGibbon, Margaret A.; Sciacchitano, Salvatore; Lesniak, Maxine A.; Quon, Michael J.; Taylor, Simeon I.

doi:10.1074/jbc.272.47.29829

Cited by 49 publications

(32 citation statements)

References 38 publications

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“…To our knowledge, this is the first study to show the physiological relevance of an IRS-2-mediated pathway in insulin-induced glucose uptake. In agreement with our findings Zhou et al (34) showed that overexpression of IRS-2 in rat adipocytes was able to increase insulin-stimulated Glut4 translocation. In contrast to our work Higaki et al (35) could not detect a difference in insulin-induced glucose uptake in isolated muscle of IRS-2 KO mice compared with wild type animals.…”

Section: Discussionsupporting

confidence: 83%

Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes

Faßhauer¹,

Klein²,

Ueki³

et al. 2000

Journal of Biological Chemistry

158

124

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Insulin and insulin-like growth factor I signals are mediated via phosphorylation of a family of insulin receptor substrate (IRS) proteins, which may serve both complementary and overlapping functions in the cell. To study the metabolic effects of these proteins in more detail, we established brown adipocyte cell lines from wild type and various IRS knockout (KO) animals and characterized insulin action in these cells in vitro. Preadipocytes derived from both wild type and IRS-2 KO mice could be fully differentiated into mature brown adipocytes. In differentiated IRS-2 KO adipocytes, insulin-induced glucose uptake was decreased by 50% compared with their wild type counterparts. This was the result of a decrease in insulin-stimulated Glut4 translocation to the plasma membrane. This decrease in insulin-induced glucose uptake could be partially reconstituted in these cells by retrovirus-mediated reexpression of IRS-2, but not overexpression of IRS-1. Insulin signaling studies revealed a total loss of IRS-2-associated phosphatidylinositol (PI) 3-kinase activity and a reduction in phosphotyrosine-associated PI 3-kinase by 30% (p < 0.05) in the KO cells. The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt-dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane. These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes. This occurs without effects in differentiation, total activation of Akt and its downstream effectors, but may be caused by alterations in compartmentalization of these downstream signals.

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Section: Discussionsupporting

confidence: 83%

Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes

Faßhauer¹,

Klein²,

Ueki³

et al. 2000

Journal of Biological Chemistry

158

124

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“…Previous work in 3T3-L1 adipocytes showed that interference with the IRS-1-IR interaction did not cause inhibition of insulin-stimulated glucose transport, suggesting that alternate pathways exist in these cells (46). More recently, Zhou et al (50) have shown that, in rat adipocytes, overexpression of high levels of IRS-1 as well as of IRS-2 increased basal and insulin-stimulated Glut4 levels in the plasma membranes indicating that both IRSs may signal Glut4 translocation when overexpressed in cells. Supramaximal IRS-2 phosphorylation or IRS-2 overexpression caused by IRS-1 deficiency may also be responsible for the residual insulin-stimulated glucose transport in soleus muscles of IRS-1 knock out mice (20).…”

Section: Discussionmentioning

confidence: 99%

“…At these low levels, overexpression of wild-type receptors in L6 as in other cells (22) is accompanied by little change in maximal insulin effects on most signaling events and cell responses. However, a 3-10-fold decrease in the ED 50 for insulin effect on IRS-1 and IRS-2 phosphorylation and on glycogen synthase activity and thymidine incorporation could be consistently detected (Table I). These cells express fully functional GLUT4 transporters (21,(23)(24)(25)(26)(27).…”

Section: Methodsmentioning

confidence: 99%

Differential Role of Insulin Receptor Substrate (IRS)-1 and IRS-2 in L6 Skeletal Muscle Cells Expressing the Arg1152 → Gln Insulin Receptor

Miele

Caruso

Calleja

et al. 1999

Journal of Biological Chemistry

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Insulin induces proliferative and metabolic responses in several different tissues (1). The biological effects of insulin in its target cells are initiated by binding and activating tyrosine kinase receptors (2), followed by phosphorylation of intracellular protein substrates (2, 3). The phosphorylated substrates, in turn, bind SH2 1 domain-containing proteins (2, 3) further propagating receptor signal into at least two major transduction routes. These pathways include the Ras/mitogen-activated protein kinase (MAP kinase) cascade and the PI 3-kinase system (2, 3), and convey insulin signal to the final cytoplasmic and nuclear effectors. Insulin receptor substrate-1 (IRS-1) is an important intracellular substrate for the insulin receptor kinase (3). IRS-1 features at least 7 tyrosine residues undergoing rapid phosphorylation upon insulin receptor activation (4) and providing binding sites for at least six distinct SH2 proteins (2-5). Tyrosine-phosphorylated IRS-1 binds the SH2 domain in the p85 regulatory subunit of PI 3-kinase (6, 7) inducing several metabolic responses (8, 9). Phosphorylated IRS-1 also interact with the Grb2⅐SOS complex, activating p21 ras , the MAP kinase cascade and mitogenesis (10

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“…IRS-2 was identified as a 190-kDa protein that is rapidly tyrosinephosphorylated in response to insulin and that partially compensates for the lack of IRS-1 in various insulin actions (20,22). For example, IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways, leading to the recruitment of GLUT4 (23). IRS-3 was first described in rat adipocytes as a 60-kDa protein that is rapidly tyrosine-phosphorylated in response to insulin, and it is considered to be a direct substrate of the activated insulin receptor (5,6,21,24 -26).…”

mentioning

confidence: 99%

Subcellular Localization of Insulin Receptor Substrate Family Proteins Associated With Phosphatidylinositol 3-Kinase Activity and Alterations in Lipolysis in Primary Mouse Adipocytes From IRS-1 Null Mice

et al. 2001

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To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. By contrast, tyrosine-phosphorylated IRS-3 (pp60), which was found to associate with PI 3-kinase, was predominantly localized in the PM fraction. In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (␣PY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. The level of isoproterenol-induced lipolysis was increased 5.1-fold in adipocytes from IRS-1 null mice as compared with wildtype mice. Moreover, hormone-sensitive lipase (HSL) protein was increased 4.3-fold in adipocytes from IRS-1-null mice compared with wild-type mice, and HSL mRNA expression was also increased. The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. Diabetes 50:1455-1463, 2001I nsulin stimulates the tyrosine phosphorylation (via the tyrosine kinase of the insulin receptor) of several endogenous substrates, such as insulin receptor substrate (IRS) family proteins, Grb2-associated binder-1, and Shc (1-11). These proteins interact through their phosphotyrosine residues with Src homology-2 (SH2) domain-containing proteins, such as the regulatory 85-kDa subunit (p85) of phosphatidylinositol (PI) 3-kinase, Grb2, Crk,. Among these, PI 3-kinase activity has been shown to be required for metabolic actions of insulin, such as glucose transport, glycogen synthesis, and antilipolysis (16 -18). The IRS family proteins IRS-1, -2, -3, and -4 contain a conserved pleckstrin homology (PH) domain and a phosphotyrosine-binding (PTB) domain that interacts with a phosphorylated NPXY motif in the insulin receptor at the NH 2 -terminus (3-9).IRS-1 has been shown to be the major substrate of the insulin receptor kinase, and we ...

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Insulin Receptor Substrate-2 (IRS-2) Can Mediate the Action of Insulin to Stimulate Translocation of GLUT4 to the Cell Surface in Rat Adipose Cells

Cited by 49 publications

References 38 publications

Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes

Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes

Differential Role of Insulin Receptor Substrate (IRS)-1 and IRS-2 in L6 Skeletal Muscle Cells Expressing the Arg1152 → Gln Insulin Receptor

Subcellular Localization of Insulin Receptor Substrate Family Proteins Associated With Phosphatidylinositol 3-Kinase Activity and Alterations in Lipolysis in Primary Mouse Adipocytes From IRS-1 Null Mice

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