Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2

Copps, Kyle D.; White, Morris F.

doi:10.1007/s00125-012-2644-8

Cited by 847 publications

(733 citation statements)

References 177 publications

(303 reference statements)

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“…To test whether Hh activates Igf signaling, we monitored the phosphorylation of insulin receptor substrate 1 (Irs1) at S632/635 (equivalent of S636/639 in human IRS1), which is stimulated by insulin or Igf signaling (31). In keeping with the maximal induction of Igf2 at 48 h, PM notably increased both total-and phospho-Irs1 at 48 and 72 h (Fig.…”

Section: Resultsmentioning

confidence: 90%

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Shi¹,

Chen²,

Karner³

et al. 2015

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

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Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

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Section: Resultsmentioning

confidence: 90%

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Shi¹,

Chen²,

Karner³

et al. 2015

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

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“…FSH Activates PP1c␤ to Dephosphorylate Inhibitory IRS1 Ser/ Thr Residues-Extensive research has attributed the development of insulin resistance and type II diabetes to inhibitory Ser/Thr phosphorylations on IRS1 that impair both tyrosine phosphorylation of IRS1 by the insulin receptor and activation of downstream targets like PI3K (44,58). As a result, we asked whether FSH could be stimulating the dephosphorylation of inhibitory Ser/Thr residues within IRS1 to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R.…”

Section: Fsh and Igf-1 Do Not Intersect Through A Tyrosinementioning

confidence: 99%

Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation

Law

Hunzicker-Dunn

2016

Journal of Biological Chemistry

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The ubiquitous phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)-dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, granulosa cells secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser 789 . Knockdown of PP1␤ blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through protein kinase B (AKT) and FOXO1 (forkhead box protein O1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT.The phosphatidylinositol-3 kinase (PI3K) signaling pathway regulates transcription, translation, proliferation, and apoptosis (1, 2). Whereas PI3K is classically activated by receptor tyrosine kinases, such as the insulin-like growth factor-1 receptor (IGF-1R), 2 PI3K is also activated in many cells by G-proteincoupled receptors (GPCRs). However, the mechanisms by which GPCRs signal to activate PI3K are much less understood compared with classical activation by receptor tyrosine kinases (1). We have used rat ovarian granulosa cells (GCs) as a model to elucidate the mechanism by which the GPCR agonist folliclestimulating hormone (FSH) activates PI3K, based on prior evidence that FSH activates PI3K in a protein kinase A (PKA)-dependent manner (3). FSH is an obligatory regulator of ovarian follicle maturation. During the menstrual cycle, preantral follicles that encompass developing oocytes mature to a preovulatory stage in response to elevated levels of FSH (4). Administration of exogenous FSH also restores follicle development in anovulatory women (5). Finally, mice harboring null alleles for either the FSH receptor or FSH␤ lack preovulatory follicles and are infertile (6, 7). Traditionally, FSH has thus been considered both necessary and sufficient to promote follicle maturation.FSH acts exclusively on GCs wit...

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“…Indeed, S6K1 participates in insulinmediated cell growth but-like mTORC1-also operates negative feedback loops at various levels of regulation. For example, several studies have shown that both mTORC1 and/or S6K1 phosphorylate specific serine residues on IRS proteins [6,7]. Moreover, some of these IRS-1 sites, notably Ser 1101 and Ser 636, were differentially regulated by mTOR and S6K1 [8,9].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2

Cited by 847 publications

References 177 publications

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

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