Genomes and Genes
Gene Symbol: Irs1
Description: insulin receptor substrate 1
Alias: G972R, IRS-1, insulin receptor substrate 1
- Li Y, Soos T, Li X, Wu J, Degennaro M, Sun X, et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J Biol Chem. 2004;279:45304-7 pubmedObesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes...
- Selman C, Partridge L, Withers D. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS ONE. 2011;6:e16144 pubmed publisherWe previously reported that global deletion of insulin receptor substrate protein 1 (Irs1) extends lifespan and increases resistance to several age-related pathologies in female mice...
- Selman C, Lingard S, Choudhury A, Batterham R, Claret M, Clements M, et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 2008;22:807-18 pubmed..Our provisional results indicate that female Irs1-/- mice are long-lived...
- Kubota N, Kubota T, Itoh S, Kumagai H, Kozono H, Takamoto I, et al. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab. 2008;8:49-64 pubmed publisherInsulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis...
- Hadsell D, Olea W, Lawrence N, George J, Torres D, Kadowaki T, et al. Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt. J Endocrinol. 2007;194:327-36 pubmed..metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either the Irs1 or Irs2 genes...
- Kulkarni R, Almind K, Goren H, Winnay J, Ueki K, Okada T, et al. Impact of genetic background on development of hyperinsulinemia and diabetes in insulin receptor/insulin receptor substrate-1 double heterozygous mice. Diabetes. 2003;52:1528-34 pubmed
- Farhang Fallah J, Yin X, Trentin G, Cheng A, Rozakis Adcock M. Cloning and characterization of PHIP, a novel insulin receptor substrate-1 pleckstrin homology domain interacting protein. J Biol Chem. 2000;275:40492-7 pubmed..We conclude that PHIP represents a novel protein ligand of the IRS-1 PH domain that may serve to link IRS-1 to the insulin receptor. ..
- Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, et al. Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading. Mol Cell Biol. 2009;29:4798-811 pubmed publisher..The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy. ..
- Potashnik R, Bloch Damti A, Bashan N, Rudich A. IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Diabetologia. 2003;46:639-48 pubmed..rat hepatoma cells (FAO) were exposed to micro-molar H(2)O(2) by adding glucose oxidase to the culture medium, and IRS1 content, its serine phosphorylation and downstream metabolic insulin effects were measured...
- Hiratani K, Haruta T, Tani A, Kawahara J, Usui I, Kobayashi M. Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1. Biochem Biophys Res Commun. 2005;335:836-42 pubmed
- Ueki K, Kondo T, Kahn C. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24:5434-46 pubmed..These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling. ..
- Werner E, Lee J, Hansen L, Yuan M, Shoelson S. Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem. 2004;279:35298-305 pubmed
- Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372:182-6 pubmed..They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs. ..
- Hennige A, Ozcan U, Okada T, Jhala U, Schubert M, White M, et al. Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells. Am J Physiol Endocrinol Metab. 2005;289:E337-46 pubmed
- Wei D, Tao R, Zhang Y, White M, Dong X. Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1. Am J Physiol Endocrinol Metab. 2011;300:E312-20 pubmed publisher..Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control. ..
- Lin X, Taguchi A, Park S, Kushner J, Li F, Li Y, et al. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest. 2004;114:908-16 pubmed..Thus, Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice. ..
- Murata Y, Tsuruzoe K, Kawashima J, Furukawa N, Kondo T, Motoshima H, et al. IRS-1 transgenic mice show increased epididymal fat mass and insulin resistance. Biochem Biophys Res Commun. 2007;364:301-7 pubmed..Our results suggest that excess IRS-1 expression may not provide a beneficial impact on glucose homeostasis in vivo. ..
- Li L, Qi X, Williams M, Shi Y, Keegan A. Overexpression of insulin receptor substrate-1, but not insulin receptor substrate-2, protects a T cell hybridoma from activation-induced cell death. J Immunol. 2002;168:6215-23 pubmed..1, which is IL-4 responsive but lacks expression of IRS family members with cDNA encoding IRS1 or IRS2...
- Kulkarni R, Jhala U, Winnay J, Krajewski S, Montminy M, Kahn C. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest. 2004;114:828-36 pubmed..This study shows that, in postdevelopmental states of beta cell growth, PDX-1 is a critical regulator of beta cell replication and is required for the compensatory response to insulin resistance. ..
- Long Y, Cheng Z, COPPS K, White M. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol. 2011;31:430-41 pubmed publisher..in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle...
- Kulkarni R, Winnay J, Daniels M, Bruning J, Flier S, Hanahan D, et al. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest. 1999;104:R69-75 pubmed..This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. ..
- Dong X, Park S, Lin X, Copps K, Yi X, White M. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest. 2006;116:101-14 pubmedInsulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism...
- Xue B, Kim Y, Lee A, Toschi E, Bonner Weir S, Kahn C, et al. Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. J Biol Chem. 2007;282:23829-40 pubmed..Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes. ..
- Kerouz N, Hörsch D, Pons S, Kahn C. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest. 1997;100:3164-72 pubmed
- Terauchi Y, Iwamoto K, Tamemoto H, Komeda K, Ishii C, Kanazawa Y, et al. Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. Genetic reconstitution of diabetes as a polygenic disease. J Clin Invest. 1997;99:861-6 pubmed..In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice. ..
- Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, et al. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes. 2000;49:1880-9 pubmed..These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells. ..
- Giraud J, Leshan R, Lee Y, White M. Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem. 2004;279:3447-54 pubmed..Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. ..
- Guo S, COPPS K, Dong X, Park S, Cheng Z, Pocai A, et al. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol. 2009;29:5070-83 pubmed publisherWe used a Cre-loxP approach to generate mice with varied expression of hepatic Irs1 and Irs2 to establish the contribution of each protein to hepatic nutrient homeostasis...
- Duan C, Li M, Rui L. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. J Biol Chem. 2004;279:43684-91 pubmed..that SH2-B, a JAK2-interacting protein, promotes activation of the PI 3-kinase pathway by recruiting insulin receptor substrate 1 (IRS1) and IRS2 in response to leptin...
- Schubert M, Brazil D, Burks D, Kushner J, Ye J, Flint C, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003;23:7084-92 pubmed..of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth...
- Withers D, Burks D, Towery H, Altamuro S, Flint C, White M. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet. 1999;23:32-40 pubmed..We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes...
- Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391:900-4 pubmed..Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes. ..
- Araki E, Lipes M, Patti M, Bruning J, Haag B, Johnson R, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372:186-90 pubmed..Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases. ..
- Lassak A, Del Valle L, Peruzzi F, Wang J, Enam S, Croul S, et al. Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen. J Biol Chem. 2002;277:17231-8 pubmedb>Insulin receptor substrate 1 (IRS-1) is the major signaling molecule for the insulin and insulin-like growth factor I receptors, which transduces both metabolic and growth-promoting signals, and has transforming properties when ..
- Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011;13:294-307 pubmed publisher..Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance. ..
- Dong X, COPPS K, Guo S, Li Y, Kollipara R, Depinho R, et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008;8:65-76 pubmed publisher..dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice)...
- Bruning J, Winnay J, Bonner Weir S, Taylor S, Accili D, Kahn C. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997;88:561-72 pubmed
- Bruning J, Michael M, Winnay J, Hayashi T, Hörsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2:559-69 pubmed..Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type 2 diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized. ..
- Longato L, de la Monte S, Kuzushita N, Horimoto M, Rogers A, Slagle B, et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology. 2009;49:1935-43 pubmed publisher..However, dual expression that activates both the IN/IRS-1/MAPK and Wnt/beta-catenin cascades is sufficient to cause dysplasia and HCC in a previously normal liver. ..
- Foukas L, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, et al. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature. 2006;441:366-70 pubmed..These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers. ..
- Cassese A, Esposito I, Fiory F, Barbagallo A, Paturzo F, Mirra P, et al. In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs. J Biol Chem. 2008;283:36088-99 pubmed publisher..These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKCalpha. ..
- Matsuda K, Araki E, Yoshimura R, Tsuruzoe K, Furukawa N, Kaneko K, et al. Cell-specific regulation of IRS-1 gene expression: role of E box and C/EBP binding site in HepG2 cells and CHO cells. Diabetes. 1997;46:354-62 pubmedb>Insulin receptor substrate 1 (IRS-1) is one of the major substrates of insulin receptor tyrosine kinase and mediates multiple insulin signals downstream. We have previously shown that the levels of IRS-1 mRNA varied in different tissues...
- Tobe K, Tamemoto H, Yamauchi T, Aizawa S, Yazaki Y, Kadowaki T. Identification of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrate-1. J Biol Chem. 1995;270:5698-701 pubmed
- Zhang Z, Turer E, Li X, Zhan X, Choi M, Tang M, et al. Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. Proc Natl Acad Sci U S A. 2016;113:E6418-E6426 pubmed..than in wild-type adipocytes, and excessive p110-free p85Î± blocked the binding of p85Î±-p110 heterodimers to IRS1, interrupting the insulin signal...
- Ishizuka K, Usui I, Kanatani Y, Bukhari A, He J, Fujisaka S, et al. Chronic tumor necrosis factor-alpha treatment causes insulin resistance via insulin receptor substrate-1 serine phosphorylation and suppressor of cytokine signaling-3 induction in 3T3-L1 adipocytes. Endocrinology. 2007;148:2994-3003 pubmed..Chronic TNFalpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes. ..
- Araki E, Haag B, Kahn C. Cloning of the mouse insulin receptor substrate-1 (IRS-1) gene and complete sequence of mouse IRS-1. Biochim Biophys Acta. 1994;1221:353-6 pubmed..The highly conserved nature of IRS-1 suggests the importance of these domains in the function of IRS-1 or its association with other proteins. ..
- Huang C, Thirone A, Huang X, Klip A. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J Biol Chem. 2005;280:19426-35 pubmed
- Cleasby M, Reinten T, Cooney G, James D, Kraegen E. Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Mol Endocrinol. 2007;21:215-28 pubmed..Consistent with Akt-mediated insulin receptor substrate 1 (IRS-1) degradation, we observed approximately 30% reductions in IRS-1 protein in muscle overexpressing ..
- Gazdag A, Dumke C, Kahn C, Cartee G. Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. Diabetes. 1999;48:1930-6 pubmed
- Li Q, Hosaka T, Harada N, Nakaya Y, Funaki M. Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. Mol Cell Endocrinol. 2013;365:25-35 pubmed publisher..Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. ..
- Zhu D, Shi S, Wang H, Liao K. Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J Cell Sci. 2009;122:2760-8 pubmed publisher..During cilium formation, insulin receptor substrate 1 (IRS-1), one of the important downstream signaling molecules of the IGF-1 receptor, was recruited to ..
- Miranda C, Greco A, Miele C, Pierotti M, Van Obberghen E. IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. J Cell Physiol. 2001;186:35-46 pubmed..On the whole, our results suggest that IRS-1 and IRS-2 could be substrates of TRK-T1 and TrkA, and hence could participate in their signal generation. ..
- Kubota N, Kubota T, Kajiwara E, Iwamura T, Kumagai H, Watanabe T, et al. Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity. Nat Commun. 2016;7:12977 pubmed publisher..Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver...
- Sun H, Baserga R. The role of insulin receptor substrate-1 in transformation by v-src. J Cell Physiol. 2008;215:725-32 pubmed..Taken together, these results indicate a significant role of IRS-1 in the activation of cell cycle progression genes and transformation of cells by v-src. ..
- Terauchi Y, Kubota N, Tamemoto H, Sakura H, Nagai R, Akanuma Y, et al. Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes. Diabetes. 2000;49:82-6 pubmed..Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes. ..
- Ueno H, Sakita Ishikawa M, Morikawa Y, Nakano T, Kitamura T, Saito M. A stromal cell-derived membrane protein that supports hematopoietic stem cells. Nat Immunol. 2003;4:457-63 pubmed..These results contribute to our understanding of the mechanisms by which the hematopoietic microenvironment regulates hematopoiesis. ..
- Harrington L, Findlay G, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166:213-23 pubmed..Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors. ..
- Ko W, Liu T, Cheng J, Tzeng T, Liu I. Effect of opioid mu-receptors activation on insulin signals damaged by tumor necrosis factor alpha in myoblast C2C12 cells. Neurosci Lett. 2006;397:274-8 pubmed..In conclusion, activation of opioid mu-receptors may reverse the insulin signals damaged by inflammatory cytokine. ..
- Liu H, Wen G, Han J, Hong T, Zhuo D, Liu Z, et al. Inhibition of gluconeogenesis in primary hepatocytes by stromal cell-derived factor-1 (SDF-1) through a c-Src/Akt-dependent signaling pathway. J Biol Chem. 2008;283:30642-9 pubmed publisher..Together, our results demonstrate that SDF-1 is capable of inhibiting gluconeogenesis in primary hepatocytes through a signaling pathway distinct from the insulin signaling. ..
- Heckman B, Chakravarty G, Vargo Gogola T, Gonzales Rimbau M, Hadsell D, Lee A, et al. Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development. Dev Biol. 2007;309:137-49 pubmed..These results indicate that IGF signaling through p190-B and IRS proteins is critical for mammary bud formation and ensuing epithelial-mesenchymal interactions necessary to sustain mammary bud morphogenesis. ..
- Le H, Ponniah S, Pallen C. Insulin signaling and glucose homeostasis in mice lacking protein tyrosine phosphatase alpha. Biochem Biophys Res Commun. 2004;314:321-9 pubmed..Our data indicate that PTPalpha is not a negative regulator of insulin signaling and does not perform an essential role in mediating the physiological action of insulin. ..