Gene Symbol: Irs1
Description: insulin receptor substrate 1
Alias: IRS1IRM, insulin receptor substrate 1, IRS-1, pp185
Species: rat
Products:     Irs1

Top Publications

  1. Usui I, Imamura T, Huang J, Satoh H, Shenoy S, Lefkowitz R, et al. beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol Cell Biol. 2004;24:8929-37 pubmed
    ..In the present study, we determined whether beta-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation...
  2. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology. 2005;146:1473-81 pubmed
    ..In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity. ..
  3. Skolnik E, Lee C, Batzer A, Vicentini L, Zhou M, Daly R, et al. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J. 1993;12:1929-36 pubmed
    ..These interactions may play a crucial role in activation of p21ras and the control of downstream effector molecules. ..
  4. Backer J, Myers M, Shoelson S, Chin D, Sun X, Miralpeix M, et al. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992;11:3469-79 pubmed
    ..We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. ..
  5. Hakuno F, Kurihara S, Watson R, Pessin J, Takahashi S. 53BP2S, interacting with insulin receptor substrates, modulates insulin signaling. J Biol Chem. 2007;282:37747-58 pubmed
    ..Together these data demonstrate that 53BP2S interacts and modulates the insulin signals mediated by IRSs. ..
  6. Pirola L, Bonnafous S, Johnston A, Chaussade C, Portis F, Van Obberghen E. Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. J Biol Chem. 2003;278:15641-51 pubmed
    ..In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. ..
  7. Walker R, Anderson N, BAHOUTH S, Steinle J. Silencing of insulin receptor substrate-1 increases cell death in retinal Müller cells. Mol Vis. 2012;18:271-9 pubmed
    ..These findings also suggest the importance of IRS-1 in beta-adrenergic receptor signaling in the prevention of cell death in retinal Müller cells. ..
  8. Aguirre V, Werner E, Giraud J, Lee Y, Shoelson S, White M. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531-7 pubmed
    ..These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. ..
  9. Yan X, Li W, Li Q, Li N, Li J. [Nuclear factor kappa B impairs insulin signaling pathway in skeletal muscle cells of rat with sepsis]. Zhonghua Wai Ke Za Zhi. 2009;47:1257-60 pubmed
    ..But the activity of NF-kappaB in skeletal muscle cells is obviously enhanced, and it is closely related with disorder of insulin signaling in skeletal muscle cells of rat with sepsis. ..

More Information


  1. Jiang Y, Wu G. [Research of the relationship between insulin signal transduction and glucose transportation in rats after trauma]. Zhonghua Wai Ke Za Zhi. 2009;47:214-7 pubmed
    ..Uncoupling of signal transduction led to decrease in glucose uptake which associated with a defect in insulin-stimulated glucose transport and GLUT-4 translocation. ..
  2. Melemedjian O, Khoutorsky A, Sorge R, Yan J, Asiedu M, Valdez A, et al. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain. 2013;154:1080-91 pubmed publisher
    ..the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop...
  3. Ola M. Effect of hyperglycemia on insulin receptor signaling in the cultured retinal Müller glial cells. Biochem Biophys Res Commun. 2014;444:264-9 pubmed publisher
    ..cell lysates were analyzed by immunoblotting experiments for insulin receptor (IR?) and insulin receptor substrate (IRS1)...
  4. Hirata A, Alvarez Rojas F, Carvalheira J, Carvalho C, Dolnikoff M, Abdalla Saad M. Modulation of IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of MSG-rats. Life Sci. 2003;73:1369-81 pubmed
    ..In 28-week-old-MSG rats there was an increase in IR/PTP1B interaction and reduced insulin signaling in liver, muscle and adipocytes, and a more pronounced insulin resistance. ..
  5. Hayashi K, Shibata K, Morita T, Iwasaki K, Watanabe M, Sobue K. Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells. J Biol Chem. 2004;279:40807-18 pubmed
  6. Lee A, Hakuno F, Northcott P, Pessin J, Rozakis Adcock M. Nexilin, a cardiomyopathy-associated F-actin binding protein, binds and regulates IRS1 signaling in skeletal muscle cells. PLoS ONE. 2013;8:e55634 pubmed publisher
    ..Previous studies in L6 skeletal muscle cells have shown that insulin-induced activation and assembly of insulin receptor substrate 1 (IRS1) and p85? the regulatory subunit of the Type 1A phosphatidylinositol-3-kinase (PI3K), within ..
  7. Mincione G, Esposito D, Di Marcantonio M, Piccirelli A, Cama A, Colletta G. TGF-beta 1 modulation of IGF-I signaling pathway in rat thyroid epithelial cells. Exp Cell Res. 2003;287:411-23 pubmed
    ..TGF-beta 1 affected IGF-I-stimulated insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with Grb2 protein...
  8. Qu W, Hao L, Chen Y, Zhou S. [Effect of chronic ethanol intake on insulin receptor, insulin receptor subsrate-1 and phosphoinositide 3-kinase mRNA expression in skeletal muscle of rats]. Wei Sheng Yan Jiu. 2007;36:172-5 pubmed
    ..05). The present results suggested that chronic ethanol intake could induce insulin resistance and down-regulated the expression of IR, IRS-land PI-3K mRNA in skeletal muscle could be the molecular mechanism. ..
  9. Khamzina L, Gruppuso P, Wands J. Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. Gastroenterology. 2003;125:572-85 pubmed
    ..However, insulin-mediated IRS-1/MAPK cascade activation contributes to growth in the adult. ..
  10. Andreozzi F, D Alessandris C, Federici M, Laratta E, Del Guerra S, Del Prato S, et al. Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cel. Endocrinology. 2004;145:2845-57 pubmed
    ..These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. ..
  11. Kho M, Lee Y, Park J, Kim H, Yoon J, Ahn Y, et al. Fermented Red Ginseng Potentiates Improvement of Metabolic Dysfunction in Metabolic Syndrome Rat Models. Nutrients. 2016;8: pubmed publisher
    ..In addition, FRG induced markedly upregulation of Insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (Glut4) in the muscle...
  12. Ropelle E, Pauli J, Prada P, De Souza C, Picardi P, Faria M, et al. Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol. 2006;577:997-1007 pubmed
    ..In addition, DIO was observed to lead to serine phosphorylation of insulin receptor substrate 1 (IRS-1), which was also reversed by exercise in muscle in parallel with a reduction in c-Jun N-terminal ..
  13. Klammt J, Garten A, Barnikol Oettler A, Beck Sickinger A, Kiess W. Comparative analysis of the signaling capabilities of the insulin receptor-related receptor. Biochem Biophys Res Commun. 2005;327:557-64 pubmed
    ..The reestablishment of autophosphorylation was paralleled by restoration of interaction with a specific range of signaling molecules. ..
  14. Rothenberg P, Lane W, Karasik A, Backer J, White M, Kahn C. Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase. J Biol Chem. 1991;266:8302-11 pubmed
    Insulin stimulates the tyrosine phosphorylation of a 185-kDa putative cytosolic substrate protein (pp185) in diverse cell types...
  15. Liberman Z, Eldar Finkelman H. Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. J Biol Chem. 2005;280:4422-8 pubmed
    ..In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. ..
  16. Fischer H, Sie C, Schumann E, Witte A, Dressel R, van den Brandt J, et al. The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity. J Immunol. 2017;198:1910-1920 pubmed publisher
    ..Taken together, our results suggest that upregulation of the INSR on T cells following activation is required for efficient adaptive immunity. ..
  17. Li B, Wang Y, Liu Y, Ma J, Li Y. Altered gene expression involved in insulin signaling pathway in type II diabetic osteoporosis rats model. Endocrine. 2013;43:136-46 pubmed publisher
  18. Nyman E, Fagerholm S, Jullesson D, Stralfors P, Cedersund G. Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes. FEBS J. 2012;279:987-99 pubmed publisher
    Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells...
  19. Rajala R, Chan M. Identification of a NPXY motif in growth factor receptor-bound protein 14 (Grb14) and its interaction with the phosphotyrosine-binding (PTB) domain of IRS-1. Biochemistry. 2005;44:7929-35 pubmed
    ..This is the first report describing the presence of the NPXY motif in Grb14 and binding of the PTB domain of IRS-1 in a phosphorylation-independent manner. ..
  20. 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. ..
  21. Miele C, Riboulet A, Maitan M, Oriente F, Romano C, Formisano P, et al. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. J Biol Chem. 2003;278:47376-87 pubmed
    ..In summary, in L6 skeletal muscle cells, exposure to HGA leads to insulin resistance selectively in glucose metabolism with no effect on growth-related pathways regulated by the hormone. ..
  22. D Alessandris C, Lauro R, Presta I, Sesti G. C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser 612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport. Diabetologia. 2007;50:840-9 pubmed
  23. He W, O Neill T, Gustafson T. Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non-SH2 domains. J Biol Chem. 1995;270:23258-62 pubmed
    b>Insulin receptor substrate 1 (IRS-1) and src homology and collagen protein (SHC) are signaling proteins which are rapidly phosphorylated on tyrosines after insulin receptor (IR) activation...
  24. Jensen M, Hansen B, De Meyts P, Schäffer L, Ursø B. Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses. J Biol Chem. 2007;282:35179-86 pubmed
    ..We show for the first time that it is possible to design insulin receptor ligand mimetics with metabolic equipotency but low mitogenicity. ..
  25. Sourbier C, Scroggins B, Ratnayake R, Prince T, Lee S, Lee M, et al. Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell. 2013;23:228-37 pubmed publisher
    ..By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors. ..
  26. Band C, Posner B, Dumas V, Contreres J. Early signaling events triggered by peroxovanadium [bpV(phen)] are insulin receptor kinase (IRK)-dependent: specificity of inhibition of IRK-associated protein tyrosine phosphatase(s) by bpV(phen). Mol Endocrinol. 1997;11:1899-910 pubmed
  27. Jensen J, Grønning Wang L, Jebens E, Whitehead J, Zorec R, Shepherd P. Adrenaline potentiates insulin-stimulated PKB activation in the rat fast-twitch epitrochlearis muscle without affecting IRS-1-associated PI 3-kinase activity. Pflugers Arch. 2008;456:969-78 pubmed publisher
    ..These results indicate that the combination of adrenaline and insulin may activate novel signalling molecules rather than just summing up their effects on linear pathways. ..
  28. Tan Y, Liu J, Deng Y, Cao H, Xu D, Cu F, et al. Caffeine-induced fetal rat over-exposure to maternal glucocorticoid and histone methylation of liver IGF-1 might cause skeletal growth retardation. Toxicol Lett. 2012;214:279-87 pubmed publisher
    ..Taken together, these results raise important concerns regarding the skeletal growth toxicity of caffeine and potentially indicate the intrauterine origins of adult osteoporosis and osteoarthritis. ..
  29. Taniyama Y, Hitomi H, Shah A, Alexander R, Griendling K. Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol. 2005;25:1142-7 pubmed
    ..These events impair insulin signaling and provide a molecular basis for understanding the clinical observation that angiotensin II type 1 receptor antagonists improve insulin resistance and its associated vasculopathies. ..
  30. Kang S, Chemaly E, Hajjar R, Lebeche D. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem. 2011;286:18465-73 pubmed publisher
    ..Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module ..
  31. Baroni M, D Andrea M, Montali A, Pannitteri G, Barilla F, Campagna F, et al. A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 1999;19:2975-80 pubmed
    ..Besides the increased frequency of diabetes, carriers showed a more atherogenic lipid profile, suggesting a potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities associated with CAD. ..
  32. Lima M, Ueno M, Thirone A, Rocha E, Carvalho C, Saad M. Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. Endocrine. 2002;18:1-12 pubmed
  33. O BRIEN K, Sekimoto H, Boney C, Malee M. Effect of fetal dexamethasone exposure on the development of adult insulin sensitivity in a rat model. J Matern Fetal Neonatal Med. 2008;21:623-8 pubmed publisher
    ..This effect did not appear to be enhanced by administration of insulin prior to sacrifice, nor was a sex-dependent differential effect noted. ..
  34. Long Smith C, Manning S, McClean P, Coakley M, O Halloran D, Holscher C, et al. The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-? plaque and glial pathology in a mouse model of Alzheimer's disease. Neuromolecular Med. 2013;15:102-14 pubmed publisher
  35. Clausen J, Hansen T, Bjørbaek C, Echwald S, Urhammer S, Rasmussen S, et al. Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet. 1995;346:397-402 pubmed
    ..0008). Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders. ..
  36. Tu X, Baffa R, Luke S, Prisco M, Baserga R. Intracellular redistribution of nuclear and nucleolar proteins during differentiation of 32D murine hemopoietic cells. Exp Cell Res. 2003;288:119-30 pubmed
    ..This nucleo-cytoplasmic shuttle may play a significant role in the changes in gene expression that occur during differentiation. ..
  37. Radhakrishnan Y, Busby W, Shen X, Maile L, Clemmons D. Insulin-like growth factor-I-stimulated insulin receptor substrate-1 negatively regulates Src homology 2 domain-containing protein-tyrosine phosphatase substrate-1 function in vascular smooth muscle cells. J Biol Chem. 2010;285:15682-95 pubmed publisher
    ..We conclude that IRS-1 is an important factor for maintaining VSMCs in the non-proliferative state and that its down-regulation is a component of the VSMC response to hyperglycemic stress that results in an enhanced response to IGF-I. ..
  38. Franch H, Raissi S, Wang X, Zheng B, Bailey J, Price S. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Am J Physiol Renal Physiol. 2004;287:F700-6 pubmed
    ..We conclude that acidosis accelerates protein degradation by impairing insulin signaling through PI3K in muscle cells. ..
  39. Barakat G, Moustafa M, Bikhazi A. Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. Biochem Genet. 2012;50:922-35 pubmed publisher
    ..Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. ..
  40. Waraich R, Weigert C, Kalbacher H, Hennige A, Lutz S, Haring H, et al. Phosphorylation of Ser357 of rat insulin receptor substrate-1 mediates adverse effects of protein kinase C-delta on insulin action in skeletal muscle cells. J Biol Chem. 2008;283:11226-33 pubmed publisher
    ..Together, these data suggest that phosphorylation of Ser(357) mediates at least in part the adverse effects of PKC-delta activation on insulin action. ..
  41. Esposito D, Li Y, Vanni C, Mammarella S, Veschi S, Della Loggia F, et al. A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling. J Clin Endocrinol Metab. 2003;88:1468-75 pubmed
    ..Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the ..
  42. Argetsinger L, Hsu G, Myers M, Billestrup N, White M, Carter Su C. Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. J Biol Chem. 1995;270:14685-92 pubmed
    ..In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor...
  43. Picha K, Patel S, Mandiyan S, Koehn J, Wennogle L. The role of the C-terminal domain of protein tyrosine phosphatase-1B in phosphatase activity and substrate binding. J Biol Chem. 2007;282:2911-7 pubmed
    ..A compound that is able to make contacts with the C-terminal domain of PTP-1B would not only have a modest improvement in affinity but may also provide for specificity over other phosphatases. ..
  44. Matsunami T, Sato Y, Ariga S, Sato T, Shimomura T, Kashimura H, et al. Regulation of synthesis and oxidation of fatty acids by adiponectin receptors (AdipoR1/R2) and insulin receptor substrate isoforms (IRS-1/-2) of the liver in a nonalcoholic steatohepatitis animal model. Metabolism. 2011;60:805-14 pubmed publisher
    ..Thus, AdipoR and IRS might be crucially important regulators for the synthesis and oxidation of fatty acids in the liver of NASH. ..
  45. Zheng Y, Zhang W, Pendleton E, Leng S, Wu J, Chen R, et al. Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6K activities in the liver of obese Zucker rats. J Endocrinol. 2009;203:337-47 pubmed publisher
    ..The aim of this study is to test the hypothesis that changes in the activity of IRS1 serine/threonine kinases may underlie the molecular mechanism of CR in improving insulin sensitivity...
  46. Skolnik E, Batzer A, Li N, Lee C, Lowenstein E, Mohammadi M, et al. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 1993;260:1953-5 pubmed
  47. Hitomi H, Kiyomoto H, Nishiyama A, Hara T, Moriwaki K, Kaifu K, et al. Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension. 2007;50:750-5 pubmed
  48. GERENA Y, Skolasky R, Velez J, Toro Nieves D, Mayo R, Nath A, et al. Soluble and cell-associated insulin receptor dysfunction correlates with severity of HAND in HIV-infected women. PLoS ONE. 2012;7:e37358 pubmed publisher
    ..Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND. ..
  49. Morris E, Whaley Connell A, Thyfault J, Britton S, Koch L, Wei Y, et al. Low aerobic capacity and high-fat diet contribute to oxidative stress and IRS-1 degradation in the kidney. Am J Nephrol. 2009;30:112-9 pubmed publisher
    ..Our data support that HFD-mediated kidney ROS is associated with reductions in IRS-1 and systemic insulin resistance. Further, high intrinsic aerobic capacity protects against IRS-1 degradation in the kidney following exposure to HFD. ..
  50. Gonzalez C, Alonso A, Fernandez R, Patterson A. Regulation of insulin receptor substrate-1 in the liver, skeletal muscle and adipose tissue of rats throughout pregnancy. Gynecol Endocrinol. 2003;17:187-97 pubmed