Genomes and Genes
insulin receptor substrate 2
Gene Symbol: insulin receptor substrate 2
Description: insulin receptor substrate 2
Alias: 4PS, IRS-2, insulin receptor substrate 2, tyrosine kinase substrate
Products: insulin receptor substrate 2
- Ueno M, Carvalheira J, Tambascia R, Bezerra R, Amaral M, Carneiro E, et al. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia. 2005;48:506-18 pubmed..These findings support the hypothesis that defective and tissue-selective insulin action contributes to the insulin resistance observed in hyperinsulinaemic states. ..
- Choi S, Jang J, Park S. Estrogen and exercise may enhance beta-cell function and mass via insulin receptor substrate 2 induction in ovariectomized diabetic rats. Endocrinology. 2005;146:4786-94 pubmed..Regular moderate exercise eliminates the risk factors of contracting diabetes in the postmenopausal state. ..
- 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. ..
- Bueno M, Guadagnini D, Gonçalves F, Barini R, Saad M, Schmidt A, et al. Assessment of the expression of IR?, IRS-1, IRS-2 and IGF-IR? in a rat model of intrauterine growth restriction. Fetal Diagn Ther. 2010;28:145-52 pubmed publisher..IUGR fetuses had less glomeruli and alterations in insulin receptors, which may be associated with an increased risk of disease occurrence in adulthood. ..
- Aleem E, Nehrbass D, Klimek F, Mayer D, Bannasch P. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol. 2011;39:524-43 pubmed publisher..Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis. ..
- Chistyakova O, Sukhov I, Loshkareva M, Shipilov V, Bondareva V, Shpakov A. Initial stages of the insulin signaling system in the brain of rats with experimental diabetes mellitus. Bull Exp Biol Med. 2012;153:25-8 pubmed..These findings attest to involvement of the brain insulin signal pathway into the response to systemic insulin deficiency in type 1 diabetes mellitus. ..
- Bouzakri K, Zachrisson A, Al Khalili L, Zhang B, Koistinen H, Krook A, et al. siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metab. 2006;4:89-96 pubmed
- Zhou L, Cai X, Han X, Ji L. P38 plays an important role in glucolipotoxicity-induced apoptosis in INS-1 cells. J Diabetes Res. 2014;2014:834528 pubmed publisher..4) Inhibition of P38, but not JNK or ERK, blocked GLU+PA-induced INS-1 cell apoptosis. P38 may be involved in the regulation of glucolipotoxicity-induced apoptosis through the phosphorylation of IRS-2. ..
- Demozay D, Tsunekawa S, Briaud I, Shah R, Rhodes C. Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet ?-cells. Diabetes. 2011;60:2892-902 pubmed publisher..This insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass. ..
- Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat Cell Biol. 2004;6:351-7 pubmedb>Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signalling in the liver, controlling insulin sensitivity...
- Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs W, Wright C, et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002;110:1839-47 pubmed..We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts. ..
- Park S, Hong S, Lee J, Sung S. Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic beta-cell function and mass through IRS2 in diabetic rats. J Appl Physiol (1985). 2007;103:1764-71 pubmed..This study suggests that dietary fat contents and exercise modulate beta-cell function and mass to overcome insulin resistance in two different pathways. ..
- Freude S, Hettich M, Schumann C, Stöhr O, Koch L, Kohler C, et al. Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 2009;23:3315-24 pubmed publisher..However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD. ..
- Ozaki Y, Takeda T, Akanishi N, Hakuno F, Toyoshima Y, Takahashi S, et al. Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats. Biosci Biotechnol Biochem. 2014;78:130-8 pubmed publisher..In summary, we found that reduced insulin secretion during protein restriction directly increased hepatic IRS-2 as a rapid response on day 1, while additional mechanisms contributed to the upregulation of IRS-2 on day 7. ..
- Bu Y, Peng D, Zhou H, Huang Q, Liu W, Luo X, et al. Insulin receptor substrate 2 plays important roles in 17beta-estradiol-induced bone formation. J Endocrinol Invest. 2009;32:682-9 pubmed publisher..gene expression of 17beta-estradiol (E2)-treated osteoblast-like cells, and the effect of E2 on the insulin receptor substrate 2 (IRS- 2) expression in human cultured osteoblast-like cells and the osteoblasts of ovariectomized (OVX) ..
- 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. ..
- Carvalheira J, Calegari V, Zecchin H, Nadruz W, Guimarães R, Ribeiro E, et al. The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance. Endocrinology. 2003;144:5604-14 pubmed..Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats. ..
- Hugl S, Merger M. Prolactin stimulates proliferation of the glucose-dependent beta-cell line INS-1 via different IRS-proteins. JOP. 2007;8:739-52 pubmed..These results define prolactin as an important hormone. mediating glucose-dependent pancreatic beta-cell proliferation primarily by the activation of PI3'K-dependent signaling pathways. ..
- 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. ..
- 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. ..
- Kessler A, Uphues I, Ouwens D, Till M, Eckel J. Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. Am J Physiol Endocrinol Metab. 2001;280:E65-74 pubmed..Furthermore, multiple defects of PI 3-kinase activation, involving both the p85 alpha and the p85 beta adaptor subunits, may contribute to cardiac insulin resistance...
- Anderwald C, Müller G, Koca G, Fürnsinn C, Waldhausl W, Roden M. Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2. Mol Endocrinol. 2002;16:1612-28 pubmed..In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway. ..
- Okazawa K, Yoshimasa Y, Miyamoto Y, Takahashi Yasuno A, Miyawaki T, Masuzaki H, et al. The haplotypes of the IRS-2 gene affect insulin sensitivity in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2005;68:39-48 pubmed..This observation raises the possibility that both the IRS-2 D1057 allele and the CA haplotype are useful genetic markers for identifying obese individuals who are particularly susceptible to insulin resistance. ..
- Fukushima T, Yoshihara H, Furuta H, Kamei H, Hakuno F, Luan J, et al. Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. Nat Commun. 2015;6:6780 pubmed publisher..Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo. We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. ..
- Tao H, Wang M, Zhang M, Zhang S, Wang C, Yuan W, et al. MiR-126 Suppresses the Glucose-Stimulated Proliferation via IRS-2 in INS-1 Î² Cells. PLoS ONE. 2016;11:e0149954 pubmed publisher..MiR-126 may take part in the glucose homeostasis both through its target IRS-2 and IRS-1. The unbalance between IRS-1 and IRS-2 caused by miR-126 may play an important role in type 2 diabetes. ..
- Tsuji Y, Kaburagi Y, Terauchi Y, Satoh S, Kubota N, Tamemoto H, et al. 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. Diabetes. 2001;50:1455-63 pubmed
- 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. ..
- Neukamm S, Toth R, Morrice N, Campbell D, MacKintosh C, Lehmann R, et al. Identification of the amino acids 300-600 of IRS-2 as 14-3-3 binding region with the importance of IGF-1/insulin-regulated phosphorylation of Ser-573. PLoS ONE. 2012;7:e43296 pubmed publisher..To conclude, our data suggest a physiologically relevant role for IGF-1/insulin-dependent 14-3-3 binding to IRS-2 involving serine 573. ..
- Moloney A, Griffin R, Timmons S, O Connor R, Ravid R, O Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31:224-43 pubmed publisher..Our results show that IGF-1R and IR signalling is compromised in AD neurons and suggest that neurons that degenerate in AD may be resistant to IGF-1R/IR signalling. ..
- Lagarrigue S, Lopez Mejia I, Denechaud P, EscotÃ© X, Castillo Armengol J, Jimenez V, et al. CDK4 is an essential insulin effector in adipocytes. J Clin Invest. 2016;126:335-48 pubmed publisher..We determined that insulin activates the CCND3-CDK4 complex, which in turn phosphorylates insulin receptor substrate 2 (IRS2) at serine 388, thereby creating a positive feedback loop that maintains adipocyte insulin ..
- Pedr s I, Petrov D, Allgaier M, Sureda F, Barroso E, Beas Zarate C, et al. Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. Biochim Biophys Acta. 2014;1842:1556-66 pubmed publisher..Our results reinforce the hypothesis that the impairments in both insulin signaling and energy metabolism precede the development of AD amyloidogenesis...
- Lingohr M, Dickson L, Wrede C, McCuaig J, Myers M, Rhodes C. IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells. Mol Cell Endocrinol. 2003;204:85-99 pubmed..In contrast, glucose/IGF-1 induced Erk-1/-2 and p70S6K activation were unaffected by IRS-3. These data emphasize the importance of IRS-2/PI3K/PKB signal transduction for beta-cell growth and survival. ..
- 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. ..
- Mohanty S, Spinas G, Maedler K, Zuellig R, Lehmann R, Donath M, et al. Overexpression of IRS2 in isolated pancreatic islets causes proliferation and protects human beta-cells from hyperglycemia-induced apoptosis. Exp Cell Res. 2005;303:68-78 pubmed..In addition, IRS2 can improve beta-cell function. Our results indicate that IRS2 acts autonomously in beta-cells in maintenance and expansion of functional beta-cell mass in vivo. ..
- Podcheko A, Northcott P, Bikopoulos G, Lee A, Bommareddi S, Kushner J, et al. Identification of a WD40 repeat-containing isoform of PHIP as a novel regulator of beta-cell growth and survival. Mol Cell Biol. 2007;27:6484-96 pubmed..RNA interference knockdown of PHIP1 in INS-1 cells abrogates insulin receptor substrate 2 (IRS2)-mediated DNA synthesis, providing for a specific role for PHIP1 in the enhancement of IRS2-..
- Kumar M, Nath S, Prasad H, Sharma G, Li Y. MicroRNAs: a new ray of hope for diabetes mellitus. Protein Cell. 2012;3:726-38 pubmed publisher..In this review, we discuss the potential roles of different microRNAs in diabetes and diabetes-related complications. ..
- 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. ..
- Mammarella S, Romano F, Di Valerio A, Creati B, Esposito D, Palmirotta R, et al. Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. Hum Mol Genet. 2000;9:2517-21 pubmed..Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive weight. ..
- Tanioka T, Tamura Y, Fukaya M, Shinozaki S, Mao J, Kim M, et al. Inducible nitric-oxide synthase and nitric oxide donor decrease insulin receptor substrate-2 protein expression by promoting proteasome-dependent degradation in pancreatic beta-cells: involvement of glycogen synthase kinase-3beta. J Biol Chem. 2011;286:29388-96 pubmed publisher..Our findings suggest that iNOS-mediated decreased IRS-2 expression may contribute to the progression and/or exacerbation of ?-cell failure in diabetes. ..
- Astolphi R, Curbete M, Chiba F, Cintra L, Ervolino E, da Mota M, et al. Periapical Lesions Decrease Insulin Signaling in Rat Skeletal Muscle. J Endod. 2015;41:1305-10 pubmed publisher..IS was evaluated according to insulin receptor substrate (pp185-insulin receptor substrate 1 [IRS-1]/insulin receptor substrate 2 [IRS-2]) tyrosine phosphorylation status, IRS-1 serine phosphorylation status, and IRS-1 and IRS-2 ..
- Killick R, Scales G, Leroy K, Causevic M, Hooper C, Irvine E, et al. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem Biophys Res Commun. 2009;386:257-62 pubmed publisher..disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance...
- Hookham M, O Donovan H, Church R, Mercier Zuber A, Luzi L, Curran S, et al. Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy. FEBS J. 2013;280:3232-43 pubmed publisher..The specific up-regulation of IRS2 in the kidney tubules of DN patients also indicates a novel role for IRS2 as a marker and/or mediator of human DN progression. ..
- Li Y, Xu W, McBurney M, Longo V. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 2008;8:38-48 pubmed publisher..These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles. ..
- Pardini A, Nguyen H, Figlewicz D, Baskin D, Williams D, Kim F, et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 2006;1112:169-78 pubmed..An improved understanding of mechanisms underlying normal and abnormal energy homeostasis may be gained by analysis of the role played by signaling through IRS-2 in these brain areas. ..
- Bouzakri K, Ribaux P, Halban P. Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. J Biol Chem. 2009;284:27892-8 pubmed publisher..We thus identify MAP4K4 as a key upstream mediator of TNF-alpha action on the beta cell, making it a potential therapeutic target for preservation of beta cell function in type 2 diabetes. ..
- Cullingford T, Butler M, Marshall A, Tham E, Sugden P, Clerk A. Differential regulation of Krüppel-like factor family transcription factor expression in neonatal rat cardiac myocytes: effects of endothelin-1, oxidative stress and cytokines. Biochim Biophys Acta. 2008;1783:1229-36 pubmed publisher..The dynamic regulation of expression of multiple Klf family members in cardiac myocytes suggests that, as a family, they are actively involved in regulating phenotypic responses (hypertrophy and apoptosis) to extracellular stimuli. ..
- Fukushima T, Okajima H, Yamanaka D, Ariga M, Nagata S, Ito A, et al. HSP90 interacting with IRS-2 is involved in cAMP-dependent potentiation of IGF-I signals in FRTL-5 cells. Mol Cell Endocrinol. 2011;344:81-9 pubmed publisher..Taking together, we conclude that HSP90 interacting with IRS-2 mediates cAMP-dependent serine/threonine phosphorylation of IRS-2 via its chaperone activity, leading to potentiation of tyrosine phosphorylation of IRS-2 induced by IGF-I. ..
- Manu M, Rachana K, Advirao G. Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy. Neuropeptides. 2017;62:71-79 pubmed publisher..These findings prove that SCs and sciatic nerve express IRS proteins that are altered by diabetes and thereby insulin signaling downstream is impaired and that contribute to the pathogenesis of DPN. ..
- Kim J, Kido Y, Scherer P, White M, Accili D. Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. Am J Physiol Endocrinol Metab. 2007;292:E1694-701 pubmed..The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of beta-cell dysfunction in type 2 diabetes should positively affect both aspects of beta-cell physiology. ..
- Zhang J. The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J Biol Chem. 2007;282:34356-64 pubmed..Suppression of SirT1 activity also selectively inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 2 (IRS-2), whereas it had minimal effect on that of IRS-1...
- Zhu B, Li C, Pan Y, Zhang Y, Zeng Y, Xue Y. [Regulation of hepatic lipid metabolism by adiponectin via IRS-2 phosphorylation in OLETF rats]. Zhonghua Yi Xue Za Zhi. 2011;91:3134-8 pubmed..431, -0.396, -0.353, -0.349, P < 0.05). Adiponectin may affect the signaling pathway of hepatic insulin via tyrosine phosphorylation of IRS-2. It is involved in the regulation of hepatic lipid metabolism. ..