IRS2 (insulin receptor substrate 2)
2016-05-01 Joao Agostinho Machado-Neto, PhD , Paula de Melo Campos , Fabiola Traina AffiliationAbstract
Insulin receptor substrate 2 (IRS2) belongs to the insulin receptor substrate protein family and was initially discovered as an alternative route for signaling mediated by the insulin receptor. Currently, IRS2 has been well-established to mediate mitogenic and antiapoptotic signaling from several important cellular receptors. In the last years, many studies have indicated that IRS2 participates in the regulation of important biological processes involved in cancer phenotype, including cell proliferation, clonogenicity, metabolism and survival. The present review contains data on IRS2 DNA\/RNA, protein encoded and function.
DNA/RNA
Description
IRS2 was discovered as an alternative route from signaling mediated by the insulin receptor in Irs1 knockout mice (Patti, et al. 1995). The entire IRS2 gene is approximately 33.8 Kb (start: 109752698 and end: 109786568 bp; orientation: Minus strand) and contains 2 exons. The IRS2 cDNA contains 7 Kb.
Proteins
Figure 1. Schematic structure of IRS2. The pleckstrin homology (PH) domain (purple), phosphotyrosine binding (PTB) domain (green) and kinase regulatory loop binding domain (KRLB) are illustrated in the Figure. Amino acid (aa) positions are indicated.
Description
IRS2 belongs to the insulin receptor substrate (IRS) protein family, which is characterized by the presence of a pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain (Figure 1) in their protein structure. The PH domain contributes to protein-protein binding and facilitates the recruitment of IRS proteins by cell membrane receptors. The PTB domain contains multiple tyrosine sites for phosphorylation and is activated by cell receptors. Differently to other IRS family members, IRS2 has a kinase regulatory loop binding domain (KRLB) that contributes to the recruitment to cellular receptor (Mardilovich, et al. 2009a).
Expression
Ubiquitous.
Figure 2. Intracellular localization of IRS2 protein in the SET2 cell line. Confocal analysis of SET2 (leukemia) cell line displaying IRS2 (red) and DAPI (blue) staining; MERGE shows the overlapped images. Scale bar: 5μm, as indicated. Note the predominant cytoplasm localization of IRS2. Anti-IRS2 (sc-1555) was from Santa Cruz Biotechnology and DAPI (P-36931) was from Life Technologies (Carlsbad, CA, USA). Personal data.
Localisation
IRS2 protein is predominantly found in the cytoplasm (Figure 2).
Function
IRS2 is a 180 kDa adapter protein described in 1995 as being equivalent to the 4PS protein previously identified as a substrate associated with the IL4 receptor in myeloid cells (Patti, et al. 1995). IRS2 mediates mitogenic and antiapoptotic signaling from insulin receptor (INSR), insulin-like growth factor 1 (IGF1R), erythropoietin receptor (EPOR), thrombopoietin receptor (MPL), vascular endothelial growth factor receptor VEGFR (KDR), leptin LEP, growth hormone (GH), interleukins and IFNα/ IFNB1/IFNG, playing an important role in the response to stimuli for cytokines and growth factors, influencing the proliferation and survival of normal and cancer cells (Argetsinger, et al. 1996; Dearth, et al. 2007; Gibson, et al. 2007; Johnston, et al. 1995; Platanias, et al. 1996; Sun, et al. 1995; Uddin, et al. 1995; Verdier, et al. 1997; White, et al. 1994; Yenush, et al. 1997). In addition, stimulation of the insulin receptor is known to result in IRS2 association with the p85 subunit of PI3K and GRB2, activating proteins involved in the PI3K/AKT/ MTOR and MAPK pathways, respectively (Patti, et al. 1995; Velloso, et al. 2006) (canonical pathway). IRS2 also activates signaling pathways through other mechanisms (non-canonical pathways). For instance, angiotensin II stimulates the rapid phosphorylation of JAK2 tyrosine residues, increasing its catalytic activity and JAK2 - IRS2 association (Folli, et al. 1997; Saad, et al. 1996; Saad, et al. 1995). The IRS2 - JAK2 association has also been described in rat left ventricular cells after stimulation with angiotensin (Velloso, et al. 2006; Velloso, et al. 1996), and in rat liver after stimulation with leptin (Carvalheira, et al. 2003). Similarly, the mutant form of JAK2 (JAK2V617F), which is constitutively activated, leads to enhanced interaction between JAK2 and IRS2 in myeloid cells (de Melo Campos, et al. 2016). The main signaling pathways stimulated by IRS2 are shown in Figure 3.
Figure 3. IRS2 signaling pathway. IRS2 is recruited by its PH/PTB domains and phosphorylated in tyrosine residues by upstream tyrosine kinase receptors (e.g. insulin receptor [IR], insulin-like growth factor receptor [IGF1R]). Tyrosine phosphorylation of IRS2 triggers PI3K/AKT/mTOR and MAPK signaling activation (canonical pathway), regulating many biological processes, including cell proliferation, protein synthesis, survival and gene expression in specific human tissues. IRS2 is also activated by cytokine and hormone receptors (e.g. IL4, leptin, angiotensin), which additionally induce JAK2 stimulation and IRS2/JAK2 interaction, leading to STAT, PI3K/AKT/mTOR and MAPK signaling activation in rat and mouse tissues. Abbreviations: P, phosphorylation; PY, tyrosine phosphorylation. Figure was produced using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).
Homology
The N-terminus of IRS2 shares high homology with that of the other members of the IRS protein family. IRS2 also has a high homology among different species (Table 1).
Table 1. Comparative identity of human IRS2 with other species
(Source: http://www.ncbi.nlm.nih.gov/homologene)
Table 1. Comparative identity of human IRS2 with other species
| % Identity for: Homo sapiens IRS2 | Symbol | Protein | DNA |
vs. P. troglodytes | IRS2 | 96.9 | 97.7 |
vs. M. mulatta | IRS2 | 97.4 | 95.9 |
vs. C. lupus | IRS2 | 88.8 | 87.4 |
vs. B. taurus | IRS2 | 85.0 | 84.8 |
vs. M. musculus | Irs2 | 84.7 | 80.8 |
vs. R. norvegicus | Irs2 | 85.7 | 81.5 |
vs. G. gallus | IRS2 | 73.7 | 74.4 |
vs. X. tropicalis | LOC100498409 | 59.4 | 57.1 |
vs. D. rerio | Irs2 | 60.7 | 61.7 |
vs. D. rerio | zgc:56306 | 58.9 | 56.5 |
(Source: http://www.ncbi.nlm.nih.gov/homologene)
Mutations
Note
Recurrent mutations in the IRS2 gene are rare, and 88 substitution missense, 2 substitution nonsense, 38 substitution synonymous, 1 insertion inframe, 3 insertion frameshift, 4 deletions inframe and 3 deletion frameshift mutations are reported in COSMIC (Catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).
Implicated in
Entity name
Breast cancer
Note
Jackson and colleagues (Jackson, et al. 1998) observed that IRS2 is widely expressed in breast cancer cell lines and primary breast cancer cells. In breast cancer patients, membrane localization of IRS-2 was associated with reduced overall survival by multivariate analysis (Clark, et al. 2011). In breast cancer cell lines, high IRS2 expression was correlated with high breast tumor invasiveness (Porter, et al. 2013), and with increased survival and cell invasion under hypoxia conditions (Mardilovich, et al. 2009b). Breast cancer IRS2-depleted cells, using specific anti-sense constructs, presented reduced IGF1-mediated cell motility and lower anchorage independent growth (Jackson, et al. 2001). In agreement, others studies demonstrated that IRS2 activation was required for IGF1-induced cell motility of the human breast cell lines MCF-7 (Ibrahim, et al. 2008; Zhang, et al. 2004) and T47D-YA(Byron, et al. 2006). Nagle and colleagues (Nagle, et al. 2004), showed that mammary tumor cells from IRS2 knockout mice were less invasive and presented more prominent apoptotic response to growth factor deprivation compared to wild type mammary tumor cells. Using breast cancer cell lines, Morelli and colleagues (Morelli, et al. 2003) and Cui and colleagues (Cui, et al. 2003) also observed that IRS2 could be a target of estrogen and progesterone receptors, respectively. Cui and colleagues (Cui, et al. 2006) demonstrated that EGF signaling was also involved in IRS2 induction/activation at the mRNA and protein levels via c-JUN/AP-1 stimulation, establishing cross-talk between IGF1R and EGFR signaling. Furthermore, the authors demonstrated in their study that IRS2 silencing reduced EGF-induced invasion and migration in the mammary adenocarcinoma cell line MDA-MB-468 (Cui, et al. 2006). Using the nontumorigenic mammary epithelial cell line MCF-10A and transgenic mice overexpressing human IRS2 by MMTV promoter, Death and colleagues (Dearth, et al. 2006) demonstrated the potential of malignant transformation of mammary cells by in vitro and in vivo IRS2 overexpression. Wu and colleagues (Wu, et al. 2010) observed that IRS2 silencing impaired breast cancer cell proliferation. In addition, they described that IGF1 induced nuclear translocation of IRS2 and NFKB, and promoted intranuclear association between IRS2 and NFKB in MCF-7 and BT-20 breast cancer cells, establishing a cross-talk between IGF1R and NFKB signaling. Slattery and colleagues (Slattery, et al. 2007), using a cohort of 1664 patients with breast cancer (1089 non-Hispanic white and 575 Hispanic) and 2054 controls (1328 non-Hispanic white and 726 Hispanic), found no association between IRS2 G1057D (rs1805097) polymorphism and breast cancer development. In contrast, Feigelson and colleagues (Feigelson, et al. 2008) observed an association between IRS2 polymorphisms rs4773082 (640 patients and 650 controls), rs2289046 (552 patients and 589 controls) and rs754204 (642 patients and 655 controls) and breast cancer development.
Entity name
Colorectal cancer
Note
Slattery and colleagues (Slattery, et al. 2004), using a cohort of 1001 patients with colon cancer and 1167 controls, and 766 patients with rectal cancer and 983 controls, reported that IRS2 G1057D (rs1805097) heterozygote GD genotype significantly reduced the risk of colon, though not rectal, cancer. In contrast, Yukseloglu and colleagues (Yukseloglu, et al. 2014), observed no association between IRS2 G1057D (rs1805097) polymorphism and risk for disease in a group of 161 patients with colorectal cancer and 197 controls. Gunter and colleagues (Gunter, et al. 2007) observed no association of IRS2 polymorphisms rs2241745 (754 patients and 765 controls) and rs2289046 (744 patients and 758 controls) with advanced colorectal adenoma. IRS2 (rs2289046) GG genotype compared with AA plus AG genotypes was found to have a protective factor for colorectal cancer risk in normal weight subjects (Karimi, et al. 2013). Day and colleagues (Day, et al. 2013) described that IRS2 mRNA and protein levels were positively correlated with progression from normal through adenoma to carcinoma in colorectal cancer, and that deregulated IRS2 expression activated the PI3K/AKT pathway and increased cell adhesion. Using FISH analysis, Huang and colleagues (Huang, et al. 2015) demonstrated that IRS2 amplification was a recurrent event and that IRS2 levels modulated the sensibility of colorectal cancer cell lines to the dual IGF-1R/IR inhibitor BMS-754807. In addition, the authors, using public available SNP array data on tumors, observed that the frequency of IRS2 copy number gain (648 samples evaluated from four datasets) is higher in colorectal cancer compared to other tumor types (Huang, et al. 2015).
Entity name
Pancreatic cancer
Note
n the rat pancreas RINm5F cell line, Irs2, but not Irs1, phosphorylation was associated with IGF1 stimulated DNA synthesis (Zhang, et al. 1998). Kornmann and colleagues (Kornmann, et al. 1998) reported that IRS2 mRNA and protein were expressed in human pancreatic cancer cell lines (ASPC-1 and COLO-357), and highly expressed in primary pancreatic cancer samples compared with normal pancreatic samples. IGF1 and IGF2 enhanced cell growth, stimulated IRS2 tyrosine phosphorylation and IRS2/PI3K association in ASPC-1 and COLO-357 cells (Kornmann, et al. 1998). In AsPC-1 cell line, IGF1R/IRS2 axis controlled the VEGF transcription, indicating that this axis is an important mediator for tumor angiogenesis (Neid, et al. 2004).
Entity name
Neuroblastoma
Note
In SH-SY5Y, a human neuroblastoma cell line lacking IRS1, IGF1 stimulation leads to IGF1R activation and IRS2 phosphorylation, and activates PI3K and MAPK signaling (Kim, et al. 1998; Kim, et al. 2004). IRS2 also protects SH-EP and SH-SY5Y neuroblastoma cell lines from glucose-induced apoptosis by activation of PI3K/AKT and MAPK signaling (Kim, et al. 2009; Stohr, et al. 2011).
Entity name
Hepatocellular carcinoma
Note
Boissan and colleagues (Boissan, et al. 2005) reported an overexpression of IRS2 in murine models of hepatocarcinogenesis. IRS2 mRNA and protein were found to be overexpressed in human hepatoma cell lines and primary human hepatocellular carcinoma specimens (Boissan, et al. 2005; Cantarini, et al. 2006). Of note, inhibition of IRS2 by siRNA resulted in increased apoptosis in the hepatocellular carcinoma Hep3B cells. In the human hepatoma SMMC-7721 cell line, IRS2 silencing suppressed aflatoxin B1-induced PI3K/AKT and MAPK activation and cell migration (Ma, et al. 2012). Rashad and colleagues (Rashad, et al. 2014) observed, in 334 patients and 426 controls, that the D allele and the DD genotype of IRS2 G1057D (rs1805097) polymorphism were significantly associated with hepatocellular carcinoma risk.
Entity name
Hematological malignancies
Note
IRS2 expression was found to be downregulated in myelodysplastic syndrome patients compared with healthy donors (Machado-Neto, et al. 2012). Increased IRS2 expression and phosphorylation was observed during erythroid, granulocytic and megakaryocytic differentiation in establish leukemia cell line models (Machado-Neto, et al. 2012). IRS2 was found to be constitutively associated with JAK2 in the JAK2 V617F-mutated HEL cells, but not in the JAK2 wild type U937 cells (de Melo Campos, et al. 2016). In HEL cells, though not in U937 cells, IRS2 silencing reduced cell viability and increased apoptosis; these effects were enhanced when combined with ruxolitinib, a selective JAK1/2 inhibitor. In addition, CD34+ cells from JAK2V617F-mutated myeloproliferative neoplasm patients presented increased IRS2 mRNA levels (de Melo Campos, et al. 2016). Savage and colleagues (Savage, et al. 2015) described IRS2 mutations (S594W and H1328R) in three out of 22 chronic myeloid leukemia patients with tyrosine kinase inhibitors resistance. Expression of each of the two of the IRS2 mutations in Ba/F3 cells demonstrated transformation capacity in the absence of IL3 (Savage, et al. 2015). When co-expressed in Ba/F3 cells with BCR-ABL1, these IRS2 mutants conferred varying degrees of reduced sensitivity to imatinib in vitro (Savage, et al. 2015).
Entity name
Glioblastoma
Note
In a study focused on PI3K/AKT-related gene expression analysis in glioblastoma involving 103 patients, the IRS2 gene was amplified and overexpressed in 2 cases and IRS2 was also highly expressed in six cases with no demonstrated amplification (Knobbe, et al. 2003). Xu and colleagues (Xu, et al. 2011) identified IRS2 as a target of MicroRNA-153 and suggested that MicroRNA-153 suppressed PI3K/AKT signaling through IRS2 inhibition in the DBTRG-05MG human glioblastoma cell line.
Entity name
Prostate cancer
Note
Szabolcs and colleagues (Szabolcs, et al. 2009) reported a high expression of IRS2 in prostate cancer cell lines and in primary human prostate cancer samples, in which IRS2 was also correlated with MYC expression in prostate tumor samples. Ibuki et al. (Ibuki, et al. 2014) demonstrated an elevated IRS2 expression by immunohistochemistry in prostate cancer biopsies when compared to normal specimens. The in vitro treatment of LNCaP human prostate cancer cells with NT157, a IRS1/2 inhibitor, resulted in increased apoptosis and decreased cell proliferation (Ibuki, et al. 2014). Huang and colleagues (Huang, et al. 2012) observed that IRS2 rs7986346 polymorphism was associated with disease progression and impaired survival in prostate cancer patients treated with androgen-deprivation.
Entity name
Thyroid cancer
Note
In the FRTL-5 rat thyroid cell line, the "RET/PTC3 rearrangement" (inv(10)(q11q11) with NCOA4/ RET rearrangement), a constitutively activated tyrosine kinase receptor that is frequent in papillary thyroid cancer, induces IRS2 upregulation, and enhances IRS2/PI3K interaction and AKT activation (Miyagi, et al. 2004). Akker and colleagues (Akker, et al. 2014) observed no association between IRS2 G1057D (rs1805097) polymorphism and differentiated thyroid cancer development in a cohort of 93 differentiated thyroid cancer patients and 111 healthy controls.
Entity name
Mesothelioma
Note
IRS2 was found to be highly expressed in pleural mesothelioma samples and associated with cell motility in the H2461 cell line (Hoang, et al. 2004).
Entity name
Clear cell renal cell carcinoma
Note
Using semi-quantitative PCR, Al-Sarraf and colleagues (Al-Sarraf, et al. 2007) investigated IRS1, IRS2 and IRS5 mRNA expression in a cohort of 10 patients with clear cell renal carcinoma, comparing normal adjacent tissue with the respective tumor tissue for the analysis, and found an upregulation of IRS2 and IRS5 mRNA in tumor samples (Al-Sarraf, et al. 2007).
Entity name
Endometrial cancer
Note
Cayan and colleagues (Cayan, et al. 2010) reported that IRS2 G1057D (rs1805097) polymorphism was associated with the development of endometrial cancer in a cohort of 44 patients with colon cancer and 101 controls.
Entity name
Malignant peripheral nerve sheath tumor
Note
High expression of IRS2 was observed in malignant peripheral nerve sheath tumor compared to neurofibromas (Shaw, et al. 2012). IRS2 expression was also associated with reduced survival in malignant peripheral nerve sheath tumors using univariate analysis (Shaw, et al. 2012).
Entity name
Bladder cancer
Note
Using cDNA microarray analysis, Zekri and colleagues (Zekri, et al. 2015) found IRS2 upregulation among the genes differently expressed identified in bladder cancer.
Entity name
Lung cancer
Note
Park and colleagues (Park, et al. 2015) identified IRS2 as a MIR146A (MicroRNA-146a) target and suggested that MicroRNA-146a might suppress lung cancer progression by IRS2 inhibition.
Entity name
Melanoma
Note
In the MDA-MB-435 melanoma cell line, IRS2 signaling was identified as a key mediator of invasion promoted by α6β4 (Shaw 2001). In A375 human melanoma cells, the in vitro treatment with NT157, a IRS1/2 inhibitor, led to growth suppression of melanoma cells by degradation of IRS1 and IRS2 (Reuveni, et al. 2013). Moreover, NT157 strongly inhibited the development of lung metastases of melanoma cells in mouse models (Reuveni et al, 2013).
Entity name
Esophageal squamous cell carcinoma
Note
iu and colleagues (Liu, et al. 2015) identified IRS2 as a target of MicroRNA-146a and suggested that MicroRNA-146a suppressed esophageal squamous cell carcinoma growth through inhibition of IRS2. Corroborating these findings, in the MicroRNA-146a-expressing EC109 esophageal squamous cell carcinoma cell line, IRS2 recovery experiments increased cell growth.
Entity name
Gastric cancer
Note
Yamashita et al. (Yamashita, et al. 2006) described that IRS2 was methylation-silenced in gastric cancer specimens. Zhao and colleagues (Zhao, et al. 2012), reported that IRS2 G1057D (rs1805097) polymorphism was associated with increased susceptibility for gastric cancer in a cohort of 197 patients with gastric cancer and 156 age- and sex-matched controls.
Entity name
Oral squamous cell carcinoma
Note
Gao and colleagues (Gao, et al. 2014) described that IRS2 expression was negatively associated with histological differentiation of oral squamous cell carcinoma. In addition, IRS2 inhibition reduces cell proliferation, clonogenicity, cell cycle progression and PI3K/AKT activation in the human oral squamous cell carcinoma Tca-8113 cell line (Gao, et al. 2014).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 24504452 | 2014 | Investigation of insulin resistance gene polymorphisms in patients with differentiated thyroid cancer. | Akker M et al |
| 17443497 | 2007 | DOK4/IRS-5 expression is altered in clear cell renal cell carcinoma. | Al-Sarraf N et al |
| 8910607 | 1996 | Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. | Argetsinger LS et al |
| 16127164 | 2005 | Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. | Boissan M et al |
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| 17043687 | 2006 | Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. | Byron SA et al |
| 16871543 | 2006 | Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. | Cantarini MC et al |
| 12674509 | 2003 | Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver. | Carvalheira JB et al |
| 20184486 | 2010 | Insulin receptor substrate-2 gene polymorphism: is it associated with endometrial cancer? | Cayan F et al |
| 21258861 | 2011 | Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. | Clark JL et al |
| 16707456 | 2006 | Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration. | Cui X et al |
| 14534541 | 2003 | Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2. | Cui X et al |
| 23594372 | 2013 | IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. | Day E et al |
| 17030631 | 2006 | Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. | Dearth RK et al |
| 18611262 | 2008 | Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II. | Feigelson HS et al |
| 26119932 | 2016 | Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling. | Flashner-Abramson E et al |
| 9410892 | 1997 | Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. | Folli F et al |
| 24810113 | 2014 | IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma. | Gao L et al |
| 26029165 | 2015 | Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines. | Garofalo C et al |
| 17361103 | 2007 | Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. | Gibson SL et al |
| 17416760 | 2007 | Insulin resistance-related genes and advanced left-sided colorectal adenoma. | Gunter MJ et al |
| 15492273 | 2004 | Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes. | Hoang CD et al |
| 25527633 | 2015 | IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. | Huang F et al |
| 22844442 | 2012 | Genetic variants in CASP3, BMP5, and IRS2 genes may influence survival in prostate cancer patients receiving androgen-deprivation therapy. | Huang SP et al |
| 18819936 | 2008 | Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2. | Ibrahim YH et al |
| 25267499 | 2014 | The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer. | Ibuki N et al |
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| 7499365 | 1995 | Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. | Johnston JA et al |
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| 8550573 | 1996 | The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. | Platanias LC et al |
| 23562473 | 2013 | IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors. | Porter HA et al |
| 24656929 | 2014 | Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma. | Rashad NM et al |
| 23651636 | 2013 | Therapeutic destruction of insulin receptor substrates for cancer treatment. | Reuveni H et al |
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| 26364612 | 2016 | Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. | Sanchez-Lopez E et al |
| 22347534 | 2012 | Association between IRS-2 G1057D polymorphism and risk of gastric cancer. | Zhao XM et al |
| 22287730 | 2012 | Elevated expression of IRS2 in the progression from neurofibroma to malignant peripheral nerve sheath tumor. | Shaw CM et al |
| 11438664 | 2001 | Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion. | Shaw LM et al |
| 17051426 | 2007 | Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. | Slattery ML et al |
| 21354306 | 2011 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. | Stöhr O et al |
| 7675087 | 1995 | Role of IRS-2 in insulin and cytokine signalling. | Sun XJ et al |
| 19095950 | 2009 | Irs2 inactivation suppresses tumor progression in Pten+/- mice. | Szabolcs M et al |
| 7608146 | 1995 | Interferon-alpha engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 3'-kinase. | Uddin S et al |
| 8901609 | 1996 | Cross-talk between the insulin and angiotensin signaling systems. | Velloso LA et al |
| 9334184 | 1997 | Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. | Verdier F et al |
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| 9495343 | 1998 | Disruption of IRS-2 causes type 2 diabetes in mice. | Withers DJ et al |
| 21042750 | 2010 | Interaction between nuclear insulin receptor substrate-2 and NF-κB in IGF-1 induces response in breast cancer cells. | Wu S et al |
| 21213215 | 2011 | Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines. | Xu J et al |
| 16367923 | 2006 | Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. | Yamashita S et al |
| 9204766 | 1997 | The IRS-signalling system during insulin and cytokine action. | Yenush L et al |
| 25061488 | 2014 | IRS-2 G1057D polymorphism in Turkish patients with colorectal cancer. | Yukseloglu EH et al |
| 25921176 | 2015 | Differentially expressed genes in metastatic advanced Egyptian bladder cancer. | Zekri AR et al |
| 9582514 | 1998 | Insulin-like growth factor-I-induced DNA synthesis in insulin-secreting cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor substrate-2. | Zhang Q et al |
| 14997047 | 2004 | Motility response to insulin-like growth factor-I (IGF-I) in MCF-7 cells is associated with IRS-2 activation and integrin expression. | Zhang X et al |
Other Information
Locus ID:
NCBI: 8660
MIM: 600797
HGNC: 6126
Ensembl: ENSG00000185950
Variants:
dbSNP: 8660
ClinVar: 8660
TCGA: ENSG00000185950
COSMIC: IRS2
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000185950 | ENST00000375856 | Q9Y4H2 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37481466 | 2024 | Insulin receptor substrate 2 gene Gly1057Asp polymorphism is a risk factor for nonalcoholic fatty liver disease. | 0 |
| 37481466 | 2024 | Insulin receptor substrate 2 gene Gly1057Asp polymorphism is a risk factor for nonalcoholic fatty liver disease. | 0 |
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Citation
Joao Agostinho Machado-Neto, PhD ; Paula de Melo Campos ; Fabiola Traina
IRS2 (insulin receptor substrate 2)
Atlas Genet Cytogenet Oncol Haematol. 2016-05-01
Online version: http://atlasgeneticsoncology.org/gene/40994/irs2-(insulin-receptor-substrate-2)
