IRS2 (insulin receptor substrate 2)

2016-05-01   Joao Agostinho Machado-Neto , Paula de Melo Campos , Fabiola Traina 




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.



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.


Atlas Image
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.


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).


Atlas Image
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.


IRS2 protein is predominantly found in the cytoplasm (Figure 2).


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.
Atlas Image
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 (


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

% Identity for: Homo sapiens IRS2




vs. P. troglodytes




vs. M. mulatta




vs. C. lupus




vs. B. taurus




vs. M. musculus




vs. R. norvegicus




vs. G. gallus




vs. X. tropicalis




vs. D. rerio




vs. D. rerio







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;

Implicated in

Entity name
Breast cancer
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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).


Pubmed IDLast YearTitleAuthors
245044522014Investigation of insulin resistance gene polymorphisms in patients with differentiated thyroid cancer.Akker M et al
174434972007DOK4/IRS-5 expression is altered in clear cell renal cell carcinoma.Al-Sarraf N et al
89106071996Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling.Argetsinger LS et al
161271642005Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma.Boissan M et al
110141932000IRS-2 pathways integrate female reproduction and energy homeostasis.Burks DJ et al
170436872006Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells.Byron SA et al
168715432006Aspartyl-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
126745092003Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver.Carvalheira JB et al
201844862010Insulin receptor substrate-2 gene polymorphism: is it associated with endometrial cancer?Cayan F et al
212588612011Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer.Clark JL et al
167074562006Epidermal 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
145345412003Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2.Cui X et al
235943722013IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer.Day E et al
170306312006Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2.Dearth RK et al
186112622008Genetic 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
261199322016Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling.Flashner-Abramson E et al
94108921997Angiotensin 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
248101132014IGF-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
260291652015Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines.Garofalo C et al
173611032007Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis.Gibson SL et al
174167602007Insulin resistance-related genes and advanced left-sided colorectal adenoma.Gunter MJ et al
154922732004Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes.Hoang CD et al
255276332015IRS2 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
228444422012Genetic variants in CASP3, BMP5, and IRS2 genes may influence survival in prostate cancer patients receiving androgen-deprivation therapy.Huang SP et al
188199362008Progesterone receptor-B regulation of insulin-like growth factor-stimulated cell migration in breast cancer cells via insulin receptor substrate-2.Ibrahim YH et al
252674992014The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer.Ibuki N et al
117048612001Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines.Jackson JG et al
74993651995Interleukins 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
20131976Rapid infusion of sodium bicarbonate and albumin into high-risk premature infants soon after birth: a controlled, prospective trial.Bland RD et al

Other Information

Locus ID:

NCBI: 8660
MIM: 600797
HGNC: 6126
Ensembl: ENSG00000185950


dbSNP: 8660
ClinVar: 8660
TCGA: ENSG00000185950


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Autophagy - animalKEGGko04140
Insulin signaling pathwayKEGGko04910
Adipocytokine signaling pathwayKEGGko04920
Type II diabetes mellitusKEGGko04930
Autophagy - animalKEGGhsa04140
Insulin signaling pathwayKEGGhsa04910
Adipocytokine signaling pathwayKEGGhsa04920
Type II diabetes mellitusKEGGhsa04930
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
FoxO signaling pathwayKEGGhsa04068
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Regulation of lipolysis in adipocytesKEGGhsa04923
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Growth hormone receptor signalingREACTOMER-HSA-982772
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS activationREACTOMER-HSA-74713
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
SOS-mediated signallingREACTOMER-HSA-112412
Signal attenuationREACTOMER-HSA-74749
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Insulin resistanceKEGGhsa04931
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
173749942007Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2.73
191092392008Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages.66
153160082004SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin.63
170306312006Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2.62
179010492007The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation.62
172223212007Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2.61
173611032007Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis.41
152471322004Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer.40
152471322004Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer.40


Joao Agostinho Machado-Neto ; Paula de Melo Campos ; Fabiola Traina

IRS2 (insulin receptor substrate 2)

Atlas Genet Cytogenet Oncol Haematol. 2016-05-01

Online version: