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IRS1 (insulin receptor substrate 1)

Written2013-03João Agostinho Machado-Neto, Fabiola Traina
Hematology, Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciencia e Tecnologia do Sangue, Campinas, Sao Paulo, Brazil (JAMN, FT); Hematology/Oncology Division, Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (FT)

(Note : for Links provided by Atlas : click)


Other aliasHIRS-1
LocusID (NCBI) 3667
Atlas_Id 384
Location 2q36.3  [Link to chromosome band 2q36]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CUL3 (2q36.2) / IRS1 (2q36.3)IRS1 (2q36.3) / C12orf40 (12q12)


Note Insulin receptor substrate 1 (IRS1) was the first IRS family member to be identified and cloned (Sun et al., 1991). The entire gene is about 68,4 kb and contains 2 exons (start: 227596033 and end: 227664745; orientation: minus strand). The cDNA contains 8743 bp.


  Figure 1. Schematic structure of IRS1. Interaction domains of IRS1: pleckstrin homology (PH) domain (purple), phosphotyrosine binding (PTB) domain (green) and effector binding sites (including PI3K, Grb2 and SHP2) are indicated.
Description IRS1 belongs to the insulin receptor substrate (IRS) protein family, these proteins are characterized by the presence of a pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain (figure 1). The PH domain contributes to protein-protein binding and facilitates the recruitment of IRS proteins by cell membrane receptors. The PTB domain is actived by receptors (Mardilovich et al., 2009).
Expression Ubiquitous.
Localisation IRS1 is predominantly found in the cytoplasm. Nuclear localization may occur in some cell types and under specific stimuli.
  Figure 2. IRS1 signaling pathway. IRS1 is recruited by its PH/PTB domains and phosphorylated in tyrosine residues (pY) by upstream tyrosine kinase receptors. Tyrosine phosphorylated IRS1 binds to signaling effectors and activates signaling cascades, regulating several biological processes, including proliferation and survival.
Function IRS1 is an intracellular signaling adaptor protein that integrates and coordinates numerous biologically key extracellular signals within the cell. First identified as a signaling intermediate of the insulin receptor (IR), it is now clear that IRS1 is the main substrate of the insulin-like grow factor 1 receptor (IGF1R) (Dearth et al., 2007). IRS1 contains multiple tyrosine phosphorylation sites, which during insulin stimulation are phosphorylated and act as docking sites for multiple SH2-containing proteins including PI3K, Grb2, Nck, Crk, Fyn, Syp and SHP2 (Mardilovich et al., 2009). The two best-studied being the PI3K/Akt/mTOR and the MAPK pathway, which includes the ERK protein (figure 2) (Mardilovich et al., 2009). IRS1 has no intrinsic kinase activity and requires upstream activators, however many studies have shown that this signaling adaptor is in itself oncogenic and can induce malignant transformation (Dearth et al., 2007).
More recently, nuclear localization of IRS1 was observed in cells expressing SV40 T antigen, fibroblasts under IGF1 stimulation, hepatocytes, 32D cells and others. Several nuclear functions have been attributed to IRS1, including DNA repair fidelity, transcriptional activity and cell growth, which contributes to tumor development and progression (Reiss et al., 2011).
Homology IRS1 shares high homology in its N-termini with the other members of the IRS proteins family. IRS1 also shares a high homology among different species (table 1).


Note Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance (Kovacs et al., 2003).

Implicated in

Entity Philadelphia chromosome-positive (Ph+) leukemias
Note IRS1 was identified as a binding partner of BCR-ABL protein and found to be involved in the activation of the PI3K/Akt/mTOR and MAPK signaling pathway in the BCR-ABL network (Traina et al., 2003). In BCR-ABL positive leukemia cells, IRS1 silencing resulted in decreased cell proliferation and clonogenicity (Machado-Neto et al., 2011). In addition, IRS1 expression was found to be negatively correlated with survival in patients with Ph+ acute lymphosblastic leukemia, regardless of age and white blood cell count at diagnosis (Juric et al., 2007).
Entity Breast cancer
Note In breast cancer tumors, IRS1 has been described as constitutively activated and its expression has been correlated with poor differentiation and positive lymph node status (Chang et al., 2002; Lee et al., 1999; Koda et al., 2005). High levels of IRS1 were associated with lower disease-free survival and positively correlated with proliferation in estrogen receptor (ER) positive breast cancer tumors (Rocha et al., 1997). In ER positive breast cancer cells, IRS1 silencing promoted apoptosis and increased the sensibility to chemotherapy (Cesarone et al., 2006).
Entity Hepatocellular carcinoma
Note IRS1 was found overexpressed in 80% of hepatocellular carcinoma (HCC) when compared with adjacent HCC-free tissue (Cantarini et al., 2006). In vitro experiments provided evidence that IRS1 overexpression was able to promote malignant transformation of hepatocytes (Tanaka et al., 1997).
Entity Lung cancer
Note Han et al. reported a downregulation of IRS1 in non-small cell lung cancer (NSCLC) and suggested that loss of IRS1 might be an early event in NSCLC development (Han et al., 2006).
Entity Medulloblastoma
Note Abundant IRS1 expression was found in medulloblastoma cell lines and medulloblastoma biopsies. Nuclear translocation of IRS1 was observed in all cell lines and primary samples in the presence of the JC virus T antigen (Del Valle et al., 2002).
Entity Mesothelioma
Note Up-regulation of IRS1 was found in mesothelioma samples and may contribute to malignant pleural mesothelioma tumorigenesis by IGF1-induced cell proliferation (Hoang et al., 2004).
Entity Ovarian cancer
Note The majority of malignant epithelial ovarian tumors showed IRS1 overexpression when compared with normal ovarian tissue, suggesting a correlation between IRS1 expression and cancer phenotype. The same study suggested that IRS1 is an important growth-regulatory protein and may be a possible target in ovarian cancer (Ravikumar et al., 2007).
Entity Pancreatic cancer
Note IRS1 was highly expressed in 43% of pancreatic cancer samples when compared with normal pancreas samples (Bergmann et al., 1996).
Entity Prostate cancer
Note High expression of IRS1 was correlated with high expression of IGF1R in both benign and malignant prostate samples (Hellawell et al., 2002), but IRS1 expression did not differ among these samples. In prostate cancer cells, IRS1 silencing plus rapamycin treatment synergistically antagonized the activation of mTOR and induced tumor suppression in vivo, through inhibition of proliferation and induction of apoptosis (Oliveira et al., 2008).
Entity Endometrial cancer
Note IRS1 activation was significantly elevated in patients with endometrial cancer (EC) compared to those without EC and was associated with aggressive features. In addition, Wang et al. suggested that the inhibition of the IR/IRS1/PI3K/Akt pathway could be used as preventive and therapeutic strategies for EC (Wang et al., 2012).
Entity Colorectal cancer
Note Esposito et al. reported that IRS1 was found highly expressed in adenomas of familial adenomatous polyposis patients, relative to paired normal mucosa, and in metastasized colorectal tumors compared with primary colorectal cancer (CRC) and colonic epithelium (Esposito et al., 2012). The authors also related that IRS1 staining was associated with high expressions of Ki67, p53, and β-catenin, suggesting that IRS1 is modulated according to CRC differentiation and plays a role in CRC progression and metastasis (Esposito et al., 2012).

To be noted

Animal model: IRS1 knockout mice were born alive but were showed retarded embryonic and postnatal growth (approximately 30% smaller than wild type littermates), and also had resistance to the glucose-lowering effects of insulin, IGF1 and IGF2 (Tamemoto et al., 1994).


Increased expression of insulin receptor substrate-1 in human pancreatic cancer.
Bergmann U, Funatomi H, Kornmann M, Beger HG, Korc M.
Biochem Biophys Res Commun. 1996 Mar 27;220(3):886-90.
PMID 8607861
Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms.
Cantarini MC, de la Monte SM, Pang M, Tong M, D'Errico A, Trevisani F, Wands JR.
Hepatology. 2006 Aug;44(2):446-57.
PMID 16871543
RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells.
Cesarone G, Garofalo C, Abrams MT, Igoucheva O, Alexeev V, Yoon K, Surmacz E, Wickstrom E.
J Cell Biochem. 2006 May 15;98(2):440-50.
PMID 16440325
Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications.
Chang Q, Li Y, White MF, Fletcher JA, Xiao S.
Cancer Res. 2002 Nov 1;62(21):6035-8.
PMID 12414625
Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2.
Dearth RK, Cui X, Kim HJ, Hadsell DL, Lee AV.
Cell Cycle. 2007 Mar 15;6(6):705-13. Epub 2007 Mar 20. (REVIEW)
PMID 17374994
Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas.
Del Valle L, Wang JY, Lassak A, Peruzzi F, Croul S, Khalili K, Reiss K.
J Neurovirol. 2002 Dec;8 Suppl 2:138-47. (REVIEW)
PMID 12491166
The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
Esposito DL, Aru F, Lattanzio R, Morgano A, Abbondanza M, Malekzadeh R, Bishehsari F, Valanzano R, Russo A, Piantelli M, Moschetta A, Lotti LV, Mariani-Costantini R.
PLoS One. 2012;7(4):e36190. doi: 10.1371/journal.pone.0036190. Epub 2012 Apr 27.
PMID 22558377
Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer.
Han CH, Cho JY, Moon JT, Kim HJ, Kim SK, Shin DH, Chang J, Ahn CM, Kim SK, Chang YS.
Oncol Rep. 2006 Dec;16(6):1205-10.
PMID 17089038
Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease.
Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM.
Cancer Res. 2002 May 15;62(10):2942-50.
PMID 12019176
Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes.
Hoang CD, Zhang X, Scott PD, Guillaume TJ, Maddaus MA, Yee D, Kratzke RA.
Cancer Res. 2004 Oct 15;64(20):7479-85.
PMID 15492273
Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias.
Juric D, Lacayo NJ, Ramsey MC, Racevskis J, Wiernik PH, Rowe JM, Goldstone AH, O'Dwyer PJ, Paietta E, Sikic BI.
J Clin Oncol. 2007 Apr 10;25(11):1341-9. Epub 2007 Feb 20.
PMID 17312329
Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases.
Koda M, Sulkowska M, Kanczuga-Koda L, Sulkowski S.
J Clin Pathol. 2005 Jun;58(6):645-9.
PMID 15917419
The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians.
Kovacs P, Hanson RL, Lee YH, Yang X, Kobes S, Permana PA, Bogardus C, Baier LJ.
Diabetes. 2003 Dec;52(12):3005-9.
PMID 14633864
Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo.
Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D.
Mol Endocrinol. 1999 May;13(5):787-96.
PMID 10319328
Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells.
Machado-Neto JA, Favaro P, Lazarini M, Costa FF, Olalla Saad ST, Traina F.
Biochim Biophys Acta. 2011 Aug;1813(8):1404-11. doi: 10.1016/j.bbamcr.2011.04.002. Epub 2011 Apr 21.
PMID 21569802
Expression and function of the insulin receptor substrate proteins in cancer.
Mardilovich K, Pankratz SL, Shaw LM.
Cell Commun Signal. 2009 Jun 17;7:14. doi: 10.1186/1478-811X-7-14.
PMID 19534786
Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts.
Oliveira JC, Souza KK, Dias MM, Faria MC, Ropelle ER, Flores MB, Ueno M, Velloso LA, Saad ST, Saad MJ, Carvalheira JB.
J Cancer Res Clin Oncol. 2008 Aug;134(8):833-9. doi: 10.1007/s00432-008-0359-5. Epub 2008 Feb 9.
PMID 18264722
Insulin receptor substrate-1 is an important mediator of ovarian cancer cell growth suppression by all-trans retinoic acid.
Ravikumar S, Perez-Liz G, Del Vale L, Soprano DR, Soprano KJ.
Cancer Res. 2007 Oct 1;67(19):9266-75.
PMID 17909034
Nuclear IRS-1 and cancer.
Reiss K, Del Valle L, Lassak A, Trojanek J.
J Cell Physiol. 2012 Aug;227(8):2992-3000. doi: 10.1002/jcp.24019. (REVIEW)
PMID 22454254
Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival.
Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng Cn, Lee AV, Yee D.
Clin Cancer Res. 1997 Jan;3(1):103-9.
PMID 9815544
Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.
Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF.
Nature. 1991 Jul 4;352(6330):73-7.
PMID 1648180
Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.
Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, et al.
Nature. 1994 Nov 10;372(6502):182-6.
PMID 7969452
Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes.
Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR.
Hepatology. 1997 Sep;26(3):598-604.
PMID 9303488
BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells.
Traina F, Carvalheira JB, Saad MJ, Costa FF, Saad ST.
FEBS Lett. 2003 Jan 30;535(1-3):17-22.
PMID 12560071
Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent.
Wang Y, Hua S, Tian W, Zhang L, Zhao J, Zhang H, Zhang W, Xue F.
Gynecol Oncol. 2012 Jun;125(3):734-41. doi: 10.1016/j.ygyno.2012.03.012. Epub 2012 Mar 14.
PMID 22426488


This paper should be referenced as such :
Machado-Neto, JA ; Traina, F
IRS1 (insulin receptor substrate 1)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(9):594-598.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(X;7)(q22;q34) IRS4/TRB

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  Colon: Colorectal adenocarcinoma
Liver: Hepatocellular carcinoma
CUL3/IRS1 (2q36)

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)3667
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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