IRS1 (insulin receptor substrate 1)

2013-03-01   Joao Agostinho Machado-Neto , Fabiola Traina 

Identity

HGNC
LOCATION
2q36.3
LOCUSID
ALIAS
HIRS-1
FUSION GENES

DNA/RNA

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.

Proteins

Atlas Image
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.
Atlas Image
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).
Atlas Image
Table 1. Comparative identity of human IRS1 with other species. Source: HomoloGene.

Mutations

Note

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

Implicated in

Entity name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
Pancreatic cancer
Note
IRS1 was highly expressed in 43% of pancreatic cancer samples when compared with normal pancreas samples (Bergmann et al., 1996).
Entity name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
86078611996Increased expression of insulin receptor substrate-1 in human pancreatic cancer.Bergmann U 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
164403252006RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells.Cesarone G et al
124146252002Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications.Chang Q et al
173749942007Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2.Dearth RK et al
124911662002Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas.Del Valle L et al
225583772012The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.Esposito DL et al
170890382006Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer.Han CH et al
120191762002Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease.Hellawell GO et al
154922732004Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes.Hoang CD et al
173123292007Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias.Juric D et al
159174192005Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases.Koda M et al
146338642003The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians.Kovacs P et al
103193281999Enhancement 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 et al
215698022011Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells.Machado-Neto JA et al
195347862009Expression and function of the insulin receptor substrate proteins in cancer.Mardilovich K et al
182647222008Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts.Oliveira JC et al
179090342007Insulin receptor substrate-1 is an important mediator of ovarian cancer cell growth suppression by all-trans retinoic acid.Ravikumar S et al
224542542012Nuclear IRS-1 and cancer.Reiss K et al
98155441997Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival.Rocha RL et al
16481801991Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.Sun XJ et al
79694521994Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.Tamemoto H et al
93034881997Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes.Tanaka S et al
125600712003BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells.Traina F et al
224264882012Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent.Wang Y et al

Other Information

Locus ID:

NCBI: 3667
MIM: 147545
HGNC: 6125
Ensembl: ENSG00000169047

Variants:

dbSNP: 3667
ClinVar: 3667
TCGA: ENSG00000169047
COSMIC: IRS1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169047ENST00000305123P35568
ENSG00000169047ENST00000305123A0A024R499

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
Insulin signaling pathwayKEGGko04910
Adipocytokine signaling pathwayKEGGko04920
Type II diabetes mellitusKEGGko04930
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
Insulin signaling pathwayKEGGhsa04910
Adipocytokine signaling pathwayKEGGhsa04920
Type II diabetes mellitusKEGGhsa04930
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Aldosterone-regulated sodium reabsorptionKEGGko04960
Aldosterone-regulated sodium reabsorptionKEGGhsa04960
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
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
PI3K-Akt signalingKEGGhsa_M00676
PI3K-Akt signalingKEGGM00676
Regulation of lipolysis in adipocytesKEGGhsa04923
DiseaseREACTOMER-HSA-1643685
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
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
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
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalClinicalAnnotationassociatedPD
PA164712711Drugs Used In DiabetesChemicalClinicalAnnotation, VariantAnnotationambiguousPD28696414
PA166124406platelet reactivityDiseaseVariantAnnotationnot associatedPD
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD
PA443796Coronary Artery DiseaseDiseaseClinicalAnnotation, VariantAnnotationambiguousPD
PA443890Diabetes Mellitus, Type 2DiseaseClinicalAnnotation, VariantAnnotationambiguousPD28696414
PA445113NeutropeniaDiseaseClinicalAnnotationassociatedPD
PA448497aspirinChemicalVariantAnnotationnot associatedPD
PA449053clopidogrelChemicalClinicalAnnotation, VariantAnnotationambiguousPD
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD
PA449476epirubicinChemicalClinicalAnnotationassociatedPD

References

Pubmed IDYearTitleCitations
162846492005Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.251
123516582002Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex.191
156042152005Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance.188
197349002009Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia.167
197349002009Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia.167
163546802006Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.146
178271562007Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells.120
217060032011Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.114
253421292015Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.104
189526042008S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2.101

Citation

Joao Agostinho Machado-Neto ; Fabiola Traina

IRS1 (insulin receptor substrate 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/gene/384/irs1-(insulin-receptor-substrate-1)