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IRS2 (insulin receptor substrate 2)

Written2016-05João Agostinho Machado-Neto, Paula de Melo Campos, Fabiola Traina
Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, (JAMN, FT), Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, (PdMC) Brazil. jamachadoneto@gmail.com, pmcampos@gmail.com, ftraina@fmrp.usp.br

Abstract 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.

Keywords IRS2; mitogenic signaling; antiapoptotic signaling

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Identity

Alias (NCBI)IRS-2
4PS
HGNC (Hugo) IRS2
Atlas_Id 40994
Location 13q34  [Link to chromosome band 13q34]
Location_base_pair Starts at 109752695 and ends at 109786583 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping IRS2.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ABHD13 (13q33.3)::IRS2 (13q34)IRS2 (13q34)::MLH1 (3p22.2)

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.

Protein

 
  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


% 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

Note
  
Entity 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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).
  

To be noted

Homozygous absence of the Irs2 gene results in type II diabetes and causes female infertility in mice (Burks, et al. 2000; Withers, et al. 1998). In view of the importance of IRS proteins for cancer development and progression, a great effort has been made in an attempt to develop or identify compounds capable of inhibiting signaling mediated by IRS proteins. In this sense, a unique subfamily of IGF1R signaling inhibitors (NT compounds) has been developed (Reuveni, et al. 2013). NT157, the most characterized NT compound, binds to IGF1R and induces a conformational change, leading to the dissociation of IRS1/2 from the receptor and IRS1/2 degradation by the proteasome. NT157 was found to lead to long-lasting IGF1R inhibition, apoptosis, and present a potent antitumor effects in melanoma cells but not in normal melanocytes (Flashner-Abramson, et al. 2015; Reuveni, et al. 2013), osteosarcoma cells (Garofalo, et al. 2015), prostate adenocarcinoma cells (Ibuki, et al. 2014) and colorectal cancer cells (Sanchez-Lopez, et al. 2015).

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Oncogene 2004 Jan 8;23(1):130-41
PMID 14712218
 
Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas
Knobbe CB, Reifenberger G
Brain Pathol 2003 Oct;13(4):507-18
PMID 14655756
 
Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer
Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger HG, White MF, Korc M
Cancer Res 1998 Oct 1;58(19):4250-4
PMID 9766646
 
The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2
Liu H, Ren G, Zhu L, Liu X, He X
Tumour Biol 2016 Apr;37(4):4641-7
 
Aflatoxin B1 up-regulates insulin receptor substrate 2 and stimulates hepatoma cell migration
Ma Y, Kong Q, Hua H, Luo T, Jiang Y
PLoS One 2012;7(10):e47961
PMID 23112878
 
Downregulation of IRS2 in myelodysplastic syndrome: a possible role in impaired hematopoietic cell differentiation
Machado-Neto JA, Favaro P, Lazarini M, da Silva Santos Duarte A, Archangelo LF, Lorand-Metze I, Costa FF, Saad ST, Traina F
Leuk Res 2012 Jul;36(7):931-5
PMID 22465474
 
Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion
Mardilovich K, Shaw LM
Cancer Res 2009 Dec 1;69(23):8894-901
PMID 19920186
 
Chronic expression of RET/PTC 3 enhances basal and insulin-stimulated PI3 kinase/AKT signaling and increases IRS-2 expression in FRTL-5 thyroid cells
Miyagi E, Braga-Basaria M, Hardy E, Vasko V, Burman KD, Jhiang S, Saji M, Ringel MD
Mol Carcinog 2004 Oct;41(2):98-107
PMID 15378648
 
Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells
Morelli C, Garofalo C, Bartucci M, Surmacz E
Oncogene 2003 Jun 26;22(26):4007-16
PMID 12821935
 
Involvement of insulin receptor substrate 2 in mammary tumor metastasis
Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM
Mol Cell Biol 2004 Nov;24(22):9726-35
PMID 15509777
 
Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells
Neid M, Datta K, Stephan S, Khanna I, Pal S, Shaw L, White M, Mukhopadhyay D
J Biol Chem 2004 Feb 6;279(6):3941-8
PMID 14604996
 
MicroRNA-146a inhibits epithelial mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2
Park DH, Jeon HS, Lee SY, Choi YY, Lee HW, Yoon S, Lee JC, Yoon YS, Kim DS, Na MJ, Kwon SJ, Kim DS, Kang J, Park JY, Son JW
Int J Oncol 2015 Oct;47(4):1545-53
PMID 26238771
 
4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice
Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR
J Biol Chem 1995 Oct 20;270(42):24670-3
PMID 7559579
 
The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2
Platanias LC, Uddin S, Yetter A, Sun XJ, White MF
J Biol Chem 1996 Jan 5;271(1):278-82
PMID 8550573
 
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, Perry A, Kingsley C, Tran NL, Keegan AD
Cancer Lett 2013 Sep 28;338(2):239-48
PMID 23562473
 
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, El-Shal AS, Abd Elbary EH, Abo Warda MH, Hegazy O
Cytokine 2014 Jul;68(1):50-8
PMID 24656929
 
Therapeutic destruction of insulin receptor substrates for cancer treatment
Reuveni H, Flashner-Abramson E, Steiner L, Makedonski K, Song R, Shir A, Herlyn M, Bar-Eli M, Levitzki A
Cancer Res 2013 Jul 15;73(14):4383-94
PMID 23651636
 
Insulin induces tyrosine phosphorylation of JAK2 in insulin-sensitive tissues of the intact rat
Saad MJ, Carvalho CR, Thirone AC, Velloso LA
J Biol Chem 1996 Sep 6;271(36):22100-4
PMID 8703019
 
Angiotensin II induces tyrosine phosphorylation of insulin receptor substrate 1 and its association with phosphatidylinositol 3-kinase in rat heart
Saad MJ, Velloso LA, Carvalho CR
Biochem J 1995 Sep 15;310 ( Pt 3):741-4
PMID 7575404
 
Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling
Sanchez-Lopez E, Flashner-Abramson E, Shalapour S, Zhong Z, Taniguchi K, Levitzki A, Karin M
Oncogene 2016 May 19;35(20):2634-44
PMID 26364612
 
Association between IRS-2 G1057D polymorphism and risk of gastric cancer
Zhao XM, Chen J, Yang L, Luo X, Xu LL, Liu DX, Zhai SL, Li P, Wang XR
World J Gastrointest Oncol 2012 Jan 15;4(1):9-15
PMID 22347534
 
Activating Mutations of Insulin Receptor Substrate 2 (IRS2) in Patients with Tyrosine Kinase Inhibitor-Refractory Chronic Myeloid Leukemia.E
Savage SL, Eide CA, Concannon KF, Bottomly D, Wilmot B, McWeeney SK, Maxson JE, Tyner JW, Tognon CE and Druker BJ.
Blood (ASH Annual Meeting Abstracts) 2015 126 (23): Abstract #2461.
 
Elevated expression of IRS2 in the progression from neurofibroma to malignant peripheral nerve sheath tumor
Shaw CM, Grobmyer SR, Ucar DA, Cance WG, Reith JD, Hochwald SN
Anticancer Res 2012 Feb;32(2):439-43
PMID 22287730
 
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
Mol Cell Biol 2001 Aug;21(15):5082-93
PMID 11438664
 
Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States
Slattery ML, Sweeney C, Wolff R, Herrick J, Baumgartner K, Giuliano A, Byers T
Breast Cancer Res Treat 2007 Aug;104(2):197-209
PMID 17051426
 
Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells
Stöhr O, Hahn J, Moll L, Leeser U, Freude S, Bernard C, Schilbach K, Markl A, Udelhoven M, Krone W, Schubert M
Biochim Biophys Acta 2011 May;1812(5):573-80
PMID 21354306
 
Role of IRS-2 in insulin and cytokine signalling
Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr, Glasheen E, Lane WS, Pierce JH, White MF
Nature 1995 Sep 14;377(6545):173-7
PMID 7675087
 
Irs2 inactivation suppresses tumor progression in Pten+/- mice
Szabolcs M, Keniry M, Simpson L, Reid LJ, Koujak S, Schiff SC, Davidian G, Licata S, Gruvberger-Saal S, Murty VV, Nandula S, Efstratiadis A, Kushner JA, White MF, Parsons R
Am J Pathol 2009 Jan;174(1):276-86
PMID 19095950
 
Interferon-alpha engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 3'-kinase
Uddin S, Yenush L, Sun XJ, Sweet ME, White MF, Platanias LC
J Biol Chem 1995 Jul 7;270(27):15938-41
PMID 7608146
 
Cross-talk between the insulin and angiotensin signaling systems
Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR
Proc Natl Acad Sci U S A 1996 Oct 29;93(22):12490-5
PMID 8901609
 
Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2
Verdier F, Chrétien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P
An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation J Biol Chem
PMID 9334184
 
The insulin signaling system
White MF, Kahn CR
J Biol Chem 1994 Jan 7;269(1):1-4
PMID 8276779
 
Disruption of IRS-2 causes type 2 diabetes in mice
Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF
Nature 1998 Feb 26;391(6670):900-4
PMID 9495343
 
Interaction between nuclear insulin receptor substrate-2 and NF-κB in IGF-1 induces response in breast cancer cells
Wu S, Zhou B, Xu L, Sun H
Oncol Rep 2010 Dec;24(6):1541-50
PMID 21042750
 
Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines
Xu J, Liao X, Lu N, Liu W, Wong CW
Int J Cancer 2011 Nov 15;129(10):2527-31
PMID 21213215
 
Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray
Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T
Cancer Sci 2006 Jan;97(1):64-71
PMID 16367923
 
The IRS-signalling system during insulin and cytokine action
Yenush L, White MF
Bioessays 1997 Jun;19(6):491-500
PMID 9204766
 
IRS-2 G1057D polymorphism in Turkish patients with colorectal cancer
Yukseloglu EH, Celik SK, Kucuk MU, Yalin E, Ozkal SS, Ates C, Berkoz M, Yalin S, Ates NA
Prz Gastroenterol 2014;9(2):88-92
PMID 25061488
 
Differentially expressed genes in metastatic advanced Egyptian bladder cancer
Zekri AR, Hassan ZK, Bahnassy AA, Khaled HM, El-Rouby MN, Haggag RM, Abu-Taleb FM
Asian Pac J Cancer Prev 2015;16(8):3543-9
PMID 25921176
 
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, Berggren PO, Hansson A, Tally M
J Endocrinol 1998 Mar;156(3):573-81
PMID 9582514
 
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, Kamaraju S, Hakuno F, Kabuta T, Takahashi S, Sachdev D, Yee D
Breast Cancer Res Treat 2004 Jan;83(2):161-70
PMID 14997047
 
Association between IRS-2 G1057D polymorphism and risk of gastric cancer
Zhao XM, Chen J, Yang L, Luo X, Xu LL, Liu DX, Zhai SL, Li P, Wang XR
World J Gastrointest Oncol 2012 Jan 15;4(1):9-15
PMID 22347534
 
IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms
de Melo Campos P, Machado-Neto JA, Eide CA, Savage SL, Scopim-Ribeiro R, da Silva Souza Duarte A, Favaro P, Lorand-Metze I, Costa FF, Tognon CE, Druker BJ, Olalla Saad ST, Traina F
Oncotarget 2016 Feb 9;7(6):6948-59
 

Citation

This paper should be referenced as such :
Joao Agostinho Machado-Neto, Paula de Melo Campos, Fabiola Traina
IRS2 (insulin receptor substrate 2)
Atlas Genet Cytogenet Oncol Haematol. 2017;21(2):35-43.
Free journal version : [ pdf ]   [ DOI ]

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

External links

 

Nomenclature
HGNC (Hugo)IRS2   6126
Cards
AtlasIRS2ID40994ch13q34
Entrez_Gene (NCBI)IRS2    insulin receptor substrate 2
AliasesIRS-2
GeneCards (Weizmann)IRS2
Ensembl hg19 (Hinxton)ENSG00000185950 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000185950 [Gene_View]  ENSG00000185950 [Sequence]  chr13:109752695-109786583 [Contig_View]  IRS2 [Vega]
ICGC DataPortalENSG00000185950
TCGA cBioPortalIRS2
AceView (NCBI)IRS2
Genatlas (Paris)IRS2
SOURCE (Princeton)IRS2
Genetics Home Reference (NIH)IRS2
Genomic and cartography
GoldenPath hg38 (UCSC)IRS2  -     chr13:109752695-109786583 -  13q34   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IRS2  -     13q34   [Description]    (hg19-Feb_2009)
GoldenPathIRS2 - 13q34 [CytoView hg19]  IRS2 - 13q34 [CytoView hg38]
ImmunoBaseENSG00000185950
Genome Data Viewer NCBIIRS2 [Mapview hg19]  
OMIM125853   600797   
Gene and transcription
Genbank (Entrez)AF073310 AF161416 BC012414 BC026044 BC042858
RefSeq transcript (Entrez)NM_003749
Consensus coding sequences : CCDS (NCBI)IRS2
Gene ExpressionIRS2 [ NCBI-GEO ]   IRS2 [ EBI - ARRAY_EXPRESS ]   IRS2 [ SEEK ]   IRS2 [ MEM ]
Gene Expression Viewer (FireBrowse)IRS2 [ Firebrowse - Broad ]
GenevisibleExpression of IRS2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
GTEX Portal (Tissue expression)IRS2
Human Protein AtlasENSG00000185950-IRS2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y4H2   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y4H2  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y4H2
PhosPhoSitePlusQ9Y4H2
Domaine pattern : Prosite (Expaxy)IRS_PTB (PS51064)    PH_DOMAIN (PS50003)   
Domains : Interpro (EBI)IRS    IRS_PTB    PH-like_dom_sf    PH_domain   
Domain families : Pfam (Sanger)IRS (PF02174)    PH (PF00169)   
Domain families : Pfam (NCBI)pfam02174    pfam00169   
Domain families : Smart (EMBL)PH (SM00233)  PTBI (SM00310)  
Conserved Domain (NCBI)IRS2
PDB (RSDB)3FQW    3FQX   
PDB Europe3FQW    3FQX   
PDB (PDBSum)3FQW    3FQX   
PDB (IMB)3FQW    3FQX   
Structural Biology KnowledgeBase3FQW    3FQX   
SCOP (Structural Classification of Proteins)3FQW    3FQX   
CATH (Classification of proteins structures)3FQW    3FQX   
SuperfamilyQ9Y4H2
AlphaFold pdb e-kbQ9Y4H2   
Human Protein Atlas [tissue]ENSG00000185950-IRS2 [tissue]
HPRD02878
Protein Interaction databases
DIP (DOE-UCLA)Q9Y4H2
IntAct (EBI)Q9Y4H2
BioGRIDIRS2
STRING (EMBL)IRS2
ZODIACIRS2
Ontologies - Pathways
QuickGOQ9Y4H2
Ontology : AmiGOMAPK cascade  positive regulation of mesenchymal cell proliferation  negative regulation of B cell apoptotic process  insulin receptor binding  protein binding  cytosol  cytosol  plasma membrane  plasma membrane  glucose metabolic process  signal transduction  axon guidance  brain development  positive regulation of cell population proliferation  insulin receptor signaling pathway  insulin receptor signaling pathway  response to glucose  negative regulation of long-chain fatty acid import across plasma membrane  positive regulation of glucose metabolic process  positive regulation of phosphatidylinositol 3-kinase signaling  regulation of lipid metabolic process  protein kinase binding  protein phosphatase binding  protein domain specific binding  positive regulation of cell migration  mammary gland development  positive regulation of B cell proliferation  positive regulation of fatty acid beta-oxidation  positive regulation of insulin secretion  cellular response to insulin stimulus  protein-containing complex  negative regulation of kinase activity  interleukin-7-mediated signaling pathway  phosphatidylinositol 3-kinase binding  positive regulation of glycogen biosynthetic process  positive regulation of glycogen biosynthetic process  positive regulation of glucose import  positive regulation of Ras protein signal transduction  phosphatidylinositol-mediated signaling  positive regulation of protein kinase B signaling  lipid homeostasis  cellular response to glucose stimulus  14-3-3 protein binding  
Ontology : EGO-EBIMAPK cascade  positive regulation of mesenchymal cell proliferation  negative regulation of B cell apoptotic process  insulin receptor binding  protein binding  cytosol  cytosol  plasma membrane  plasma membrane  glucose metabolic process  signal transduction  axon guidance  brain development  positive regulation of cell population proliferation  insulin receptor signaling pathway  insulin receptor signaling pathway  response to glucose  negative regulation of long-chain fatty acid import across plasma membrane  positive regulation of glucose metabolic process  positive regulation of phosphatidylinositol 3-kinase signaling  regulation of lipid metabolic process  protein kinase binding  protein phosphatase binding  protein domain specific binding  positive regulation of cell migration  mammary gland development  positive regulation of B cell proliferation  positive regulation of fatty acid beta-oxidation  positive regulation of insulin secretion  cellular response to insulin stimulus  protein-containing complex  negative regulation of kinase activity  interleukin-7-mediated signaling pathway  phosphatidylinositol 3-kinase binding  positive regulation of glycogen biosynthetic process  positive regulation of glycogen biosynthetic process  positive regulation of glucose import  positive regulation of Ras protein signal transduction  phosphatidylinositol-mediated signaling  positive regulation of protein kinase B signaling  lipid homeostasis  cellular response to glucose stimulus  14-3-3 protein binding  
Pathways : KEGGFoxO signaling pathway    Insulin signaling pathway    Adipocytokine signaling pathway    Type II diabetes mellitus    Non-alcoholic fatty liver disease (NAFLD)    MicroRNAs in cancer   
REACTOMEQ9Y4H2 [protein]
REACTOME PathwaysR-HSA-982772 [pathway]   
NDEx NetworkIRS2
Atlas of Cancer Signalling NetworkIRS2
Wikipedia pathwaysIRS2
Orthology - Evolution
GeneTree (enSembl)ENSG00000185950
Phylogenetic Trees/Animal Genes : TreeFamIRS2
Homologs : HomoloGeneIRS2
Homology/Alignments : Family Browser (UCSC)IRS2
Gene fusions - Rearrangements
Fusion : QuiverIRS2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIRS2 [hg38]
dbVarIRS2
ClinVarIRS2
MonarchIRS2
1000_GenomesIRS2 
Exome Variant ServerIRS2
GNOMAD BrowserENSG00000185950
Varsome BrowserIRS2
ACMGIRS2 variants
VarityQ9Y4H2
Genomic Variants (DGV)IRS2 [DGVbeta]
DECIPHERIRS2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIRS2 
Mutations
ICGC Data PortalIRS2 
TCGA Data PortalIRS2 
Broad Tumor PortalIRS2
OASIS PortalIRS2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIRS2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DIRS2
Mutations and Diseases : HGMDIRS2
intOGen PortalIRS2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaIRS2
DgiDB (Drug Gene Interaction Database)IRS2
DoCM (Curated mutations)IRS2
CIViC (Clinical Interpretations of Variants in Cancer)IRS2
OncoKBIRS2
NCG (London)IRS2
Cancer3DIRS2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM125853    600797   
Orphanet
DisGeNETIRS2
MedgenIRS2
Genetic Testing Registry IRS2
NextProtQ9Y4H2 [Medical]
GENETestsIRS2
Target ValidationIRS2
Huge Navigator IRS2 [HugePedia]
ClinGenIRS2
Clinical trials, drugs, therapy
MyCancerGenomeIRS2
Protein Interactions : CTDIRS2
Pharm GKB GenePA375
Pharm GKB PathwaysPA153627758   
PharosQ9Y4H2
Clinical trialIRS2
Miscellaneous
canSAR (ICR)IRS2
HarmonizomeIRS2
DataMed IndexIRS2
Probes
Litterature
PubMed256 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXIRS2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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