IRS2

Summary

IRS2 (insulin receptor substrate 2, HGNC:6126) is a protein-coding gene on chromosome 13q34, encoding Insulin receptor substrate 2 (Q9Y4H2). Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R. It is a selective cancer dependency (DepMap: 26.1% of cell lines).

This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment.

Source: NCBI Gene 8660 — RefSeq curated summary.

At a glance

• GWAS associations: 33
• Clinical variants (ClinVar): 165 total
• Phenotypes (HPO): 5
• Cancer dependency (DepMap): dependent in 26.1% of screened cell lines
• MANE Select transcript: NM_003749

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6126
Approved symbol	IRS2
Name	insulin receptor substrate 2
Location	13q34
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000185950
Ensembl biotype	protein_coding
OMIM	600797
Entrez	8660

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000375856

RefSeq mRNA: 1 — MANE Select: NM_003749 NM_003749

CCDS: CCDS9510

Canonical transcript exons

ENST00000375856 — 2 exons

Exon	Start	End
ENSE00001434305	109752695	109756308
ENSE00001468589	109782042	109786583

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.4157 / max 2369.7778, expressed in 1715 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138198	39.7977	1710
138189	0.5211	204
138197	0.0528	15
138188	0.0441	17

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	99.36	gold quality
CA1 field of hippocampus	UBERON:0003881	98.90	gold quality
postcentral gyrus	UBERON:0002581	98.42	gold quality
parietal lobe	UBERON:0001872	98.16	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.07	gold quality
orbitofrontal cortex	UBERON:0004167	98.03	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.88	gold quality
entorhinal cortex	UBERON:0002728	97.80	gold quality
middle temporal gyrus	UBERON:0002771	97.68	gold quality
inferior olivary complex	UBERON:0002127	97.59	gold quality
medial globus pallidus	UBERON:0002477	97.47	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.47	gold quality
globus pallidus	UBERON:0001875	97.30	gold quality
lower lobe of lung	UBERON:0008949	97.29	gold quality
buccal mucosa cell	CL:0002336	97.17	gold quality
pericardium	UBERON:0002407	97.14	gold quality
upper leg skin	UBERON:0004262	96.90	gold quality
type B pancreatic cell	CL:0000169	96.83	gold quality
tibialis anterior	UBERON:0001385	96.80	gold quality
epithelium of mammary gland	UBERON:0003244	96.74	gold quality
left ventricle myocardium	UBERON:0006566	96.70	gold quality
mammary duct	UBERON:0001765	96.65	gold quality
caput epididymis	UBERON:0004358	96.65	gold quality
cauda epididymis	UBERON:0004360	96.65	gold quality
endothelial cell	CL:0000115	96.58	gold quality
adult organism	UBERON:0007023	96.48	gold quality
medulla oblongata	UBERON:0001896	96.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.16
E-HCAD-13	yes	7.01
E-CURD-112	no	2.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ARNT, ATF3, DLX5, EIF2AK2, FOXO1, FOXO3, NFATC1, NFIC, NR3C1, PGR, SP1, SREBF1, STAT6, TFE3, ZNF148

miRNA regulators (miRDB)

177 targeting IRS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• IRS-2, not IRS-1, signals insulin activation of glycogen synthase in the L6hIR skeletal muscle cells. In these cells, insulin inhibition of GSK3 alpha and -beta requires dual phosphorylation by both Akt/PKB and PKC zeta. (PMID:11481324)
• the 5’ flanking sequence of IRS2 was investigated and two single nucleotide polymorphisms (SNPs) were identified; the SNP at -765 was suggested to be involved in the insulin-mediated regulation of the transcriptional activity of IRS2 (PMID:12189449)
• Relationship of genotypes to phenotypic features of polycystic ovary syndrome (PMID:12213887)
• Data suggest that insulin receptor substrate-2 (IRS-2) is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover. (PMID:12379806)
• inhibition of insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor (PMID:12493740)
• Polymorphisms of the insulin receptor substrate-2 in patients with type 2 diabetes. No major role of IRS-2 polymorphisms in the pathogenesis of type 2 diabetes. (PMID:12519871)
• Mutations in IRS2 gene are associated with severe obesity (PMID:12687350)
• the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits (PMID:12765968)
• IRS-2 is degraded by estrogen receptor alpha and is not involved in IGF-I signaling (PMID:12821935)
• Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of IRS2. (PMID:14534541)
• Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. (PMID:14604996)
• B cells derived from transgenic mice expressing IRS2 levels elevated by 2- to 3-fold demonstrate alterations in the B cell intrinsic density-dependence of IgE and IgG1 production in vitro and an elevated serum IgE response after in vivo challenge. (PMID:14978080)
• IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway (PMID:15123681)
• data demonstrate cell-specific alterations in IRS protein concentrations in theca cells from polycystic ovaries consistent with exaggerated amplification of the insulin signal & which may play a role in ovarian hyperandrogenism & thecal hyperplasia (PMID:15155816)
• The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9)except for those with the IRS1 R allele. (PMID:15247132)
• IRS-2/PI 3-kinase pathway does not restore insulin-stimulated glucose uptake in myotubes from Type 2 diabetic patients. (PMID:15292987)
• SH2-B dramatically enhanced leptin-stimulated tyrosine phosphorylation of IRS1 and IRS2 in human and mouse cells. (PMID:15316008)
• type 2 diabetic patients, particularly obese patients, carrying the D1057 allele and the CA haplotype were associated with insulin resistance (PMID:15811564)
• Carriers of Pro allele compared with carriers of Ala allele of PPARG2 gene had higher frequency of insulin resistance. No association was found between insulin resistance and alleles and genotypes of PPAR and IRS2 genes. (PMID:15940190)
• Data show that the relationships between G1057D variants of IRS2 and type 2 diabetes mellitus are mediated by obesity. (PMID:16086274)
• Emergence of IRS-2 overexpression at preneoplastic stages during experimental hepatocarcinogenesis and its protective effect against apoptosis suggest that IRS-2 contributes to liver tumor progression. (PMID:16127164)
• IRS-1 and -2 degradation are mediated by phosphatidylinositol 3-kinase and proteasome sensitive pathway. High levels of IGF-IR, and possibly the subsequent increase in Akt phosphorylation, are required for efficient IRS degradation. (PMID:16150916)
• after an acute bout of exercise, insulin-stimulated IRS-2 signaling is enhanced in human skeletal muscle (PMID:16839840)
• Transgenic mice overexpressing IRS2 in the mammary gland show progressive mammary hyperplasia, tumorigenesis and metastasis. (PMID:17030631)
• Genetic variation in IRS2 is associated with breast cancer risk (PMID:17051426)
• phosphorylation is a mechanism for regulation of insulin receptor substrate-1/2, Akt, and ERK1/2 (PMID:17068339)
• We showed that clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression. (PMID:17222321)
• This review points out that IRS-2, which is implicated in mediating signals to promote tumor cell survival, growth and motility, is a positive regulator of breast cancer metastasis. (PMID:17361103)
• This review discusses the roles of IRS-1 and IRS-2 in oncogenic transformation and cancer progression. (PMID:17374994)
• possible regulatory effect of SirT1 on insulin-induced tyrosine phosphorylation of IRS-2, a vital step in insulin signaling pathway, through deacetylation of IRS-2 protein. (PMID:17901049)
• Altered osteoblast proliferation in human osteoporosis may result from dysregulation of IGF-I receptor signaling, including constitutive activation of the IRS-2/Erk signaling pathway. (PMID:18079194)
• IRS2 expression was localised to macrophages and endothelial cells in vivo. The elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD. (PMID:18506362)
• SNPs in HSD11B1 and IRS2 mark regions of the genome that may harbor risk alleles for breast cancer (PMID:18611262)
• contribution of defective Irs2 signaling to metabolic syndrome-associated alterations (PMID:18802016)
• During in-vitro decidualization of cultured human ESCs, levels of IRS-1 increased, suggesting a potential involvement of the IGF signalling pathway in the decidualization process. (PMID:19038974)
• IL-4 induced highly efficient, gammaC-dependent tyrosine phosphorylation of IRS-2, whereas IL-13 was less effective, even when phosphorylation of STAT6 was maximal (PMID:19109239)
• Regulatory role of IRS-2 on the expression of IGF-I receptor through Protein kinase c-delta in pancreatic cancer cells. (PMID:19190347)
• The differential degradation of IRS-1 and IRS-2 contributes to their distinct modes of action. (PMID:19259821)
• These results strongly argue against a major role of the Gly1057Asp IRS-2 polymorphism in the pathogenesis of type 2 diabetes in Djerbian subjects. (PMID:19332049)
• Study has revealed several new non-synonymous variants in the IRS2 gene in both a cohort of predominately Europid individuals with severe insulin resistance and in insulin-sensitive Europid volunteers. (PMID:19377890)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	irs2a	ENSDARG00000037099
danio_rerio	irs2b	ENSDARG00000075282
mus_musculus	Irs2	ENSMUSG00000038894
rattus_norvegicus	Irs2	ENSRNOG00000023509
drosophila_melanogaster	chico	FBGN0024248

Paralogs (2): IRS4 (ENSG00000133124), IRS1 (ENSG00000169047)

Protein

Protein identifiers

Insulin receptor substrate 2 — Q9Y4H2 (reviewed: Q9Y4H2)

All UniProt accessions (1): Q9Y4H2

UniProt curated annotations — full annotation on UniProt →

Function. Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R. Plays therefore an important role in development, growth, glucose homeostasis as well as lipid metabolism. Upon phosphorylation by the insulin receptor, functions as a signaling scaffold that propagates insulin action through binding to SH2 domain-containing proteins including the p85 regulatory subunit of PI3K, NCK1, NCK2, GRB2 or SHP2. Recruitment of GRB2 leads to the activation of the guanine nucleotide exchange factor SOS1 which in turn triggers the Ras/Raf/MEK/MAPK signaling cascade. Activation of the PI3K/AKT pathway is responsible for most of insulin metabolic effects in the cell, and the Ras/Raf/MEK/MAPK is involved in the regulation of gene expression and in cooperation with the PI3K pathway regulates cell growth and differentiation. Acts a positive regulator of the Wnt/beta-catenin signaling pathway through suppression of DVL2 autophagy-mediated degradation leading to cell proliferation. Plays a role in cell cycle progression by promoting a robust spindle assembly checkpoint (SAC) during M-phase. In macrophages, IL4-induced tyrosine phosphorylation of IRS2 leads to the recruitment and activation of phosphoinositide 3-kinase (PI3K).

Subunit / interactions. Interacts with PHIP. Interacts with SH2B1; this interaction enhances leptin-induced activation of the PI3-kinase pathway. Interacts with GRB2. Interacts with PIK3R1. Interacts with DVL2; this interaction promotes the Wnt/beta-catenin signaling pathway.

Subcellular location. Cytoplasm. Cytosol.

Post-translational modifications. Phosphorylation fluctuates in a cell-cycle dependent manner with hyperphosphorylation during mitosis. Phosphorylated at Ser-560 and Ser-1109 by PLK1; these phosphorylations prevent the activation of the PI3K pathway upon growth factor stimulation by inhibiting the binding between IRS2 and the PI3K pathway components and increasing the level of IRS2 protein degradation. In addition, they prevent premature mitotic exit. Monoubiquitinated by NEDD4; leading to enhanced IGF1 signaling. During cell cycle, ubiquitination and proteasomal degradation are controlled by FZR1.

RefSeq proteins (1): NP_003740* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR039011	IRS	Family

Pfam: PF00169, PF02174

UniProt features (107 total): modified residue 43, sequence conflict 25, compositionally biased region 16, short sequence motif 7, region of interest 7, sequence variant 5, domain 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3FQX	X-RAY DIFFRACTION	1.7
3FQW	X-RAY DIFFRACTION	1.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4H2-F1	48.33	0.14

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (44): 306, 346, 350, 365, 384, 388, 391, 412, 520, 523, 527, 540, 560, 577, 579, 580, 594, 608, 620, 653 …

Function

Pathways and Gene Ontology

Reactome pathways

41 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-112399	IRS-mediated signalling
R-HSA-112412	SOS-mediated signalling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266695	Interleukin-7 signaling
R-HSA-198203	PI3K/AKT activation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2428928	IRS-related events triggered by IGF1R
R-HSA-2586552	Signaling by Leptin
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-74713	IRS activation
R-HSA-74749	Signal attenuation
R-HSA-8853659	RET signaling
R-HSA-9006335	Signaling by Erythropoietin
R-HSA-9027276	Erythropoietin activates Phosphoinositide-3-kinase (PI3K)
R-HSA-9027277	Erythropoietin activates Phospholipase C gamma (PLCG)
R-HSA-9027283	Erythropoietin activates STAT5
R-HSA-9027284	Erythropoietin activates RAS
R-HSA-982772	Growth hormone receptor signaling
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166520	Signaling by NTRKs
R-HSA-168256	Immune System
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-2404192	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)

MSigDB gene sets: 602 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_LIPID_MODIFICATION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_TRANSPORT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (31): positive regulation of mesenchymal cell proliferation (GO:0002053), negative regulation of B cell apoptotic process (GO:0002903), glucose metabolic process (GO:0006006), signal transduction (GO:0007165), brain development (GO:0007420), positive regulation of cell population proliferation (GO:0008284), insulin receptor signaling pathway (GO:0008286), response to glucose (GO:0009749), epithelial cell migration (GO:0010631), positive regulation of epithelial cell migration (GO:0010634), negative regulation of long-chain fatty acid import across plasma membrane (GO:0010748), positive regulation of glucose metabolic process (GO:0010907), regulation of lipid metabolic process (GO:0019216), mammary gland development (GO:0030879), positive regulation of B cell proliferation (GO:0030890), positive regulation of fatty acid beta-oxidation (GO:0032000), positive regulation of insulin secretion (GO:0032024), cellular response to insulin stimulus (GO:0032869), type B pancreatic cell proliferation (GO:0044342), positive regulation of glycogen biosynthetic process (GO:0045725), positive regulation of D-glucose import across plasma membrane (GO:0046326), insulin-like growth factor receptor signaling pathway (GO:0048009), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), lipid homeostasis (GO:0055088), cellular response to glucose stimulus (GO:0071333), positive regulation of type B pancreatic cell proliferation (GO:1904692), cellular response to endothelin (GO:1990859), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), cell population proliferation (GO:0008283), cell migration (GO:0016477), positive regulation of transport (GO:0051050)

GO Molecular Function (11): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), insulin receptor binding (GO:0005158), protein phosphatase binding (GO:0019903), protein domain specific binding (GO:0019904), signaling adaptor activity (GO:0035591), phosphatidylinositol 3-kinase binding (GO:0043548), 14-3-3 protein binding (GO:0071889), phosphatidylinositol 3-kinase activator activity (GO:0141038), protein binding (GO:0005515), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by Erythropoietin	4
Insulin receptor signalling cascade	3
IRS-mediated signalling	2
Signal Transduction	2
IRS-related events triggered by IGF1R	1
Intracellular signaling by second messengers	1
Signaling by Interleukins	1
Signaling by NTRK1 (TRKA)	1
PI3K/AKT Signaling in Cancer	1
IGF1R signaling cascade	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Axon guidance	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cell surface receptor protein tyrosine kinase signaling pathway	2
cellular anatomical structure	2
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
B cell apoptotic process	1
regulation of B cell apoptotic process	1
negative regulation of lymphocyte apoptotic process	1
hexose metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
central nervous system development	1
animal organ development	1
head development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular response to insulin stimulus	1
response to hexose	1
ameboidal-type cell migration	1
epithelium migration	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
regulation of long-chain fatty acid import across plasma membrane	1
long-chain fatty acid import across plasma membrane	1
negative regulation of transmembrane transport	1
negative regulation of long-chain fatty acid import into cell	1
glucose metabolic process	1
regulation of glucose metabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of small molecule metabolic process	1
lipid metabolic process	1
regulation of primary metabolic process	1
gland development	1
regulation of B cell proliferation	1

Protein interactions and networks

STRING

2594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRS2	GRB2	P29354	989
IRS2	INS	P01308	986
IRS2	IGF1R	P08069	974
IRS2	IRS1	P35568	970
IRS2	IGF1	P01343	970
IRS2	H3BTC1	H3BTC1	960
IRS2	INSR	P06213	903
IRS2	AKT1	P31749	876
IRS2	IRS4	O14654	845
IRS2	PTPN11	Q06124	823
IRS2	PIK3R1	P27986	815
IRS2	SLC2A4	P14672	805
IRS2	FOXO1	Q12778	796
IRS2	JAK2	O60674	789
IRS2	LEP	P41159	785

IntAct

86 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R1	psi-mi:“MI:0914”(association)	0.960
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
YWHAG	IRS2	psi-mi:“MI:0915”(physical association)	0.860
YWHAB	IRS2	psi-mi:“MI:0915”(physical association)	0.830
IRS2	YWHAZ	psi-mi:“MI:0915”(physical association)	0.820
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
PIK3R3	PIK3CD	psi-mi:“MI:0914”(association)	0.800
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
PIK3R1	IRS2	psi-mi:“MI:0915”(physical association)	0.690
IRS2	PIK3R1	psi-mi:“MI:0915”(physical association)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
IRS2	SIRT1	psi-mi:“MI:0915”(physical association)	0.590
SIRT1	IRS2	psi-mi:“MI:0915”(physical association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAE	IRS2	psi-mi:“MI:0914”(association)	0.570

BioGRID (144): Sirt1 (Affinity Capture-Western), IRS2 (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), IRS2 (Biochemical Activity), IRS2 (Affinity Capture-Western), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Biochemical Activity), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-MS), IRS2 (Affinity Capture-Western)

ESM2 similar proteins: A4IHR5, A6H7J1, A6NKL6, A6NL88, A7UKY7, A7YY54, B8ZZ34, C9J069, C9JLR9, E9Q1P8, O15209, O35615, O35779, P04198, P15066, P17535, P39881, P52909, Q01101, Q0PHV7, Q14526, Q14934, Q15742, Q32KV8, Q4VA45, Q52KG4, Q5TJE2, Q61976, Q63ZV0, Q6NUJ5, Q6P0F9, Q7T3H2, Q7Z5L9, Q7Z6J2, Q8C3Q5, Q8IX07, Q8R4T5, Q8TF61, Q8VCG9, Q96B18

Diamond homologs: B3MPN6, B3N946, B4HWI2, B4NZ70, O14654, P35568, P35569, P35570, P81122, P84770, Q28224, Q5RJW5, Q6P4Y6, Q91615, Q9DF49, Q9XTN2, Q9Y4H2, Q9Z0Y7

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
IL4R	up-regulates	IRS2	phosphorylation
IRS2	up-regulates	PIK3CG	binding
IRS2	“up-regulates activity”	PIK3CA	binding
APC-c	“down-regulates quantity by destabilization”	IRS2	polyubiquitination
CREB1	“up-regulates quantity by expression”	IRS2	“transcriptional regulation”
mTORC2	“up-regulates quantity by expression”	IRS2	“transcriptional regulation”
NEDD4	“up-regulates activity”	IRS2	ubiquitination
IGF1R	up-regulates	IRS2	phosphorylation
IRS2	“up-regulates activity”	PI3K	binding
INSR	“down-regulates activity”	IRS2	phosphorylation
INSR	up-regulates	IRS2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	166.5×	8e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	146.9×	1e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	146.9×	1e-12
Activation of BH3-only proteins	7	108.6×	1e-11
Regulation of signaling by CBL	6	93.1×	1e-09
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	81.1×	6e-08
Interleukin receptor SHC signaling	6	76.5×	3e-09
Interleukin-3, Interleukin-5 and GM-CSF signaling	7	69.4×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	45.8×	1e-05
insulin receptor signaling pathway	7	38.8×	2e-07
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	31.6×	8e-06
cellular response to insulin stimulus	5	21.3×	2e-04
intracellular protein localization	7	18.3×	1e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

165 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	17
Benign	15

Top pathogenic / likely-pathogenic (0)

SpliceAI

541 predictions. Top by Δscore:

Variant	Effect	Δscore
13:109756307:CT:C	acceptor_gain	1.0000
13:109756307:CTCT:C	acceptor_loss	1.0000
13:109756309:C:CA	acceptor_loss	1.0000
13:109756309:C:CC	acceptor_gain	1.0000
13:109756310:T:A	acceptor_loss	1.0000
13:109756305:CACT:C	acceptor_gain	0.9900
13:109782036:CCTCA:C	donor_loss	0.9800
13:109782037:CTCAC:C	donor_loss	0.9800
13:109782038:TCACC:T	donor_loss	0.9800
13:109782039:CA:C	donor_loss	0.9800
13:109782040:ACCTT:A	donor_loss	0.9800
13:109782041:C:A	donor_loss	0.9800
13:109756263:CTCTG:C	donor_gain	0.9600
13:109756306:ACT:A	acceptor_gain	0.9600
13:109756307:CTC:C	acceptor_gain	0.9600
13:109756308:TCT:T	acceptor_gain	0.9600
13:109756309:C:G	acceptor_gain	0.9600
13:109756304:TCACT:T	acceptor_gain	0.9500
13:109756305:CACTC:C	acceptor_gain	0.9500
13:109756311:GAAAA:G	acceptor_loss	0.9400
13:109756312:AAAAA:A	acceptor_loss	0.9400
13:109760766:C:T	acceptor_gain	0.9300
13:109758072:T:TA	donor_gain	0.9100
13:109755954:C:CT	acceptor_gain	0.9000
13:109782040:A:AC	donor_gain	0.9000
13:109782041:C:CC	donor_gain	0.9000
13:109756130:G:T	donor_gain	0.8800
13:109782059:T:TA	donor_gain	0.8600
13:109756136:G:A	donor_gain	0.8400
13:109755955:A:T	acceptor_gain	0.8300

AlphaMissense

8580 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:109782618:G:T	R1146S	1.000
13:109785181:C:A	M291I	1.000
13:109785181:C:G	M291I	1.000
13:109785181:C:T	M291I	1.000
13:109785186:C:G	A290P	1.000
13:109785191:A:G	L288P	1.000
13:109785194:A:T	I287N	1.000
13:109785202:G:C	H284Q	1.000
13:109785202:G:T	H284Q	1.000
13:109785203:T:G	H284P	1.000
13:109785204:G:C	H284D	1.000
13:109785204:G:T	H284N	1.000
13:109785206:A:T	I283N	1.000
13:109785212:T:G	Q281P	1.000
13:109785215:G:T	A280E	1.000
13:109785227:T:A	D276V	1.000
13:109785227:T:G	D276A	1.000
13:109785228:C:A	D276Y	1.000
13:109785228:C:G	D276H	1.000
13:109785239:A:C	M272R	1.000
13:109785239:A:G	M272T	1.000
13:109785239:A:T	M272K	1.000
13:109785241:C:A	W271C	1.000
13:109785241:C:G	W271C	1.000
13:109785242:C:G	W271S	1.000
13:109785243:A:G	W271R	1.000
13:109785243:A:T	W271R	1.000
13:109785245:A:G	L270P	1.000
13:109785251:C:A	G268V	1.000
13:109785251:C:T	G268D	1.000

dbSNP variants (sampled 300 via entrez): RS1000090189 (13:109773878 G>A,C), RS1000280917 (13:109759379 T>C), RS1000417619 (13:109787793 A>G), RS1000496699 (13:109769372 C>T), RS1000597670 (13:109762084 A>G), RS1000600695 (13:109772010 C>T), RS1000669797 (13:109762324 A>G), RS1000929028 (13:109781317 T>A), RS1000982178 (13:109774885 T>A,C), RS1001056130 (13:109769631 C>G,T), RS1001172214 (13:109767024 G>A), RS1001256591 (13:109781111 C>T), RS1001259541 (13:109759112 A>G), RS1001290277 (13:109774729 T>C), RS1001336577 (13:109758127 A>G)

Disease associations

OMIM: gene MIM:600797 | disease phenotypes: MIM:125853

GenCC curated gene-disease

Mondo (1): type 2 diabetes mellitus (MONDO:0005148)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000855	Insulin resistance
HP:0003584	Late onset
HP:0005978	Type II diabetes mellitus
HP:0031819	Increased waist to hip ratio

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST003151_5	White matter lesion progression	4.000000e-06
GCST003152_2	White matter lesion progression (adjusted for white matter lesion burden at baseline)	1.000000e-06
GCST003999_6	Nose size	3.000000e-10
GCST004602_172	Mean corpuscular volume	5.000000e-12
GCST004619_32	Reticulocyte fraction of red cells	5.000000e-10
GCST004630_195	Mean corpuscular hemoglobin	4.000000e-13
GCST004982_1	Prostate cancer	6.000000e-12
GCST005352_24	Paclitaxel disposition in epithelial ovarian cancer	2.000000e-06
GCST005991_33	Platelet count	1.000000e-09
GCST005993_10	Mean corpuscular hemoglobin	2.000000e-08
GCST006011_41	Mean corpuscular volume	2.000000e-08
GCST006288_400	Heel bone mineral density	1.000000e-07
GCST006288_430	Heel bone mineral density	1.000000e-11
GCST006979_1039	Heel bone mineral density	8.000000e-28
GCST009302_18	Antipsychotic drug-induced weight gain in schizophrenia	7.000000e-06
GCST009379_189	Type 2 diabetes	4.000000e-08
GCST009379_190	Type 2 diabetes	9.000000e-08
GCST009724_53	Vertical cup-disc ratio (multi-trait analysis)	8.000000e-11
GCST009863_20	Insulin-related traits (multivariate analysis)	4.000000e-09
GCST010083_85	Hemoglobin levels	1.000000e-10
GCST90002383_250	Hematocrit	5.000000e-10
GCST90002384_329	Hemoglobin	5.000000e-10
GCST90002385_16	High light scatter reticulocyte count	2.000000e-09
GCST90002390_195	Mean corpuscular hemoglobin	2.000000e-33
GCST90002392_415	Mean corpuscular volume	3.000000e-30
GCST90002396_555	Mean reticulocyte volume	4.000000e-26
GCST90002397_65	Mean spheric corpuscular volume	6.000000e-13
GCST90002404_380	Red cell distribution width	1.000000e-14
GCST90002405_359	Reticulocyte count	5.000000e-13
GCST90002405_360	Reticulocyte count	2.000000e-18

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007746	white matter lesion progression measurement
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004309	platelet count
EFO:0009270	heel bone mineral density
EFO:0004567	antipsychotic drug related weight gain
EFO:0006939	cup-to-disc ratio measurement
EFO:0004467	insulin measurement
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

101 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation, increases expression	4
Estradiol	affects cotreatment, increases expression, increases reaction, increases phosphorylation, decreases expression	4
Progesterone	increases expression, increases reaction, increases phosphorylation, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
Glucose	decreases expression, decreases reaction, affects cotreatment, decreases phosphorylation, increases phosphorylation	3
Valproic Acid	increases expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
cupric chloride	increases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
Resveratrol	decreases reaction, increases expression, increases phosphorylation, decreases expression	2
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Benzo(a)pyrene	increases methylation, increases expression	2
Cadmium	decreases phosphorylation, decreases expression, increases abundance, affects cotreatment	2
Metformin	decreases expression, decreases reaction	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
Genistein	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
afuresertib	increases expression	1
fumosorinone	increases phosphorylation	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1B4	Abcam HEK293 IRS2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus