IRS2 Gene: Insulin Receptor Substrate 2
Key mediator of insulin and insulin-like growth factor signaling, implicated in diabetes, cancer, and metabolic disorders.
Gene Information Card
| Symbol | IRS2 |
|---|---|
| Full Name | Insulin Receptor Substrate 2 |
| Gene Type | protein-coding |
| Chromosomal Location | 13q34 |
| NCBI Gene ID | 8660 ncbi.nlm.nih.gov/gene/8660 |
| Ensembl ID | ENSG00000185950 |
| UniProt ID | Q9Y4H2 |
| OMIM ID | 600797 |
| HGNC ID | 6126 |
| Aliases | IRS-2, IRS2_HUMAN |
Description
The IRS2 gene encodes insulin receptor substrate 2, a cytoplasmic adaptor protein that mediates signaling downstream of insulin and insulin-like growth factor 1 receptors. Upon receptor activation, IRS2 is tyrosine-phosphorylated and recruits SH2 domain-containing proteins such as PI3K and Grb2, thereby regulating glucose metabolism, cell growth, and survival. IRS2 is widely expressed and plays critical roles in metabolic homeostasis, pancreatic beta-cell function, and neuronal development. Dysregulation of IRS2 is associated with type 2 diabetes, insulin resistance, and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Type 2 Diabetes Mellitus | Impaired IRS2 signaling reduces insulin sensitivity and beta-cell compensation, leading to glucose intolerance. | OMIM #125853; multiple GWAS studies |
| Breast Cancer | IRS2 overexpression enhances PI3K/AKT signaling, promoting cell proliferation and metastasis. | COSMIC; PMID: 21558396 |
| Colorectal Cancer | IRS2 amplification and overexpression activate oncogenic pathways, correlating with poor prognosis. | COSMIC; PMID: 23431147 |
| Non-Alcoholic Fatty Liver Disease | IRS2 deficiency in liver exacerbates steatosis and insulin resistance. | PMID: 19029979 |
| Alzheimer's Disease | Reduced IRS2 expression in brain impairs insulin signaling, contributing to neurodegeneration. | PMID: 22956769 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adipose tissue | 12.5 | Medium |
| Liver | 8.3 | Medium |
| Pancreas | 15.2 | High |
| Brain | 6.7 | Low |
| Skeletal muscle | 9.1 | Medium |
| Kidney | 7.4 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 14.3 | Liver cancer cell line |
| MCF7 | 18.6 | Breast cancer cell line |
| HeLa | 11.2 | Cervical cancer cell line |
| HEK293 | 9.8 | Embryonic kidney cell line |
| MIN6 | 22.1 | Mouse pancreatic beta-cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs1805097 (G1057D) | SNP | ~30% in European populations | Reduced IRS2 phosphorylation and insulin signaling; associated with type 2 diabetes risk. |
| rs754204 (R1221H) | SNP | ~5% in East Asian populations | Impaired PI3K binding; linked to insulin resistance. |
| Amplification | Copy number gain | Variable in breast and colorectal cancers | Increased IRS2 expression; drives PI3K/AKT activation. |
| Deletion | Loss of heterozygosity | Rare in tumors | Reduced IRS2 expression; may impair metabolic signaling. |
Mutation functional classification
Loss of Function (LOF)
Missense variants (e.g., G1057D) that reduce tyrosine phosphorylation or PI3K binding, impairing insulin signaling and contributing to insulin resistance.
Gain of Function (GOF)
Gene amplification or overexpression in cancers, leading to sustained PI3K/AKT activation and enhanced cell proliferation.
Dominant Negative (DN)
Not well documented; some rare variants may interfere with wild-type IRS2 function in heterozygotes.
View complete mutation data：
Gene Ontology (GO)
| • insulin receptor signaling pathway | • phosphatidylinositol 3-kinase signaling |
| • positive regulation of cell proliferation | • glucose homeostasis |
| • protein tyrosine kinase activity | • SH2 domain binding |
Pathways
• Insulin signaling pathway (KEGG: hsa04910)
• PI3K-Akt signaling pathway (KEGG: hsa04151)
• Type II diabetes mellitus (KEGG: hsa04930)
• IGF-1 receptor signaling (Reactome: R-HSA-2404192)
Protein Summary
Insulin receptor substrate 2 (IRS2) is a 1338-amino-acid cytoplasmic protein containing an N-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and multiple tyrosine phosphorylation sites. It acts as a docking protein for insulin and IGF-1 receptors, recruiting downstream effectors such as PI3K and Grb2. IRS2 is essential for metabolic actions of insulin in liver, muscle, and adipose tissue, and for beta-cell growth and survival. Its dysregulation contributes to insulin resistance, diabetes, and cancer progression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IRS2 Knockout HEK293 Cell Line | EDJ-KQ50812 | Human | 8660 | Details Get a Quote |
| IRS2 Knockout HeLa Cell Line | EDJ-KQ54974 | Human | 8660 | Details Get a Quote |
| IRS2 Knockout A-549 Cell Line | EDJ-KQ63455 | Human | 8660 | Details Get a Quote |
| IRS2 Knockout HCT 116 Cell Line | EDJ-KQ71923 | Human | 8660 | Details Get a Quote |
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