IRS1 Gene - Insulin Receptor Substrate 1
Key mediator of insulin and insulin-like growth factor 1 (IGF1) signaling
Gene Information Card
| Symbol | IRS1 |
|---|---|
| Full Name | Insulin Receptor Substrate 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q36.3 |
| NCBI Gene ID | 3667 ncbi.nlm.nih.gov/gene/3667 |
| Ensembl ID | ENSG00000169047 |
| UniProt ID | P35568 |
| OMIM ID | 147545 |
| HGNC ID | 6125 |
| Aliases | HIRS-1, IRS-1 |
Description
IRS1 encodes insulin receptor substrate 1, a cytoplasmic adaptor protein that is a key mediator of insulin and insulin-like growth factor 1 (IGF1) signaling. Upon receptor activation, IRS1 is tyrosine phosphorylated and recruits downstream effectors such as PI3K and GRB2, regulating glucose metabolism, cell growth, and survival. Variants in IRS1 are associated with insulin resistance, type 2 diabetes, and susceptibility to certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Type 2 Diabetes | Impaired insulin signaling due to IRS1 variants or reduced expression leads to insulin resistance | OMIM 125853; multiple association studies |
| Insulin Resistance | Defective IRS1 phosphorylation and PI3K activation disrupt glucose uptake | OMIM 147545; ClinVar |
| Coronary Artery Disease | IRS1 Gly972Arg variant associated with increased risk | NCBI Gene; literature |
| Breast Cancer | IRS1 overexpression and altered signaling promote tumor growth and metastasis | COSMIC; literature |
| Obesity | IRS1 polymorphisms linked to adiposity and metabolic syndrome | OMIM; GWAS catalog |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adipose tissue | 12.3 | Medium |
| Liver | 8.7 | Medium |
| Skeletal muscle | 15.1 | High |
| Pancreas | 6.2 | Low |
| Brain | 4.5 | Low |
| Heart | 7.8 | Medium |
| Kidney | 9.4 | Medium |
| Lung | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 18.2 | Liver cancer cell line; high expression |
| MCF7 | 22.5 | Breast cancer cell line; high expression |
| 3T3-L1 (adipocyte) | 14.0 | Differentiated adipocytes; medium-high |
| C2C12 (myoblast) | 11.3 | Muscle cell line; medium |
| HEK293 | 9.8 | Embryonic kidney; medium |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Gly972Arg | Missense | 5-10% in some populations | Reduced insulin signaling; associated with insulin resistance and type 2 diabetes |
| Arg1221Cys | Missense | Rare | Impaired IRS1 phosphorylation; linked to severe insulin resistance |
| Ser892Gly | Missense | Common (MAF ~0.3) | Modest effect on signaling; associated with metabolic traits |
| Ala513Pro | Missense | Rare | Unknown functional effect; reported in cancer |
Mutation functional classification
Loss of Function (LOF)
Gly972Arg reduces IRS1 tyrosine phosphorylation and PI3K activation, impairing insulin signaling.
Gain of Function (GOF)
Not well characterized; overexpression in cancer may enhance IGF1 signaling.
Dominant Negative (DN)
Some rare variants may interfere with wild-type IRS1 function, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • GO:0005158 - insulin receptor binding | • GO:0004871 - signal transducer activity |
| • GO:0008286 - insulin receptor signaling pathway | • GO:0046626 - regulation of insulin receptor signaling pathway |
| • GO:0005515 - protein binding | • GO:0019901 - protein kinase binding |
| • GO:0048015 - phosphatidylinositol 3-kinase signaling | • GO:0007165 - signal transduction |
| • GO:0005737 - cytoplasm | • GO:0005886 - plasma membrane |
Pathways
• Insulin signaling pathway (KEGG hsa04910)
• PI3K-Akt signaling pathway (KEGG hsa04151)
• IGF1 signaling pathway
• IRS-mediated signaling (Reactome R-HSA-112399)
• Signaling by Insulin receptor (Reactome R-HSA-74752)
Protein Summary
IRS1 is a 1242-amino-acid cytoplasmic adaptor protein with a pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain. It is tyrosine phosphorylated by activated insulin and IGF1 receptors, creating docking sites for SH2 domain-containing proteins such as PI3K and GRB2. IRS1 is central to metabolic and mitogenic signaling. Dysregulation contributes to insulin resistance, diabetes, and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IRS1 Knockout HEK293 Cell Line | EDJ-KQ1190 | Human | 3667 | Details Get a Quote |
| IRS1 Knockout A-549 Cell Line | EDJ-KQ19126 | Human | 3667 | Details Get a Quote |
| IRS1 Knockout HCT 116 Cell Line | EDJ-KQ20483 | Human | 3667 | Details Get a Quote |
| IRS1 Knockout HeLa Cell Line | EDJ-KQ20484 | Human | 3667 | Details Get a Quote |
| IRS1 Knockout HAP1 Cell Line | EDC08206 | Human | 3667 | Details Get a Quote |
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