IRS4 Gene - Insulin Receptor Substrate 4
Comprehensive genomic and functional analysis of IRS4, a key adaptor protein in insulin and IGF-1 signaling pathways.
Gene Information Card
| Symbol | IRS4 |
|---|---|
| Full Name | Insulin Receptor Substrate 4 |
| Gene Type | protein-coding |
| Chromosomal Location | Xq22.3 |
| NCBI Gene ID | 8471 ncbi.nlm.nih.gov/gene/8471 |
| Ensembl ID | ENSG00000133124 |
| UniProt ID | O14654 |
| OMIM ID | 300904 |
| HGNC ID | 6128 |
| Aliases | IRS-4, IRS4_HUMAN |
Description
IRS4 (Insulin Receptor Substrate 4) is a member of the insulin receptor substrate family of adaptor proteins. It acts as a docking protein for the insulin and insulin-like growth factor 1 (IGF-1) receptors, mediating downstream signaling through the PI3K/AKT and MAPK pathways. IRS4 is predominantly expressed in the brain, kidney, and certain endocrine tissues, and its dysregulation has been implicated in cancer and metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast Cancer | IRS4 overexpression activates PI3K/AKT signaling, promoting cell proliferation and survival. | COSMIC; PMID: 25691885 |
| Hepatocellular Carcinoma | IRS4 upregulation correlates with poor prognosis and enhanced tumor growth via AKT/mTOR pathway. | PMID: 29367642 |
| Type 2 Diabetes | IRS4 polymorphisms may alter insulin signaling, contributing to insulin resistance. | OMIM #300904; PMID: 11549627 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Kidney | 8.3 | Low |
| Adrenal Gland | 6.7 | Low |
| Thyroid | 5.1 | Low |
| Testis | 4.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 (breast cancer) | 15.2 | High expression; associated with hormone receptor status |
| HepG2 (liver cancer) | 10.1 | Moderate expression; linked to AKT activation |
| HEK293 (embryonic kidney) | 7.4 | Basal expression; used in functional studies |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.214G>A (p.Gly72Arg) | Missense | <0.01% | Unknown; predicted damaging by SIFT |
| c.1025C>T (p.Thr342Met) | Missense | <0.01% | Unknown; likely benign |
| c.1472_1473insA (p.Tyr491*) | Frameshift | <0.01% | Loss of function; truncation |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., p.Tyr491*) lead to truncated protein lacking PH and PTB domains, impairing insulin signaling.
Gain of Function (GOF)
Amplification or overexpression of IRS4 in cancers (e.g., breast, liver) enhances PI3K/AKT signaling, promoting oncogenesis.
Dominant Negative (DN)
Not reported for IRS4; dominant-negative effects are not documented in current literature.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Insulin signaling pathway (KEGG: hsa04910)
• PI3K-Akt signaling pathway (KEGG: hsa04151)
• IGF-1 signaling pathway (Reactome: R-HSA-2404192)
Protein Summary
IRS4 is a 1257-amino acid adaptor protein with an N-terminal pleckstrin homology (PH) domain and a phosphotyrosine binding (PTB) domain. It lacks intrinsic enzymatic activity but serves as a scaffold for SH2 domain-containing proteins such as PI3K and Grb2. IRS4 is phosphorylated on multiple tyrosine residues upon receptor activation, enabling downstream signal propagation. Its expression is tissue-specific, with highest levels in the brain and kidney. Post-translational modifications include serine/threonine phosphorylation that can modulate its stability and function.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IRS4 Knockout HEK293 Cell Line | EDJ-KQ1524 | Human | 8471 | Details Get a Quote |
| IRS4 Knockout HeLa Cell Line | EDJ-KQ54914 | Human | 8471 | Details Get a Quote |
| IRS4 Knockout A-549 Cell Line | EDJ-KQ63401 | Human | 8471 | Details Get a Quote |
| IRS4 Knockout HCT 116 Cell Line | EDJ-KQ71868 | Human | 8471 | Details Get a Quote |
