Insulin receptor substrate 1
GeneName
IRS1
Summary
IRS1, also known as IRS-1 or insulin receptor substrate 1, is a 132 kDa cytoplasmic protein that plays a pivotal role in insulin and insulin-like growth factor signalling pathways. It is expressed in various tissues, particularly in the liver, muscle, and adipose tissue, where it acts as an adaptor protein that mediates the effects of insulin by linking the insulin receptor to downstream signalling pathways. IRS1 is localised to several cellular compartments including the plasma membrane, cytoplasm, and nucleus, and is involved in processes such as glucose homeostasis and fatty acid metabolism through its interactions with various signalling molecules, including phosphatidylinositol 3-kinase and protein kinase C. Its function is crucial for the transduction of signals that regulate cellular responses to insulin and growth factors.
Importance
IRS1 is relevant to: - Insulin resistance and type 2 diabetes due to its central role in insulin signalling and glucose metabolism - Obesity and metabolic syndrome as it influences fatty acid oxidation and glucose uptake - Cancer research, particularly in relation to how insulin signalling can affect cell proliferation and survival - Cardiovascular diseases, given its involvement in metabolic processes that impact vascular health
Top Products
For researchers investigating IRS1, we highly recommend the top-selling recombinant antibody, Anti-IRS1+IRS2 antibody [EP263Y] (ab40777). This antibody has been validated for use in several applications, including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), and flow cytometry (FC), making it a versatile tool for your research needs. With 30 citations, it is well-regarded in the scientific community, reflecting its reliability and effectiveness in detecting IRS1 and IRS2. This product is an excellent choice for those seeking the consistency and performance that recombinant antibodies offer. The Recombinant Human IRS1 protein ELISA Kit (ab71377) is an excellent option for researchers looking to measure IRS1 levels in their samples.
Abcam Product Citation Summary
The data indicates that IRS1 is being studied in the context of IGF-IR signalling and drug resistance. The use of Abcam antibody ab40777 in both mouse and human models highlights its relevance in various biological contexts.
Abcam Product Citation Table
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 (PubMed:7541045, PubMed:33991522, PubMed:38625937). Plays therefore an important role in development, growth, glucose homeostasis as well as lipid metabolism (PubMed:19639489). 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 (PubMed:11171109, PubMed:8265614). 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 (By similarity). 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 (PubMed:24616100).
Involvement in disease
Type 2 diabetes mellitus
T2D
A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
None
The gene represented in this entry may be involved in disease pathogenesis.
Post-translational modifications
Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-307, Ser-312, Ser-315, and Ser-323 phosphorylations inhibit insulin action through disruption of IRS1 interaction with the insulin receptor INSR (PubMed:38625937). Phosphorylation of Tyr-896 is required for GRB2-binding (By similarity). Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1 (PubMed:18952604). Phosphorylated on tyrosine residues in response to insulin (PubMed:23401856). In skeletal muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1 (PubMed:23401856).
Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2). Ubiquitinated by TRAF4 through 'Lys-29' linkage; this ubiquitination regulates the interaction of IRS1 with IGFR and IRS1 tyrosine phosphorylation upon IGF1 stimulation (PubMed:33991522).
S-nitrosylation at by BLVRB inhibits its activity.
Cellular localization
- Cytoplasm
- Nucleus
- Nuclear or cytoplasmic localization of IRS1 correlates with the transition from proliferation to chondrogenic differentiation.
Alternative names
Insulin receptor substrate 1, IRS-1, IRS1