IRS1

IRS1, or insulin receptor substrate 1, is a cytoplasmic adaptor protein that plays a central role in insulin and IGF-1 signaling. It acts as a docking platform that transduces signals from the activated insulin receptor to downstream pathways, influencing metabolism, growth, and gene expression.

The protein features an N-terminal pleckstrin homology (PH) domain and a phosphotyrosine-binding (PTB) domain that help target IRS1 to the membrane and interact with the insulin receptor. Its long C-terminal tail contains numerous tyrosine phosphorylation sites that, when phosphorylated, serve as binding motifs for SH2-domain-containing signaling proteins such as PI3K p85 and Grb2. This enables activation of major signaling cascades, notably the PI3K-AKT pathway and the MAPK pathway, which regulate glucose uptake, lipid metabolism, protein synthesis, and cell growth.

Regulation of IRS1 signaling is complex. Upon insulin binding, the receptor tyrosine kinase activity phosphorylates IRS1, promoting downstream signaling. Serine/threonine phosphorylation of IRS1 by kinases such as mTOR, JNK, and IKK can attenuate signaling, providing feedback that can contribute to insulin resistance under certain conditions. IRS1 activity is modulated by nutritional state, inflammation, and hormonal signals, and multiple splice variants of IRS1 exist.

Clinical and research relevance: Altered IRS1 signaling has been linked to metabolic disorders, including insulin resistance and type 2 diabetes. A common variant, R972, has been associated with increased risk of insulin resistance in some populations. In animal models, loss or impairment of IRS1 disrupts insulin signaling and can lead to insulin resistance and growth defects, underscoring its essential role in metabolic regulation. IRS1 belongs to a family of IRS proteins that coordinate insulin/IGF signaling, with IRS2 offering complementary functions.