Insulin receptor substrate 2 (IRS2) (IRS2)

Insulin receptor substrate 2 (IRS2) is a critical cytoplasmic adapter protein that mediates the intracellular effects of the insulin and insulin-like growth factor 1 (IGF-1) receptors (UniProt P35568). Upon receptor activation, IRS2 is recruited and phosphorylated on multiple tyrosine residues, creating docking sites for SH2-domain-containing proteins such as phosphoinositide 3-kinase (PI3K) and Grb2, which initiate downstream metabolic and growth-promoting pathways (NCBI Gene ID: 8660). In metabolic physiology, IRS2 is essential for maintaining glucose homeostasis and pancreatic beta-cell function; its dysregulation or degradation is a primary driver of insulin resistance and type 2 diabetes (PubMed: 11069141). In oncology, IRS2 is frequently overexpressed, promoting tumor cell survival, metastasis, and resistance to chemotherapy in various malignancies, including breast and pancreatic cancers (PubMed: 25132260). Therapeutic strategies targeting IRS2 include small molecule degraders like NT157 and experimental antisense oligonucleotides designed to suppress IRS2 messenger RNA translation (PubMed: 22964583). While inhibiting IRS2 offers potential for cancer treatment, it presents significant challenges due to the risk of systemic metabolic side effects, such as hyperglycemia and impaired insulin sensitivity.

Other names

IRS-2Insulin receptor substrate 2 messenger RNAIRS2

Targeted protein degradation (TPD) of IRS2 or antisense-mediated knockdown of IRS2 messenger RNA to inhibit downstream PI3K/AKT and MAPK signaling pathways.