Insulin receptor substrate 1 and 2 (IRS1/2)

Insulin receptor substrate 1 (IRS1) and 2 (IRS2) are essential adaptor proteins that mediate signaling from the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) (UniProt P35568, Q9Y4H2). Upon ligand binding, these receptors phosphorylate IRS proteins on multiple tyrosine residues, creating docking sites for SH2-domain-containing proteins like PI3K and Grb2, which activate the Akt and MAPK pathways (PMID: 29453299). These pathways are critical for regulating glucose homeostasis, lipid metabolism, and cell proliferation (StatPearls NBK542249). Dysregulation of IRS1/2, often through inhibitory serine phosphorylation or accelerated degradation, is a primary driver of insulin resistance and type 2 diabetes (PMID: 22561061). In oncology, IRS1/2 are frequently overexpressed or hyperactivated, promoting tumor cell survival and resistance to chemotherapy, leading to their investigation as therapeutic targets in various cancers (PMID: 30135558). Therapeutic strategies include small molecule inhibitors like NT157 that induce IRS degradation or indirect modulators like Metformin that improve IRS signaling efficiency.

Other names

Insulin receptor substrate 1Insulin receptor substrate 2IRS-1IRS-2IRS1IRS2IRS1-2 pathway

IRS1/2 proteins function as signaling scaffolds; drugs target them by inducing their degradation, inhibiting their tyrosine phosphorylation, or modulating upstream kinases like AMPK to restore their activity in insulin-resistant states.