| IRS1 and IRS2 are major adaptor proteins of the insulin receptor substrate family that mediate intracellular signaling downstream of insulin and IGF-1 receptors, with IRS1 predominantly expressed in skeletal muscle and adipose tissue and IRS2 enriched in the liver and pancreatic β-cells, enabling tissue-specific regulation of glucose homeostasis. Upon insulin receptor activation, multiple tyrosine residues on IRS proteins are phosphorylated, creating docking sites for the p85 regulatory subunit of PI3K, which activates the p110 catalytic subunit to convert PIP2 into PIP3. PIP3 recruits Akt/PKB to the plasma membrane via its pleckstrin homology domain, where Akt is activated by PDK1-mediated phosphorylation at Thr308 and mTORC2-mediated phosphorylation at Ser473, leading to downstream signaling events such as AS160 phosphorylation, GLUT4 translocation, glucose uptake, glycogen synthesis through GSK3β inhibition, and suppression of hepatic gluconeogenesis. IRS proteins also activate the Grb2-Sos-Ras-Raf-MEK-ERK signaling cascade, promoting gene transcription through factors such as Elk-1 and c-Fos to regulate cell proliferation and differentiation. IRS1 and IRS2 contain conserved PH and PTB domains for receptor interaction and membrane localization, along with C-terminal YXXM motifs that recruit PI3K and serine-rich regions involved in inhibitory regulation. Negative regulation occurs through serine/threonine phosphorylation by stress- and nutrient-responsive kinases, including JNK, S6K, and PKCθ, which impair IRS tyrosine phosphorylation, promote IRS:14-3-3 or IRS:SHP2 complex formation, and enhance IRS degradation, thereby contributing to insulin resistance. IRS1 primarily controls peripheral glucose disposal in muscle and adipose tissue, whereas IRS2 is essential for β-cell compensation and hepatic insulin action; accordingly, IRS1 knockout models exhibit impaired glucose uptake, while IRS2 deficiency leads to hyperglycemia and β-cell failure. In obesity and type 2 diabetes, reduced IRS signaling, particularly marked suppression of hepatic IRS2 expression and altered PI3K regulatory subunit composition, contributes significantly to metabolic dysfunction. |
