Insulin-like growth factor 1 receptor (IGF1R) signaling pathway (IGF-1R signaling; IGF1R signaling)

The IGF-1 signaling pathway is driven primarily by the insulin-like growth factor 1 receptor (IGF-1R), a heterotetrameric transmembrane receptor tyrosine kinase composed of two extracellular α-subunits and two transmembrane β-subunits containing the kinase domain[6]. Upon binding of IGF-1 or IGF-2, IGF-1R undergoes autophosphorylation and activates downstream cascades, principally PI3K–AKT and RAS–MAPK, promoting cell proliferation, survival, growth, and metabolic effects[4][6][7]. The pathway includes ligands (insulin, IGF-1, IGF-2), receptors (IGF-1R, IGF-2R, insulin receptor), and six high-affinity IGF-binding proteins (IGFBP1–6) that regulate ligand bioavailability and can also signal independently[1][2][6]. IGF-1R can form hybrids with insulin receptor isoforms and engage in receptor cross-talk, contributing to therapeutic resistance and safety considerations[1][2][6]. Clinically, IGF-1R is an investigated therapeutic target in multiple cancers, with agents including IGF-1R monoclonal antibodies, dual IGF-1R/INSR TKIs, and ligand-neutralizing antibodies; combinations with mTOR inhibitors have been explored to counteract feedback activation[1].

Other names

IGF-1R signalingIGF1R pathwayInsulin-like growth factor signalingIGF signaling pathway

IGF-1R monoclonal antibodies: block IGF-1/IGF-2 binding and promote receptor downregulation to inhibit downstream PI3K–AKT and MAPK signaling. IGF-1R/INSR TKIs: inhibit the tyrosine kinase activity of IGF-1R (and often INSR), preventing receptor autophosphorylation and downstream signaling. Anti-IGF-1/IGF-2 ligands: sequester ligands to reduce receptor activation. Combination with mTOR inhibitors: targets feedback activation of IGF-1R signaling induced by mTOR inhibition.