Insulin-like growth factor 1 receptor (IGF-1R) signaling axis (IGF-1R/PI3K/Akt/mTOR)

The Insulin-like growth factor 1 receptor (IGF-1R) signaling axis is a central pathway regulating cellular growth, proliferation, and survival (UniProt P08069). Upon activation by its ligands, IGF-1 or IGF-2, the receptor undergoes autophosphorylation and recruits the adaptor protein Insulin Receptor Substrate 1 (IRS-1), which subsequently activates Phosphoinositide 3-kinase (PI3K) (PMID: 17620530). This activation triggers a cascade involving the generation of PIP3, recruitment of the kinase Akt to the plasma membrane, and its subsequent activation (PMID: 21622715). Activated Akt then stimulates the Mammalian Target of Rapamycin Complex 1 (mTORC1), a master regulator of protein synthesis and metabolism (PMID: 24651010). Dysregulation of this axis, often through IGF-1R overexpression or mutations in downstream components like PI3K, is a hallmark of many cancers and contributes to therapeutic resistance (PMID: 18566335). Drugs targeting this axis include monoclonal antibodies against IGF-1R (e.g., Teprotumumab) and small-molecule inhibitors of PI3K, Akt, and mTOR (PMID: 22431504). However, clinical development has faced challenges such as compensatory signaling and metabolic side effects, particularly hyperglycemia, due to the high homology between IGF-1R and the insulin receptor (PMID: 21622715).

Other names

PI3K/Akt/mTORC1 pathway via IGF-1 receptor/IRS-1 signaling axisIGF-1R signaling pathwayIGF-1R/IRS-1/PI3K/Akt/mTORC1 axisInsulin-like growth factor 1 receptor signaling

Inhibition of IGF-1R tyrosine kinase activity, inhibition of PI3K catalytic activity, inhibition of Akt phosphorylation, and inhibition of mTORC1 kinase activity.