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

The Insulin-like growth factor 1 receptor (IGF-1R) signaling pathway is a critical mediator of cell growth, differentiation, and survival. Upon binding of the ligand IGF-1, the IGF-1R undergoes autophosphorylation, creating docking sites for adaptor proteins like Insulin Receptor Substrate 1 (IRS-1). This recruitment triggers the activation of Phosphoinositide 3-kinase (PI3K), which converts PIP2 to PIP3, leading to the membrane recruitment and activation of the serine/threonine kinase Akt. Once active, Akt phosphorylates numerous downstream targets that promote protein synthesis and inhibit apoptosis (Source: UniProt P08069, NIH/NCI Thesaurus). Dysregulation of this axis is a hallmark of many malignancies, where overexpressed IGF-1R or mutations in the PI3K/Akt components drive uncontrolled tumor growth and resistance to therapy. Consequently, this pathway has been a major focus for drug development, resulting in various monoclonal antibodies and kinase inhibitors. However, therapeutic challenges remain, particularly due to the high structural homology between IGF-1R and the Insulin Receptor (IR), which can lead to metabolic side effects such as hyperglycemia when the pathway is systemically inhibited (Source: StatPearls NBK536923, PubMed PMC4127615).

Other names

IGF-1/IGF-1R axisIGF-1/PI3K/Akt pathwaySomatomedin C signalingIGF-1R/IRS-1/PI3K/Akt/mTOR pathway

Drugs targeting this pathway typically act as monoclonal antibodies to block ligand binding to the IGF-1R extracellular domain, small molecule inhibitors of the IGF-1R tyrosine kinase domain, or inhibitors of downstream nodes such as PI3K and Akt to prevent pro-survival signaling (Source: PubMed PMC2923229, PMC3614012).