Insulin-like growth factor 1 receptor and insulin-like growth factor 2 receptor (IGF-1R/IGF-2R)

The Insulin-like growth factor 1 receptor (IGF-1R) and Insulin-like growth factor 2 receptor (IGF-2R) are distinct transmembrane proteins that play critical, yet opposing, roles in growth regulation. IGF-1R is a receptor tyrosine kinase that mediates the mitogenic and anti-apoptotic effects of IGF-1 and IGF-2, making it a significant therapeutic target in oncology and autoimmune conditions like Graves' ophthalmopathy (UniProt P08069). In contrast, IGF-2R, also known as the cation-independent mannose-6-phosphate receptor, lacks intrinsic signaling activity and primarily serves to clear IGF-2 from the extracellular space, thus acting as a natural antagonist to IGF-1R-mediated growth (UniProt P11717). Dysregulation of the IGF-1R pathway is linked to various cancers, where overactivity promotes tumor progression and resistance to therapy (PMID: 29334376). Therapeutic agents such as teprotumumab target IGF-1R to treat thyroid eye disease, while various monoclonal antibodies have been explored in clinical trials for cancer (PMID: 18216240). Because IGF-1R shares high structural homology with the insulin receptor, a major safety concern for inhibitors is the development of hyperglycemia. IGF-2R is also vital for the transport of lysosomal enzymes, and its dysfunction is associated with lysosomal storage disorders.

Other names

IGF1RIGF2RCD221CD222Cation-independent mannose-6-phosphate receptorCI-MPRM6P/IGF2RInsulin-like growth factor I receptorInsulin-like growth factor II receptor

IGF-1R inhibitors function by blocking the extracellular ligand-binding site or the intracellular tyrosine kinase domain to prevent downstream signaling through the PI3K/Akt and MAPK pathways. IGF-2R acts primarily as a non-signaling decoy receptor that internalizes and targets IGF-2 for lysosomal degradation, thereby limiting its availability to IGF-1R.