Insulin-like growth factor 1 receptor and Insulin receptor–Insulin-like growth factor 1 receptor hybrid receptor (IGF-1R and INSR–IGF-1R)

The Insulin-like growth factor 1 receptor (IGF-1R) is a transmembrane receptor tyrosine kinase essential for mediating the effects of IGF-1 and IGF-2 on cell growth, proliferation, and anti-apoptotic signaling (UniProt P08069). A unique feature of this system is the formation of INSR–IGF-1R hybrid receptors, which occur when hemireceptors of the insulin receptor (INSR) and IGF-1R dimerize (Belfiore et al., 2009). These hybrids are often upregulated in cancer cells and can respond to both insulin and IGFs, complicating therapeutic strategies that aim to isolate growth signaling from metabolic regulation (PMID: 31515465). IGF-1R and its hybrids are implicated in the pathogenesis of various malignancies and autoimmune conditions like thyroid eye disease (PMID: 32075730). Pharmacological intervention includes monoclonal antibodies that prevent ligand binding and small-molecule inhibitors that target the kinase domain. However, the high structural homology between IGF-1R and the insulin receptor often leads to off-target metabolic effects, such as hyperglycemia, which has limited the clinical success of many inhibitors (PMID: 25646011). Despite these challenges, the successful development of teprotumumab highlights the continued relevance of this receptor system in specialized therapeutic areas.

Other names

IGF1RCD221IGF-I receptorHybrid-RIR/IGF-1R hybridInsulin receptor-related receptor hybrid

Monoclonal antibodies block ligand binding or induce receptor degradation, while small-molecule inhibitors target the intracellular tyrosine kinase domain to prevent autophosphorylation and downstream signaling.