Insulin receptor and Insulin-like growth factor 1 receptor hybrid receptor (INSR/IGF1R)

The Insulin receptor (INSR) and Insulin-like growth factor 1 receptor (IGF1R) are homologous receptor tyrosine kinases that can form heterodimeric complexes known as INSR/IGF1R hybrid receptors (PubMed PMID: 18434304). These hybrids consist of one INSR alpha-beta hemireceptor and one IGF1R alpha-beta hemireceptor, which assemble in cells expressing both parent receptors (UniProt P06213). Functionally, these hybrid receptors primarily respond to IGF-1 and IGF-2 with high affinity, while showing a much lower affinity for insulin compared to the classic insulin receptor homodimer (PubMed PMID: 25646712). In the context of oncology, hybrid receptors are frequently overexpressed and play a pivotal role in promoting tumor cell proliferation, survival, and resistance to anti-IGF1R monotherapies (PubMed PMID: 21135154). Because of the high structural similarity between INSR and IGF1R, many small-molecule tyrosine kinase inhibitors, such as linsitinib, target both homodimers and the hybrid forms (PubChem CID 23658848). However, therapeutic targeting is complicated by the risk of metabolic side effects, such as hyperglycemia, due to the inhibition of the closely related insulin receptor (PubMed PMID: 22431504). Consequently, these receptors represent a complex therapeutic target requiring precise modulation to balance anti-tumor efficacy with metabolic safety. They are also implicated in insulin resistance, as their formation can sequester insulin receptors into a form that is less responsive to insulin (PubMed PMID: 18434304).

Other names

IR/IGF-1R hybrid receptorHybrid insulin receptorINSR-IGF1R complexInsulin/IGF-1 hybrid receptor

Ligand-induced activation of the tyrosine kinase domain leading to phosphorylation of insulin receptor substrates (IRS) and activation of PI3K/AKT and MAPK pathways (PubMed PMID: 18434304). Small molecule inhibitors competitively block the ATP-binding site of the kinase domain, while monoclonal antibodies prevent ligand binding or induce receptor internalization (PubMed PMID: 21135154).