Insulin/Insulin-like Growth Factor I Hybrid Receptors Have Different Biological Characteristics Depending on the Insulin Receptor Isoform Involved

The insulin receptor (IR) and the insulin-like growth factor I receptor (IGF-IR) have a highly homologous structure, but different biological effects. Insulin and IGF-I half-receptors can heterodimerize, leading to the formation of insulin/IGF-I hybrid receptors (Hybrid-Rs) that bind IGF-I with high affinity. As the IR exists in two isoforms (IR-A and IR-B), we evaluated whether the assembly of the IGF-IR with either IR-A or IR-B moieties may differently affect Hybrid-R signaling and biological role. Three different models were studied: ( a ) 3T3-like mouse fibroblasts with a disrupted IGF-IR gene (R − cells) cotransfected with the human IGF-IR and with either the IR-A or IR-B cDNA; ( b ) a panel of human cell lines variably expressing the two IR isoforms; and ( c ) HepG2 human hepatoblastoma cells predominantly expressing either IR-A or IR-B, depending on their differentiation state. We found that Hybrid-Rs containing IR-A (Hybrid-Rs A ) bound to and were activated by IGF-I, IGF-II, and insulin. By binding to Hybrid-Rs A , insulin activated the IGF-I half-receptor β-subunit and the IGF-IR-specific substrate CrkII. In contrast, Hybrid-Rs B bound to and were activated with high affinity by IGF-I, with low affinity by IGF-II, and insignificantly by insulin. As a consequence, cell proliferation and migration in response to both insulin and IGFs were more effectively stimulated in Hybrid-R A -containing cells than in Hybrid-R B -containing cells. The relative abundance of IR isoforms therefore affects IGF system activation through Hybrid-Rs, with important consequences for tissue-specific responses to both insulin and IGFs.