Journal of Biological Chemistry
Volume 277, Issue 42, 18 October 2002, Pages 39684-39695
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MECHANISMS OF SIGNAL TRANSDUCTION
Insulin/Insulin-like Growth Factor I Hybrid Receptors Have Different Biological Characteristics Depending on the Insulin Receptor Isoform Involved*

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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-RsA) bound to and were activated by IGF-I, IGF-II, and insulin. By binding to Hybrid-RsA, insulin activated the IGF-I half-receptor β-subunit and the IGF-IR-specific substrate CrkII. In contrast, Hybrid-RsBbound 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-RA-containing cells than in Hybrid-RB-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.

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Published, JBC Papers in Press, July 22, 2002, DOI 10.1074/jbc.M202766200

*

This work was supported in part by grants from the Associazione Italiana per la Ricerca sul Cancro and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (1999, 2001) (to A. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from the Fondazione Giuseppe Alazio per la Ricerca sul Cancro.

Recipients of fellowships from the Fondazione Italiana per la Ricerca sul Cancro.