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

Abstract

The insulin receptor (IR)1 and the insulin-like growth factor (IGF) I receptor (IGF-IR) are tetrameric glycoproteins composed of two extracellular ␣-and two transmembrane ␤-subunits linked by disulfide bonds. Each ␣-subunit, containing the ligand-binding site, is ϳ130 kDa, whereas each ␤-subunit, containing the tyrosine kinase domain, is ϳ95-97 kDa. These receptors share Ͼ50% overall amino acid sequence homology and 84% homology in the tyrosine kinase domains. After ligand binding, activated receptors recruit and phosphorylate docking proteins, including the insulin receptor substrate-1 family proteins Gab1 and Shc (1-5), leading to the activation of many intracellular mediators, including phosphatidylinositol 3-kinase, Akt, and ERK1/2, involved in the regulation of cell metabolism, proliferation, and survival. Although both the IR and IGF-IR similarly activate major signaling pathways, subtle differences exist in the recruitment of certain docking proteins and intracellular mediators between the two receptors (6 -9). These differences are the basis for the predominant metabolic effect elicited by IR activation and the predominant mitogenic, transforming, and anti-apoptotic effect elicited by IGF-IR activation (10 -13). According to the classical view, insulin binds with high affinity to the IR (100-fold higher than to the IGF-IR), whereas both insulin-like growth factors (IGF-I and IGF-II) bind to the IGF-IR (with 100-fold higher affinity than to the IR).Given the high degree of homology, the insulin and IGF-I half-receptors (composed of one ␣-and one ␤-subunit) can heterodimerize, leading to the formation of insulin/IGF-I hybrid receptors (Hybrid-Rs) (14 -16). In many tissues, Hybrid-Rs are the most represented receptor subtype (17). Hybrid-Rs may also be overexpressed in a variety of human malignancies as a result of both IR and IGF-IR overexpression (18 -21). However, the biological role of these Hybrid-Rs is still unclear. Functional studies have indicated that Hybrid-Rs behave more like IGF-IRs than IRs because they bind to and are activated by IGF-I with an affinity similar to that of the typical IGF-IR. In contrast, Hybrid-R activation in response to insulin occurs with much lower affinity (22, 23). Hybrid-Rs are therefore believed to provide additional binding sites to IGF-I and to increase cell sensitivity to this growth factor (17-19). These studies have not, however, taken into account the different IR isoform contribution to Hybrid-R formation and function.The human IR exists in two isoforms (IR-A and IR-B), gen-* 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 (1999Tecnologica ( , 2001. The costs of publication of this article were defrayed in part by the payment of page charges. This 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 l...

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