Endocrinology, Vol 136, 1978-1986, Copyright © 1995 by Endocrine Society

ARTICLES

Functional characterization of hybrid receptors composed of a truncated insulin receptor and wild type insulin-like growth factor 1 or insulin receptors

WJ Langlois, T Sasaoka, CC Yip and JM Olefsky
Department of Medicine, University of California, San Diego, La Jolla 92093, USA.

To assess the characteristics of hybrid receptors composed of one kinase-inactive alpha beta-insulin half-receptor and one endogenous alpha beta-insulin-like growth factor 1 (IGF-1) or insulin half- receptor, a cell line expressing an insulin receptor truncated by 365 amino acids (HIR delta 978) was studied, which lacks most of the cytoplasmic beta-subunit. Analysis by sodium dodecyl sulfate polyacrylamide gel electrophoresis under nonreducing conditions revealed four distinct receptor species: endogenous receptors, the more rapidly migrating HIR delta 978 homodimer, and two intermediate species representing HIR delta 978/IGF-1 hybrid receptors and HIR delta 978/IR hybrid receptors. In vivo ligand-binding affinity of the hybrid receptors was studied by receptor-ligand cross-linking, and the delta 978/IGF-1R hybrid receptor was found to have a high affinity for IGF-1, whereas its affinity for insulin was low. Autophosphorylation studies of lectin-purified receptors revealed that neither the HIR delta 978 holoreceptor nor the hybrid receptors underwent autophosphorylation in response to either ligand, despite the presence of intact IGF-1 or insulin half-receptors in the hybrids. Neither hybrid receptor underwent ligand-induced endocytosis, as assessed with the bioactive photoaffinity probes B2(2-nitro-4-azidophenylacetyl)-des-PheB1-insulin and N-epsilon B28-monoazidobenzoyl-IGF-1. In conclusion, the HIR delta 978/IGF-1R hybrid receptor has a high in vivo affinity for IGF-1 but not for insulin. Neither the delta 978/IGF-1R nor the delta 978/IR hybrids undergo autophosphorylation or ligand-induced endocytosis in response to either ligand, indicating that intramolecular trans-, rather than cis-, signal transduction is important in mediating autophosphorylation and endocytosis.

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