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J. Biol. Chem., Vol. 277, Issue 42, 39684-39695, October 18, 2002
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From the 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
Insulin/Insulin-like Growth Factor I Hybrid Receptors Have
Different Biological Characteristics Depending on the Insulin Receptor
Isoform Involved*
§¶,
,,,§, and
Istituto di Medicina Interna, Malattie
Endocrine e del Metabolismo, University of Catania, Ospedale Garibaldi,
95123 Catania, Italy, the § Istituto Mediterraneo di
Oncologia, 95100 Catania, Italy, and the
** Dipartimento di Medicina Clinica e Sperimentale,
University of Catanzaro, Policlinico Mater Domini, via T. Campanella
115, 88100 Catanzaro, Italy
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 
-subunit and the IGF-IR-specific substrate CrkII. In contrast, Hybrid-RsB
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-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.
*
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.
Recipients of fellowships from the Fondazione Italiana per la
Ricerca sul Cancro.
To whom correspondence should be addressed. Tel.:
39-0961-712423; Fax: 39-0957-158072; E-mail: belfiore@unicz.it.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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