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This version published online on June 17, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0183
A more recent version of this article appeared on October 1, 2004
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Submitted on April 29, 2004
Accepted on June 7, 2004

Structural determinants for high affinity binding of IGF-II to IR-A, the exon 11 minus isoform of the insulin receptor

Adam Denley, Eric R. Bonython, Grant W. Booker, Leah J. Cosgrove, Briony E. Forbes, Colin W. Ward, and John C. Wallace*

School of Molecular and Biomedical Science, The University of Adelaide, Australia; CSIRO Division of Health Sciences and Nutrition, Adelaide, Australia; **CSIRO Division of Health Sciences and Nutrition, Parkville, Australia

* To whom correspondence should be addressed. E-mail: john.wallace{at}adelaide.edu.au.

The insulin receptor lacking the alternatively spliced exon 11 (IR-A) is preferentially expressed in fetal and cancer cells. The IR-A has been identified as a high affinity receptor for insulin and the insulin-like growth factor-II (IGF-II) but not IGF-I which it binds with substantially lower affinity. Several cancer cell types that express the IR-A also overexpress IGF-II suggesting a possible autocrine proliferative loop. To determine the regions of IGF-I and IGF-II responsible for this differential affinity, chimeras were made where the C and D domains were exchanged between IGF-I and IGF-II either singly or together. The abilities of these chimeras to bind to, and activate, the IR-A was investigated. We also investigated the ability of these chimeras to bind and activate the IR exon 11 plus isoform (IR-B) and as a positive control, the insulin-like growth factor I receptor (IGF-1R). We show that the C domain, and to a lesser extent the D domains represent the principal determinants of the binding differences between IGF-I and IGF-II to IR-A. The C and D domains of IGF-II promote higher affinity binding to the IR-A than the equivalent domains of IGF-I, resulting in an affinity close to that of insulin for the IR-A. The C and D domains also regulate the IR-B binding specificity of the IGFs in a similar manner, although the level of binding for all IGF ligands to IR-B is lower than to IR-A. In contrast the C and D domains of IGF-I allow higher affinity binding to the IGF-1R than the analogous domains of IGF-II. Activation of IGF-1R by the chimeras reflected their binding affinities while the phosphorylation of the two IR isoforms was more complex.
Key words: IGF-II • insulin receptor isoform A • chimeras • binding specificity




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