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https://hdl.handle.net/2440/3116
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Type: | Journal article |
Title: | Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR |
Author: | Denley, A. Bonython, E. Booker, G. Cosgrove, L. Forbes, B. Ward, C. Wallace, J. |
Citation: | Molecular Endocrinology, 2004; 18(10):2502-2512 |
Publisher: | Endocrine Soc |
Issue Date: | 2004 |
ISSN: | 0888-8809 1944-9917 |
Statement of Responsibility: | Adam Denley, Eric R. Bonython, Grant W. Booker, Leah J. Cosgrove, Briony E. Forbes, Colin W. Ward and John C. Wallace |
Abstract: | The insulin receptor (IR) 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 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 were investigated. We also investigated the ability of these chimeras to bind and activate the IR exon 11+ isoform (IR-B) and as a positive control, the IGF-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 whereas the phosphorylation of the two IR isoforms was more complex. |
Keywords: | 3T3 Cells Animals Mice, Inbred BALB C Humans Mice Insulin Receptor, Insulin Insulin-Like Growth Factor I Insulin-Like Growth Factor II Protein Isoforms Recombinant Fusion Proteins Restriction Mapping Alternative Splicing Sequence Deletion Amino Acid Sequence Exons Molecular Sequence Data |
Rights: | © 2004 by The Endocrine Society |
DOI: | 10.1210/me.2004-0183 |
Published version: | http://mend.endojournals.org/cgi/content/abstract/18/10/2502 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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