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https://hdl.handle.net/2440/3116
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dc.contributor.author | Denley, A. | - |
dc.contributor.author | Bonython, E. | - |
dc.contributor.author | Booker, G. | - |
dc.contributor.author | Cosgrove, L. | - |
dc.contributor.author | Forbes, B. | - |
dc.contributor.author | Ward, C. | - |
dc.contributor.author | Wallace, J. | - |
dc.date.issued | 2004 | - |
dc.identifier.citation | Molecular Endocrinology, 2004; 18(10):2502-2512 | - |
dc.identifier.issn | 0888-8809 | - |
dc.identifier.issn | 1944-9917 | - |
dc.identifier.uri | http://hdl.handle.net/2440/3116 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Adam Denley, Eric R. Bonython, Grant W. Booker, Leah J. Cosgrove, Briony E. Forbes, Colin W. Ward and John C. Wallace | - |
dc.language.iso | en | - |
dc.publisher | Endocrine Soc | - |
dc.rights | © 2004 by The Endocrine Society | - |
dc.source.uri | http://mend.endojournals.org/cgi/content/abstract/18/10/2502 | - |
dc.subject | 3T3 Cells | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred BALB C | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Insulin | - |
dc.subject | Receptor, Insulin | - |
dc.subject | Insulin-Like Growth Factor I | - |
dc.subject | Insulin-Like Growth Factor II | - |
dc.subject | Protein Isoforms | - |
dc.subject | Recombinant Fusion Proteins | - |
dc.subject | Restriction Mapping | - |
dc.subject | Alternative Splicing | - |
dc.subject | Sequence Deletion | - |
dc.subject | Amino Acid Sequence | - |
dc.subject | Exons | - |
dc.subject | Molecular Sequence Data | - |
dc.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 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1210/me.2004-0183 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Booker, G. [0000-0001-7207-4699] | - |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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