Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/23133
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain |
Author: | Denley, A. Brierley, G. Carroll, J. Lindenberg, A. Booker, G. Cosgrove, L. Wallace, J. Forbes, B. Roberts, C. |
Citation: | Endocrinology, 2006; 147(2):1029-1036 |
Publisher: | Endocrine Soc |
Issue Date: | 2006 |
ISSN: | 0013-7227 0013-7227 |
Statement of Responsibility: | Adam Denley, Gemma V. Brierley, Julie M. Carroll, Anne Lindenberg, Grant W. Booker, Leah J. Cosgrove, John C. Wallace, Briony E. Forbes and Charles T. Roberts, Jr. |
Abstract: | The actions of IGF-I and IGF-II are thought to be largely due to their activation of the IGF-I receptor. However, IGF-II can also bind with high affinity to, and effectively activate, an isoform of the insulin receptor (IR-A) that lacks a sequence at the carboxyl-terminal end of the extracellular subunit due to the alternative splicing of exon 11. This isoform is poorly activated by IGF-I. Here, we show that IGF-II, but not IGF-I, induces potent autophosphorylation of residues Y1158, Y1162, and Y1163 in the activation loop of the kinase domain and tyrosine 960 in the juxtamembrane region of both IR-A and IR-B (exon 11+) isoforms. We have also found, by using IGF chimeras, that the C domain of IGF-II completely accounts for the ability of IGF-II to stimulate IR autophosphorylation compared with IGF-I. We further show that the C domains are responsible for the differential abilities of IGF-II and IGF-I to activate phosphorylation of insulin receptor substrate-1 and Akt, as well as their ability to induce migration and cell survival via the IR-A. Finally, we show for the first time that IGF signaling through the IR-A can protect cells from butyrate-induced apoptosis. In summary, our studies define the structural determinants that allow potent IGF-II signaling and regulation of cellular functions through the IR-A and provide novel insights into IGF signaling via the IR. |
Keywords: | 3T3 Cells Adipocytes Animals Mice Receptor, Insulin Insulin-Like Growth Factor I Insulin-Like Growth Factor II Protein Isoforms Gene Expression Regulation Protein Structure, Tertiary Phosphorylation |
Description: | Copyright © 2006 by The Endocrine Society |
DOI: | 10.1210/en.2005-0736 |
Published version: | http://dx.doi.org/10.1210/en.2005-0736 |
Appears in Collections: | Aurora harvest 6 Obstetrics and Gynaecology publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.