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Submitted on June 17, 2005
Accepted on October 13, 2005
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, Australia 5005; CSIRO Division of Molecular and Health Technologies, Adelaide, Australia 5000; Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA 97239
* To whom correspondence should be addressed. E-mail: robertsc{at}ohsu.edu.
The actions of the insulin-like growth factors (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 IRS-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.
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