Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain.
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 alpha 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.
Denley
Adam
A
School of Molecular and Biomedical Science, The University of Adelaide, Australia.
Brierley
Gemma V
GV
Carroll
Julie M
JM
Lindenberg
Anne
A
Booker
Grant W
GW
Cosgrove
Leah J
LJ
Wallace
John C
JC
Forbes
Briony E
BE
Roberts
Charles T
CT
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary / Q000502:physiology; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*
D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011972:Receptor, Insulin