IGF-I and insulin activate mitogen-activated protein kinase via the type 1 IGF receptor in mouse embryonic stem cells.
Although IGF-I and insulin are important modulators of preimplantation embryonic physiology, the signalling pathways activated during development remain to be elucidated. As a model of preimplantation embryos, pluripotent mouse embryonic stem cells were used to investigate which receptor mediated actions of physiological concentrations of IGF-I and insulin on growth measured by protein synthesis. Exposure of mouse embryonic stem (ES) cells to 1.7 pM IGF-I or 1.7 nM insulin for 4 h caused approximately 25% increase in protein synthesis when compared with cells cultured in basal medium containing BSA. Dose-response studies showed 100-fold higher potency of IGF-I that pointed to the type 1 IGF receptor as the mediating receptor for both ligands. This was confirmed using an anti-type 1 IGF receptor-blocking antibody (alphaIR3). Both 1.7 pM IGF-I and 1.7 nM insulin increased phosphorylation of the type 1 IGF receptor and this increase was blocked by alphaIR3, but the insulin receptor was not phosphorylated. Finally, binding of either agonist led to downstream phosphorylation of ERK1/2 mitogen-activated protein kinase (MAPK) also via IGF-1R as this was blocked by alphaIR3. Together, these results suggest that IGF-I and insulin modulate ES cell physiology through binding to the type 1 IGF receptor and subsequent activation of MAPK pathway.
Nguyen
Thanh T
TT
School of Biomedical of Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
Sheppard
Allan M
AM
Kaye
Peter L
PL
Noakes
Peter G
PG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001681:Biological Assay; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000378:metabolism*; D013268:Stimulation, Chemical
D000911:Antibodies, Monoclonal; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases