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IGF-I and insulin activate mitogen-activated protein kinase via the type 1 IGF receptor in mouse embryonic stem cells

School of Biomedical of Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia and ¹ AgResearch Limited, Ruakura Research Centre, Hamilton, 3240, New Zealand

Correspondence should be addressed to P L Kaye; Email: p.kaye{at}uq.edu.au

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 ~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 (IR3). 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 IR3, 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 IR3. 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.

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