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Cell-type-specific roles of IGF-1R and EGFR in mediating Zn2+-induced ERK1/2 and PKB phosphorylation
Authors:Nihar R Pandey  George Vardatsikos  Mohamad Z Mehdi  Ashok K Srivastava
Institution:1. Laboratory of Cell Signaling, Montreal Diabetes Research Center, Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM), Angus Campus, 2901 Rachel Est, Montreal, QC, H1W 4A4, Canada
2. Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada
3. Department of Medicine, University of Montreal, Montreal, QC, H1W 4A4, Canada
Abstract:Zn2+ exerts insulin-mimetic and antidiabetic effects in rodent models of insulin resistance, and activates extracellular-signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (PKB), key components of the insulin signaling pathway. Zn2+-induced signaling has been shown to be associated with an increase in the tyrosine phosphorylation of insulin receptor (IR), as well as of insulin-like growth factor 1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) in several cell types. However, the specific contribution of these receptor protein tyrosine kinases (R-PTKs) in mediating Zn2+-induced responses in a cell-specific fashion remains to be established. Therefore, using a series of pharmacological inhibitors and genetically engineered cells, we have investigated the roles of various R-PTKs in Zn2+-induced ERK1/2 and PKB phosphorylation. Pretreatment of Chinese hamster ovary (CHO) cells overexpressing a human IR (CHO-HIR cells) with AG1024, an inhibitor for IR protein tyrosine kinase (PTK) and IGF-1R-PTK, blocked Zn2+-induced ERK1/2 and PKB phosphorylation, but AG1478, an inhibitor for EGFR, was without effect in CHO cells. On the other hand, both of these inhibitors were able to attenuate Zn2+-induced phosphorylation of ERK1/2 and PKB in A10 vascular smooth muscle cells. In addition, in CHO cells overexpressing tyrosine kinase deficient IR, Zn2+ was still able to induce the phosphorylation of these two signaling molecules, whereas the insulin effect was significantly attenuated. Furthermore, both Zn2+ and insulin-like growth factor 1 failed to stimulate ERK1/2 and PKB phosphorylation in IGF-1R knockout cells. Also, Zn2+-induced responses in CHO-HIR cells were not associated with an increase in the tyrosine phosphorylation of the IR β-subunit and insulin receptor substrate 1 in CHO-HIR cells. Taken together, these data suggest that distinct R-PTKs mediate Zn2+-evoked ERK1/2 and PKB phosphorylation in a cell-specific manner.
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