The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR) that activates the “metabolic” Akt kinase signaling pathway while having little or no effect on the “mitogenic” extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, a detailed investigation of XMetA was conducted to evaluate specific phosphorylation and activation of IR, Akt, and ERK in CHO cell lines expressing the human IR. Maximally effective concentrations of XMetA were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the “preferential signaling” of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathway-biased mechanism. The metabolic selectivity of partial IR agonists, like XMetA, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.
See article at J Pharmacol Exp Ther 2015, 353:35–43.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics