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J Pharmacol Exp Ther. 2015 Apr;353(1):35-43. doi: 10.1124/jpet.114.221309. Epub 2015 Jan 22.

Differential pathway coupling of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody.

Author information

1
XOMA Corporation, Berkeley, California (D.H.B., I.D.G., J.A.C., M.K.R.); Obesity & Metabolism Research Unit, United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center and Department of Nutrition, Davis, California (S.H.A.); and Molecular, Cellular and Integrative Physiology Graduate Group, University of California at Davis, Davis, California (D.H.B., S.H.A.).
2
XOMA Corporation, Berkeley, California (D.H.B., I.D.G., J.A.C., M.K.R.); Obesity & Metabolism Research Unit, United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center and Department of Nutrition, Davis, California (S.H.A.); and Molecular, Cellular and Integrative Physiology Graduate Group, University of California at Davis, Davis, California (D.H.B., S.H.A.) shadams@uams.edu.

Abstract

The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which 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, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which 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, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.

PMID:
25613982
DOI:
10.1124/jpet.114.221309
[Indexed for MEDLINE]
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