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.
Footnotes
- Received November 7, 2014.
- Accepted January 22, 2015.
This work was funded by a Cooperative Research and Development Agreement [CRADA 58-3K95-1-1497] between XOMA and United States Department of Agriculture–Agricultural Research Service (USDA-ARS), as well as through a USDA-ARS Intramural Project [5306-51530-019-00D]. USDA is an equal opportunity provider and employer. D.H.B., I.D.G., J.A.C., and M.K.R. are employees of XOMA (US), LLC. No other potential conflicts of interest relevant to this article are reported. S.H.A. has no conflict of interest to declare.
Portions of this work were previously presented in a poster at the following conference: Bedinger D, Corbin J, Roell M, Goldfine I, and Adams S (2014) “Metabolic” vs. “mitogenic” insulin receptor signaling by an allosteric monoclonal antibody: specific metabolic pathway bias or partial agonism? American Diabetes Association 74th Scientific Sessions; 2014 Jun 13–17; San Francisco, CA.
- U.S. Government work not protected by U.S. copyright
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