دورية أكاديمية
Differential pathway coupling of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody.
| العنوان: | Differential pathway coupling of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody. |
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| المؤلفون: | Bedinger DH; 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.)., Goldfine ID; 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.)., Corbin JA; 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.)., Roell MK; 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.)., Adams SH; 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. |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2015 Apr; Vol. 353 (1), pp. 35-43. Date of Electronic Publication: 2015 Jan 22. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Antibodies, Monoclonal/*pharmacology , Receptor, Insulin/*metabolism, Allosteric Regulation ; Animals ; Antibodies, Monoclonal/metabolism ; CHO Cells ; Cricetulus ; Drug Partial Agonism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Insulin/metabolism ; Insulin/pharmacology ; Phosphorylation ; Protein Binding ; Protein Isoforms/agonists ; Protein Isoforms/immunology ; Protein Isoforms/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Insulin/agonists ; Receptor, Insulin/immunology ; Signal Transduction |
| مستخلص: | 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. (U.S. Government work not protected by U.S. copyright.) |
| المشرفين على المادة: | 0 (Antibodies, Monoclonal) 0 (Insulin) 0 (Protein Isoforms) EC 2.7.10.1 (Receptor, Insulin) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) |
| تواريخ الأحداث: | Date Created: 20150124 Date Completed: 20150509 Latest Revision: 20150220 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1124/jpet.114.221309 |
| PMID: | 25613982 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.114.221309 |