The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion

Harashima, Shin-ichi and Clark, Anne and Christie, Michael R. and Notkins, Abner Louis (2005) The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. Proceedings of the National Academy of Sciences, 102 (24). pp. 8704-8709. ISSN 0027-8424

Full content URL: http://www.pnas.org/content/102/24/8704.full

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The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion

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Abstract

IA-2 is an enzymatically inactive member of the transmembrane protein tyrosine phosphate family located in dense core secretory vesicles and a major autoantigen in type 1 diabetes. Recent studies showed that targeted disruption of the IA-2 gene in mice resulted in impairment of insulin secretion and glucose intolerance. Insulin homeostasis, however, is a complex process involving a cascade of regulatory factors, and IA-2 is widely expressed in neuroendocrine cells throughout the body. Consequently, it is uncertain whether the impairment of insulin secretion in IA-2 knockout mice is a direct result of the knockout of IA-2 in beta cells or to counter regulatory alterations resulting from IA-2 knockout in other neuroendocrine cells. To define the function of IA-2, we studied the secretion of insulin in a single cell type, MIN-6, by overexpressing and knocking down IA-2. Our experiments showed that overexpression of IA-2 resulted in a 6-fold increase in glucose- or K+-induced insulin secretion and a ≈3-fold increase in the number of secretory vesicles and the insulin content of cells. In contrast, knockdown of endogenous IA-2 by short interfering RNA resulted in nearly a complete loss of glucose-induced insulin secretion and a 50% decrease in basal insulin release. The half-life of insulin in cells overexpressing IA-2 was nearly twice as great as that in mock-transfected cells, suggesting that IA-2 was stabilizing the insulin-containing vesicles. From these results we conclude that in beta cells, IA-2 is an important regulator of dense core vesicle number and glucose-induced and basal insulin secretion. © 2005 by the National Academy of Sciences of the USA.

Keywords:complementary DNA, insulin, membrane protein, protein IA 2, protein tyrosine phosphatase, unclassified drug, animal cell, article, enzyme linked immunosorbent assay, fluorescence activated cell sorting, genetic transfection, half life time, insulin release, membrane vesicle, mouse, nonhuman, pancreas islet beta cell, plasmid, polyacrylamide gel electrophoresis, priority journal, Animals, Autoantigens, Blotting, Western, Cell Line, DNA Primers, Flow Cytometry, Gene Expression Regulation, Half-Life, Islets of Langerhans, Membrane Proteins, Mice, Plasmids, Protein-Tyrosine-Phosphatase, RNA, Small Interfering, Secretory Vesicles, Transfection
Subjects:B Subjects allied to Medicine > B120 Physiology
Divisions:College of Science > School of Life Sciences
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ID Code:18127
Deposited On:05 Aug 2015 15:23

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