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题名:Transglutaminase 2 transamidation activity during first-phase insulin secretion: natural substrates in INS-1E.
作者:RUSSO L; MARSELLA C; NARDO G; MASSIGNAN T; ALESSIO M; PIERMARINI E; LA ROSA S; FINZI G; BONETTO V; BERTUZZI F; MAECHLER P; MASSA O;
来源:Acta Diabetol. 2013 Feb;50(1):61-72. doi: 10.1007/s00592-012-0381-6. Epub 2012 [ IF= 0.00 ] ]
URL :10.1007/s00592-012-0381-6
日期:20130228
摘要:Transglutaminase 2 (TG2) is a multifunctional protein with Ca(2+)-dependent
transamidating and G protein activity. Previously, we reported that tgm2 -/- mice
have an impaired insulin secretion and that naturally occurring TG2 mutations
associated with familial, early-onset type 2 diabetes, show a defective
transamidating activity. Aim of this study was to get a better insight into the
role of TG2 in insulin secretion by identifying substrates of TG2 transamidating
activity in the pancreatic beta cell line INS-1E. To this end, we labeled INS-1E
that are capable of secreting insulin upon glucose stimulation in the physiologic
range, with an artificial acyl acceptor (biotinamido-pentylamine) or donor
(biotinylated peptide), in basal condition and after stimulus with glucose for 2,
5, and 8 min. Biotinylated proteins were analyzed by two-dimensional
electrophoresis and mass spectrometry. In addition, subcellular localization of
TG2 in human endocrine pancreas was studied by electron microscopy. Among several
TG2's transamidating substrates in INS-1E, mass spectrometry identified
cytoplasmic actin (a result confirmed in human pancreatic islet), tropomyosin,
and molecules that participate in insulin granule structure (e.g., GAPDH),
glucose metabolism, or [Ca(2+)] sensing (e.g., calreticulin). Physical
interaction between TG2 and cytoplasmic actin during glucose-stimulated
first-phase insulin secretion was confirmed by co-immunoprecipitation. Electron
microscopy revealed that TG2 is localized close to insulin and glucagon granules
in human pancreatic islet. We propose that TG2's role in insulin secretion may
involve cytoplasmic actin remodeling and may have a regulative action on other
proteins during granule movement. A similar role of TG2 in glucagon secretion is
also suggested.

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