Abstract
Transglutaminase 2 (TG2) is a multifunctional mammalian protein with transamidase and signaling properties. Using selective TG2 inhibitors and tagged nucleophilic amine substrates, we show that the majority of extracellular TG2 is inactive under normal physiological conditions in cell culture and in vivo. However, abundant TG2 activity was detected around the wound in a standard cultured fibroblast scratch assay. To demonstrate wounding-induced activation of TG2 in vivo, the toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly(I:C)), was injected in mice to trigger small intestinal injury. Although no TG2 activity was detected in vehicle-treated mice, acute poly(I:C) injury resulted in rapid TG2 activation in the small intestinal mucosa. Our findings provide a new basis for understanding the role of TG2 in physiology and disease.
Highlights
Transglutaminase 2 (TG2, tissue transglutaminase, transglutaminase C, Gah) is a multifunctional protein found in most mammalian tissues capable of enzymatic, cell adhesion, cell signaling, and G-protein activities [1,2,3,4]
In order to determine if 3-bromo-4,5-dihydroisoxazole irreversible inhibitors are able to covalently bind cellular TG2, 100 mM compound 1 was diluted into culture media and incubated at 37uC for one hour with WI-38 fibroblasts and MDA-MB-231 cells, two cell lines previously shown to express abundant TG2 protein [27,28,29,30]
Because TG2 is believed to contribute to many important biological processes, it is thought that pharmacological inhibition of TG2 may have undesirable side effects
Summary
Transglutaminase 2 (TG2, tissue transglutaminase, transglutaminase C, Gah) is a multifunctional protein found in most mammalian tissues capable of enzymatic, cell adhesion, cell signaling, and G-protein activities [1,2,3,4]. A ubiquitous protein, its function is presumably dictated by its cellular localization, interaction with other proteins and binding to cofactors [1,2,3]. In the presence of calcium and the absence of GTP or GDP, TG2 can act as an enzyme capable of post-translationally modifying proteins through transamidation or deamidation. Certain small molecule amines can be attached onto glutamine side-chains of proteins by TG2. In the absence of adequate concentrations of any suitable amine substrate, TG2 deamidates the targeted glutamine side chain, resulting in its conversion to glutamate [2,3,5]
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