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Title: A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis
Authors: Wang, Z.
Perez, M.
Caja, S.
Melino, G.
Johnson, T. S.
Lindfors, K.
Griffin, M.
First Published: 19-Sep-2013
Publisher: Nature Publishing Group for Associazione Differenziamento e Morte Cellulare
Citation: Cell Death and Disease (2013) 4, e808
Abstract: The importance of tissue transglutaminase (TG2) in angiogenesis is unclear and contradictory. Here we show that inhibition of extracellular TG2 protein crosslinking or downregulation of TG2 expression leads to inhibition of angiogenesis in cell culture, the aorta ring assay and in vivo models. In a human umbilical vein endothelial cell (HUVEC) co-culture model, inhibition of extracellular TG2 activity can halt the progression of angiogenesis, even when introduced after tubule formation has commenced and after addition of excess vascular endothelial growth factor (VEGF). In both cases, this leads to a significant reduction in tubule branching. Knockdown of TG2 by short hairpin (shRNA) results in inhibition of HUVEC migration and tubule formation, which can be restored by add back of wt TG2, but not by the transamidation-defective but GTP-binding mutant W241A. TG2 inhibition results in inhibition of fibronectin deposition in HUVEC monocultures with a parallel reduction in matrix-bound VEGFA, leading to a reduction in phosphorylated VEGF receptor 2 (VEGFR2) at Tyr1214 and its downstream effectors Akt and ERK1/2, and importantly its association with β1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity.
DOI Link: 10.1038/cddis.2013.318
ISSN: 2041-4889
eISSN: 2041-4889
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit
Description: Supplementary Information accompanies this paper on Cell Death and Disease website
Appears in Collections:Published Articles, MRC Toxicology Unit

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