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Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses

Stephens, Philip ORCID:, Grenard, Pascale Marie, Aeschlimann, Pascale Corinne, Langley, Martin Simon, Blain, Emma Jane ORCID:, Errington, Rachel Jane ORCID:, Kipling, David Glyn, Thomas, David William ORCID: and Aeschlimann, Daniel ORCID: 2004. Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. Journal of cell science 117 (15) , pp. 3389-3403. 10.1242/jcs.01188

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Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading, migration and extracellular matrix (ECM) reorganisation. Using fibroblasts deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we show that the extracellular crosslinking activity and intracellular G-protein function in signal transduction contribute differentially to regulation of cell-matrix interactions. TG2-deficient cells displayed normal attachment but delayed spreading on ECM substrata and defects in motility unrelated to crosslinking. Blocking antibodies to TG2 failed to induce similar defects in normal fibroblasts. TG2-deficient fibroblasts had defects in focal adhesion turnover and stress fibre formation, showed changes in focal adhesion kinase (FAK) phosphorylation and failed to activate protein kinase C (PKC). Phospholipase C (PLC) and PKC inhibitors blocked spreading of normal fibroblasts whilst PKC activators induced spreading in TG2-deficient cells. In contrast, ECM remodelling was not only compromised by TG2 deficiency but also by overexpression of dominant negative enzyme and TG inhibitors. TG2 activity increased matrix tension and was required for membrane type 1-MMP (MT1-MMP)-dependent activation of MMP-2. Our results demonstrate that TG2 is involved in the control of dynamic adhesion formation in cell spreading and migration via regulation of phospholipase C activity. By virtue of its crosslinking activity, the enzyme plays a central role in regulating ECM remodelling.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Uncontrolled Keywords: Transglutaminase ; Cell adhesion ; Wound healing ; Signalling
Publisher: The Company of Biologists
ISSN: 14779137
Last Modified: 01 Sep 2023 07:06

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