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First published online 15 June 2004
doi: 10.1242/jcs.01188

Journal of Cell Science 117, 3389-3403 (2004)
Published by The Company of Biologists 2004
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Research Article

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

Phil Stephens1,2,*, Pascale Grenard6,*, Pascale Aeschlimann3,6, Martin Langley3, Emma Blain6, Rachael Errington4, David Kipling2,5, David Thomas1,2 and Daniel Aeschlimann2,3,6,{ddagger}

1 Department of Oral Surgery, Medicine and Pathology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XY, UK
2 Cardiff Institute of Tissue Engineering and Repair, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XY, UK
3 Matrix Biology and Tissue Repair Research Unit, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XY, UK
4 Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XY, UK
5 Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XY, UK
6 Connective Tissue Biology Laboratories, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK

{ddagger} Author for correspondence (e-mail: aeschlimanndp{at}cardiff.ac.uk)

Accepted 26 February 2004

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 {alpha} (PKC{alpha}). Phospholipase C (PLC) and PKC{alpha} 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.

Key words: Transglutaminase, Cell adhesion, Wound healing, Signalling




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