Tissue transglutaminase: a novel cell adhesion protein

Telci, D., 2004. Tissue transglutaminase: a novel cell adhesion protein. PhD, Nottingham Trent University.

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When purified tissue transglutaminase (tTG) is immobilised on plasma fibronectin it forms an extracellular complex (FN-tTG), which partially restores attachment and spreading of human osteoblast cells and mouse Swiss 3T3 fibroblasts when the integrin mediated direct binding to FN is impaired using Arg-Gly-Asp (RGD) containing peptides. However, the molecular mechanism(s) and the physiological importance of this RGD-independent cell adhesion process, are not fully understood. The role of the FN-bound tTG complex in mediating the RGD- independent cell adhesion was investigated by characterisation of the FN-tTG matrix and the intracellular signals that lead to changes in protein phosphorylation during this process. The FN-tTG matrix compensated for the RGD inhibition of cell adhesion in different cell types, which was independent of the endogenous ECM protein synthesis. A physiological matrix composed of cell-assembled FN with increased levels of bound cell-secreted tTG supported RGD-independent cell adhesion of Swiss 3T3 fibroblasts. tTG bound to tissue culture plastic or N-terminal FN fragments, which contain a putative high affinity binding site for tTG, was not sufficient to sustain the RGD-independent cell adhesion, suggesting a requirement for the association of tTG with the entire FN molecule. The compensatory effect of the FN-tTG complex for the RGD-inhibition of cell adhesion did not require transamidating activity of tTG, or the binding of tTG to α4β1 integrins, but was dependent on the interaction of tTG with cell-surface heparan sulphate chains and the activity of PKC-α. The RGD-independent cell adhesion to FN-tTG was linked to the activation of cell survival focal adhesion kinase, extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase and also required the Raf-1 kinase activity. Apoptosis of tTG-null mouse dermal fibroblasts induced by inhibition of integrin function by RGD peptide (anoikis) could be rescued in response to FN-tTG, suggesting an extracellular survival role for tTG. The correlation between the externalisation and binding of tTG to FN in situations of cell stress and wounding supports the idea that extracellular tTG in complex with FN acts as a pro-survival adhesion factor for anchorage-dependent cells.

Item Type: Thesis
Creators: Telci, D.
Date: 2004
ISBN: 9781369312737
Divisions: Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 26 Aug 2020 10:23
Last Modified: 07 Jun 2023 08:07
URI: https://irep.ntu.ac.uk/id/eprint/40521

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