A novel RGD-independent cel adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis.
Specific association of tissue transglutaminase (tTG) with matrix fibronectin (FN) results in the formation of an extracellular complex (tTG-FN) with distinct adhesive and pro-survival characteristics. tTG-FN supports RGD-independent cell adhesion of different cell types and the formation of distinctive RhoA-dependent focal adhesions following inhibition of integrin function by competitive RGD peptides and function blocking anti-integrin antibodies alpha5beta1. Association of tTG with its binding site on the 70-kDa amino-terminal FN fragment does not support this cell adhesion process, which seems to involve the entire FN molecule. RGD-independent cell adhesion to tTG-FN does not require transamidating activity, is mediated by the binding of tTG to cell-surface heparan sulfate chains, is dependent on the function of protein kinase Calpha, and leads to activation of the cell survival focal adhesion kinase. The tTG-FN complex can maintain cell viability of tTG-null mouse dermal fibroblasts when apoptosis is induced by inhibition of RGD-dependent adhesion (anoikis), suggesting an extracellular survival role for tTG. We propose a novel RGD-independent cell adhesion mechanism that promotes cell survival when the anti-apoptotic role mediated by RGD-dependent integrin function is reduced as in tissue injury, which is consistent with the externalization and binding of tTG to fibronectin following cell damage/stress.
Department of Life Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, United Kingdom.
Elisabetta A M
EA
Verderio
Dilek
D
Telci
Afam
A
Okoye
Gerry
G
Melino
Martin
M
Griffin
D016475:3T3 Cells; D000818:Animals; D023102:Anoikis; D002448:Cell Adhesion; D002478:Cells, Cultured; D003599:Cytoskeleton; D005347:Fibroblasts / Q000166:cytology; D005353:Fibronectins / Q000378:metabolism*; D022001:Focal Adhesions; D006168:Guinea Pigs; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology; D011485:Protein Binding; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D011509:Proteoglycans / Q000494:pharmacology; D011503:Transglutaminases / Q000378:metabolism*
D005353:Fibronectins; D009842:Oligopeptides; D011509:Proteoglycans; C036090:heparin proteoglycan; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin; D011503:Transglutaminases; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha