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J. Biol. Chem., Vol. 278, Issue 43, 42604-42614, October 24, 2003

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A Novel RGD-independent Cell Adhesion Pathway Mediated by Fibronectin-bound Tissue Transglutaminase Rescues Cells from Anoikis^*

Elisabetta A. M. Verderio, Dilek Telci, Afam Okoye, Gerry Melino||, and Martin Griffin¶

From the Department of Life Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, United Kingdom, the the Department of Experimental and Biochemical Sciences, D26/F153, University of Rome "Tor Vergata," 00133 Rome, Italy, and the ^||Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester LE1 9HN, United Kingdom

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 ₅₁. 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 C, 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.

Received for publication, March 31, 2003

^* This work was supported in part by grants from Engineering and Physical Research Council (GR/L43688), Telethon (E872, E1224), Associazione Italiana per la Ricerca sul Cancro, European Commission, and Ministero dell'Istruzione dell'Università e della Ricerca. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

^¶ To whom correspondence should be addressed: Dept. of Life Sciences, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK. Tel.: 44-115-848-6670; Fax: 44-115-848-6636; E-mail: martin.griffin{at}ntu.ac.uk.

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