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Cell-surface transglutaminase promotes fibronectin assembly via interaction with the gelatin-binding domain of fibronectin

a role in TGFß-dependent matrix deposition

¹ Department of Biochemistry, The Holland Laboratory, American Red Cross, Rockville, MD 20855, USA
² Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA
^* Author for correspondence (e-mail: belkina{at}usa.redcross.org )

Accepted May 3, 2001

Assembly of fibronectin into a fibrillar matrix is critical for regulation of cell growth and migration, embryogenesis and wound healing. We have previously shown that cell-surface tissue transglutaminase serves as an integrin-binding adhesion coreceptor for fibronectin. Here we report that transglutaminase strongly promotes fibronectin assembly mediated by 5ß1 integrin. This effect is independent from transglutaminase-mediated enzymatic crosslinking of fibronectin and separate from the ability of transglutaminase to stimulate cell spreading. Surface transglutaminase increases the binding of fibronectin to cells via interaction with its gelatin-binding domain that contains modules I₆II_1,2I_7-9 and lacks integrin-binding motifs. The gelatin-binding fragment of fibronectin binds to surface transglutaminase on cells in suspension but does not interact with cell monolayers where surface transglutaminase is occupied by fibronectin. Surface transglutaminase colocalizes with growing fibronectin fibrils at early timepoints of matrix formation and remains codistributed with fibronectin matrices thereafter. The observed stimulation of matrix assembly by transglutaminase is blocked by the gelatin-binding fragment of fibronectin, but is not strongly perturbed by its N-terminal fragment consisting of modules I_1-5. These results implicate an interaction between transglutaminase and the gelatin-binding domain of fibronectin in matrix assembly and suggest its role in initiation of fibrillogenesis. However, blocking antibodies against 5ß1 integrin or the cell-binding fragment of fibronectin that contains modules III_2-11 most strongly suppress matrix formation and abolish the effects of transglutaminase. Hence, transglutaminase cooperates with but can not substitute for 5ß1 integrin in fibronectin assembly. Treatment of fibroblasts with transforming growth factor ß (TGFß) significantly increases surface expression of transglutaminase and its association with ß1 integrins, but not with Vß3 integrin. TGFß enhances the binding of fibronectin to the cell surface and elevates matrix formation, whereas antibody against transglutaminase or the gelatin-binding fragment of fibronectin suppresses these effects, indicating an involvement of transglutaminase in TGFß-dependent fibronectin assembly. Therefore, TGFß-induced fibronectin matrix deposition during normal wound healing or fibrotic disorders may depend on upregulation of integrin-associated surface transglutaminase.

Key words: Transgutaminase, Integrin, Fibronectin assembly

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