Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin

The protein cross-linking enzyme tissue transglutaminase binds in vitro wit h high affinity to fibronectin via its 42-kD gelatin-binding domain. Here w e report that cell surface transglutaminase mediates adhesion and spreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding m otifs. Overexpression of tissue transglutaminase increases its amount on th e cell surface, enhances adhesion and spreading on fibronectin and its 42-k D fragment, enlarges focal adhesions, and amplifies adhesion-dependent phos phorylation of focal adhesion kinase, These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalyt ic subunit of factor XIII. Adhesive function of tissue trans-glutaminase do es not require its cross-linking activity but depends on its stable noncova lent association with integrins. Transglutaminase interacts directly with m ultiple integrins of beta 1 and beta 3 subfamilies, but not with beta 2 int egrins. Complexes of transglutaminase with integrins are formed inside the cell during biosynthesis and accumulate on the surface and in focal adhesio ns, Together our results demonstrate that tissue transglutaminase mediates the interaction of integrins with fibronectin, thereby acting as an integri n-associated coreceptor to promote cell adhesion and spreading.