Tissue transglutaminase (TG2) is upregulated in the pathogenesis of a wide variety of chronic diseases. In this review special emphasis will be placed on fundamental mechanisms underlying the critical role of TG2 in fibroproliferative disorders. TG2 is best known for its cross-linking capacities in the extracellular space but has many critical and multifaceted roles beyond protein cross-linking, which are driven by the conformation and specific localization of the molecule.
As extracellular crosslinker TG2 promotes fibrotic disease through the storage of latent TGF-β1 in a stiffened extracellular matrix (ECM). As membrane-bound cell adhesion cofactor and signaling protein and intracellular crosslinker or G-protein, TG2 promotes fibrotic disease through cell survival and profibrotic pathway activation on a signaling, transcriptional and translational level. Similarities between the roles that TG2 plays in scar tissue and in the tumor stroma suggest that a deeper understanding of key common pathways in disease pathogenesis and progression might lead to the identification of novel treatment targets and the development of new drugs and diagnostic methods.