Protein crosslinking in assembly and remodelling of extracellular matrices: The role of transglutaminases

Transglutaminases form a family of proteins that have evolved for specializ ed functions such as protein crosslinking in haemostasis, semen coagulation , or keratinocyte cornified envelope formation. In contrast to the other me mbers of this protein family, tissue transglutaminase is a multifunctional enzyme apparently involved in very disparate biological processes. By virtu e of its reciprocal Ca2+-dependent crosslinking activity or GTP-dependent s ignal transducing activity, tissue transglutaminase exhibits true multifunc tionality at the molecular level, The crosslinking activity can subserve di sparate biological phenomena depending on the location of the target protei ns. Intracellular activation of tissue transglutaminase can give rise to cr osslinked protein envelopes in apoptotic cells, whereas estracellular activ ation contributes to stabilization of the extracellular matrix and promotes cell-substrate interaction. While tissue transglutaminase synthesis and ac tivation is normally part of a protective cellular response contributing to tissue homeostasis, the enzyme has also been implicated in a number of pat hological conditions including fibrosis, artherosclerosis, neurodegenerativ e diseases, celiac disease, and cancer metastasis, This review discusses th e role of transglutaminases in estracellular matrix crosslinking with a foc us on the multifunctional enzyme tissue transglutaminase.