Cellular Functions of Tissue Transglutaminase

Abstract

Transglutaminase 2 (TG2 or tissue transglutaminase) is a highly complex multifunctional protein that acts as transglutaminase, GTPase/ATPase, protein disulfide isomerase, and protein kinase. Moreover, TG2 has many well-documented nonenzymatic functions that are based on its noncovalent interactions with multiple cellular proteins. A vast array of biochemical activities of TG2 accounts for its involvement in a variety of cellular processes, including adhesion, migration, growth, survival, apoptosis, differentiation, and extracellular matrix organization. In turn, the impact of TG2 on these processes implicates this protein in various physiological responses and pathological states, contributing to wound healing, inflammation, autoimmunity, neurodegeneration, vascular remodeling, tumor growth and metastasis, and tissue fibrosis. TG2 is ubiquitously expressed and is particularly abundant in endothelial cells, fibroblasts, osteoblasts, monocytes/macrophages, and smooth muscle cells. The protein is localized in multiple cellular compartments, including the nucleus, cytosol, mitochondria, endolysosomes, plasma membrane, and cell surface and extracellular matrix, where Ca2+, nucleotides, nitric oxide, reactive oxygen species, membrane lipids, and distinct protein–protein interactions in the local microenvironment jointly regulate its activities. In this review, we discuss the complex biochemical activities and molecular interactions of TG2 in the context of diverse subcellular compartments and evaluate its wide ranging and cell type-specific biological functions and their regulation.

Role of transglutaminase 2 in PAC1 receptor mediated protection against hypoxia-induced cell death and neurite outgrowth in differentiating N2a neuroblastoma cells

“…TG2 can catalyse two types of transamidation, namely (i) intra-, and/or inter-molecular covalent cross-links between protein-bound glutamine and protein-bound lysine residues, and (ii) cross-links between primary amines and protein-bound glutamine (Nurminskaya and Belkin, 2012).…”

“…Our recent studies have shown that the Gi/o-protein coupled A1 adenosine receptor stimulates TG2 activation in H9c2 cardiomyocyte-like cells (Vyas et al, 2016). Since TG2 transamidase activity modulates protein function by cross-linking and incorporation of small molecule mono-and polyamines into protein substrates, it is likely that activation of TG2 by GPCRs plays a major role in the regulation of cellular function (Nurminskaya and Belkin, 2012;Eckert et al, 2014).…”

“…Transglutaminases (TGs) are a family of Ca 2+ )-dependent enzymes that catalyse the post-translational modification of proteins (for extensive reviews see Nurminskaya and Belkin, 2012;Eckert et al, 2014). There are eight distinct catalytically active members of the TG family which exhibit differential expression (Factor XIIIa and TGs 1-7).…”

“…The ubiquitously expressed TG2 is the most widely studied member of the TG family which is involved in the regulation of numerous cellular processes, including cell adhesion, migration, growth, survival, apoptosis, differentiation, and extracellular matrix organization (Nurminskaya and Belkin, 2012). In neuronal cells, TG2 is involved in neural differentiation, neurite outgrowth and neuroprotection following cerebral ischaemia (Tucholski et al, 2001;Filiano et al, 2010;Vanella et al, 2015).…”

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

“…Once Ca 2+ binds to TG, a cysteine is exposed leading to the formation of a bond between ε-amide (as an isodipeptide or polyamine bond) and γ-carboxamide of protein bound glutamine residues [1]. Transglutaminase 2 (TG2), the most widely studied member of the TG family, has been implicated in the regulation of a wide range of processes, including cell adhesion, migration, growth, survival, apoptosis, differentiation, and extracellular matrix organization [2]. The role of TG2 in cell survival and cell death is cell-specific with respect to whether it has pro-or anti-apoptotic effects [3].…”