ReviewTransglutaminase 2: A multi-tasking protein in the complex circuitry of inflammation and cancer
Graphical abstract
Introduction
Transglutaminases (TGs; EC 2.3.2.13) are a family of enzymes that catalyze posttranslational modification of proteins by cross-linking proteins via ɛ-(γ-glutamyl)lysine isopeptide bonds or through incorporating primary amines at selected peptide-bound glutamine residues [1]. Eight TGs have been identified in mammals and humans and they all require Ca2+ for catalytic activity, some require proteolytic cleavage of propeptides, and three of them (TG2, TG3 and TG5) are inhibited by GTP [2]. Tissue transglutaminase (TG2 or tTG) is the most diverse and ubiquitous member of the TG family. The entire gene of TG2 (TGM2 on human chromosome 20q11-12) is composed of 13 exons and 12 introns [2] and encodes a monomeric protein of 687 amino acids (MW ≈ 78 kDa) with four distinct domains: an N-terminal β-sandwich domain, a catalytic core domain, and two C-terminal β-barrel domains (Fig. 1). TG2 is structurally and functionally a complex protein with both intracellular and extracellular functions. In addition to catalyzing the calcium-dependent posttranslational modification of proteins, TG2 can bind and hydrolyze GTP and ATP [3]. Moreover, it can catalyze protein disulfide isomerase reaction [4] and may even function as a protein kinase [5].
GTPase activity has been linked to the function of TG2 as a G protein (Gαh) involved in signaling from α1B/D adrenergic receptors to downstream effectors such as phospholipase Cδ1 [3], [6]. TG2 has a high-affinity fibronectin-binding site located in the N-terminal domain (Fig. 1). Although predominantly an intracellular protein (localized in the cytosol, nucleus, and cell membrane compartments), TG2 can also be secreted outside the cell, by an as-yet unknown mechanism, and it has extracellular functions. TG2 is thought to serve distinct physiological functions within different cellular compartments. Under normal conditions, TG2 in the intracellular environment exists as a latent protein due to the presence of low Ca2+ and the inhibitory effect of GTP/GDP (Fig. 2). However, under extreme conditions of cell stress or trauma after the disturbance or loss of Ca2+ homeostasis, TG2 may be activated and cause cross-linking of intracellular proteins, as is observed during apoptosis or necrosis [7], [8].
Various important functions have, therefore, been ascribed to TG2 both in the intra- and extracellular environment, including its role in matrix stabilization, cell adhesion and migration and cell death and survival (Fig. 2). TG2 can interact with various intra- and extracellular proteins, altering their structure, function, and/or stability [9]. For example, the interaction between TG2 and IκBα is implicated in the constitutive activation of NF-κB and conferring protection against stress-induced cell damage by reactive oxygen species, inflammatory cytokines, and chemotherapeutic drugs [10], [11]. Therefore, it is possible that the functions of TG2 are dictated by its cellular location, interaction with other proteins, and binding to cofactors. Interestingly, despite the variety of functions in which TG2 participates, TG2 knockout mice (TG2−/−) are anatomically, developmentally, and reproductively normal [12]. However, studies using these animal models have indicated that TG2 plays a critical role in wound healing and that chronic expression of TG2 promotes abnormal wound healing by the accumulation of extracellular matrix (ECM) leading to fibroproliferative disorders [13].
Section snippets
TG2 in inflammation
Inflammation is essential for wound healing and tissue repair and involves a complex series of events such as cell migration, cell proliferation, synthesis and stabilization of the ECM, neovascularization, and apoptosis. It is a dynamic process mediated as a result of altered homotypic (cell–cell) and heterotypic (cell–ECM) interactions among multiple cell types (fibroblasts, endothelial cells, macrophages, granulocytes, immune cells, etc.). Chronic inflammation due to ageing, infection or
TG2 in cancer
Cancer progression shares many similarities with the inflammatory response and tissue injury and remodeling [33], [34]. Increased TG2 expression and transamidation activity is a common feature of many inflammatory diseases [13], [15], [18]. Hence, various cytokines and growth factors (such as, TGF-β1, TNF-α, and IL-6) secreted during tissue injury or wound healing are potent inducers of TG2 gene expression [16], [17], [19]. It is also becoming evident that inflammatory responses play a critical
Epithelial to mesenchymal transition (EMT), inflammation, and cancer
Cancer progression shares many similarities with inflammatory responses and tissue injury and remodeling. As early as 1863, Rudolph Virchow provided the first indication of a possible link between inflammation and cancer. He hypothesized that cancer originates at the sites of chronic inflammation and suggested that some classes of irritants together with the tissue injury and ensuing inflammation that they cause, may enhance cell proliferation and cancer progression [59]. This idea remained
TG2-induced EMT in cancer cells
As discussed earlier (Section 3), multiple cancer cell types with inherent or acquired resistance to drugs or from metastatic sites exhibit increased expression of TG2. TG2 expression in cancer cells is associated with increased cell survival and invasive signaling functions. TG2 expression induces the activation of FAK, Akt, cyclic AMP response element binding protein, and NF-κB and down-regulates the tumor suppressor protein PTEN. Activation of these TG2-induced oncogenic signaling pathways
TG2 as a therapeutic target
About 11 million new cases of cancer are diagnosed annually worldwide and 6.7 million people die of the disease. Virtually, all the cancer-related deaths can be said to have occurred because the chemotherapy failed or the disease has metastasized. Therefore, the discovery that aberrant expression of TG2 in cancer cells contributes to chemoresistance and metastasis in a wide spectrum of cancer types, offers a unique opportunity to treat/manage cancer during early and advanced stages. The
Acknowledgements
The work in authors’ laboratory was supported in part by a grant from Susan G. Komen for the Cure Foundation and by National Institutes of Health grant CA131062 (to KM). The authors wish to acknowledge important contributions by various investigators in the field, which we are unable to cite due to space limitations. We wish to thank Ms. Virginia M. Mohlere for editorial help of this manuscript.
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