Elsevier

Biochemical Pharmacology

Volume 80, Issue 12, 15 December 2010, Pages 1921-1929
Biochemical Pharmacology

Review
Transglutaminase 2: A multi-tasking protein in the complex circuitry of inflammation and cancer

https://doi.org/10.1016/j.bcp.2010.06.029Get rights and content

Abstract

Metastasis of primary tumors to distant sites and their inherent or acquired resistance to currently available therapies pose major clinical challenge to the successful treatment of cancer. The identification of tumor-coded genes and how they contribute to the progression of cancer is required to improve patient outcomes. Recently, cells that have undergone the epithelial–mesenchymal transition (EMT), which share characteristics with cancer stem cells (CSC) have been implicated to play a role in drug resistance and metastasis of several types of cancer. In this review, we discuss the relationship among transglutaminase 2 (TG2), the EMT, and CSCs in inflammation and cancer. TG2 is a structurally and functionally complex protein implicated in such diverse processes as tissue fibrosis, wound healing, apoptosis, neurodegenerative disorders, celiac disease, atherosclerosis and cancer. Depending on the cellular context, TG2 can either promote or inhibit cell death. Increased expression of TG2 in several types of cancer cells has been associated with increased cell invasiveness, cell survival and decreased survival of patients with cancer. Down-regulation of TG2 by small interfering RNA (siRNA) or its inhibition by small molecule inhibitors has been shown to significantly enhances the therapeutic efficacy of anticancer drugs and inhibit metastatic spread. In addition, TG2-regulated pathways are involved in promoting or protecting normal and tumor cells from death-induced signaling. We discuss the contribution of TG2-regulated pathways to the development of drug resistance and progression to metastatic disease and the therapeutic potential of TG2 for treating advanced-stage cancer.

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.

References (91)

  • S. Grivennikov et al.

    Immunity, inflammation, and cancer

    Cell

    (2010)
  • A. Verma et al.

    Tissue transglutaminase-mediated chemoresistance in cancer cells

    Drug Resist Updat

    (2007)
  • M.A. Antonyak et al.

    Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells

    J Biol Chem

    (2004)
  • D. Hanahan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • F. Balkwill et al.

    Inflammation and cancer: back to Virchow?

    Lancet

    (2001)
  • S.A. Mani et al.

    The epithelial–mesenchymal transition generates cells with properties of stem cells

    Cell

    (2008)
  • E.A. Verderio et al.

    A novel RGD-independent cel adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis

    J Biol Chem

    (2003)
  • R.Z. Orlowski et al.

    NF-κB as a therapeutic target in cancer

    Trends Mol Med

    (2002)
  • Y. Wu et al.

    Stabilization of Sanil by NF-kB is required for inflammation-induced cell migration and invasion

    Cell

    (2009)
  • Y. Kim et al.

    Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammation

    Mol Immunol

    (2010)
  • S.J. Ritter et al.

    Identification of a transforming growth factor-beta1/bone morphogenetic protein 4 (TGF-beta1/BMP4) response element within the mouse tissue transglutaminase gene promoter

    J Biol Chem

    (1998)
  • D. Telci et al.

    Increased TG2 expression can result in induction of transforming growth factor beta1, causing increased synthesis and deposition of matrix proteins, which can be regulated by nitric oxide

    J Biol Chem

    (2009)
  • K.R. Levental et al.

    Matrix crosslinking forces tumor progression by enhancing integrin signaling

    Cell

    (2009)
  • E.A. Zemskov et al.

    Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase

    J Biol Chem

    (2009)
  • L. Lorand et al.

    Transglutaminases: crosslinking enzymes with pleiotropic functions

    Nat Rev Mol Cell Biol

    (2003)
  • K. Mehta

    Mammalian transglutaminases: a family portrait

    Prog Exp Tumor Res

    (2005)
  • H. Nakaoka et al.

    Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function

    Science

    (1994)
  • G. Hasegawa et al.

    A novel function of tissue-type transglutaminase: protein disulphide isomerase

    Biochem J

    (2003)
  • L. Fesus et al.

    Transglutaminase induction by various cell death and apoptosis pathways

    Experientia

    (1996)
  • B. Nicholas et al.

    Crosslinking of cellular proteins by tissue transglutaminase during nectrotic cell death: mechanism for maintaining tissue integrity

    Biochem J

    (2003)
  • A. Chhabra et al.

    Tissue transglutaminase promotes or suppresses tumors depending on cell context

    Anticancer Res

    (2009)
  • D.S. Kim et al.

    Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-kappaB inactivation

    Cancer Res

    (2006)
  • A. Verma et al.

    Transglutaminase-mediated activation of nuclear transcription factor-kappaB in cancer cells: a new therapeutic opportunity

    Curr Cancer Drug Targets

    (2007)
  • E.A.M. Verderio et al.

    Transglutaminases in wound healing and inflammation

  • S.E. Iismaa et al.

    Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders

    Physiol Rev

    (2009)
  • E.A.M. Verderio et al.

    Tissue transglutaminase in normal and abnormal wound healing: review article

    Amino Acids

    (2004)
  • G. Quan et al.

    TGF-beta1 upregulates transglutaminase 2 and fibronectin in dermal fibroblasts: a possible mechanism for the stabilization of tissue inflammation

    Arch Dermatol Res

    (2005)
  • G.S. Kuncio et al.

    TNF-alpha modulates expression of the tissue transglutaminase gene in liver cells

    Am J Physiol

    (1998)
  • S.Y. Kim

    Transglutaminase 2 in inflammation

    Front Biosci

    (2006)
  • Z.A. Haroon et al.

    Tissue transglutaminase is expressed, active, and directly involved in rat dermal wound healing and angiogenesis

    FASEB J

    (1999)
  • L. Falasca et al.

    Transglutaminase type II is involved in the pathogenesis of endotoxic shock

    J Immunol

    (2008)
  • H. Tatsukawa et al.

    Recent advances in understanding the roles of transglutaminase 2 in alcoholic steatohepatitis

    Cell Biol Int

    (2010)
  • B. Seiving et al.

    Transglutaminase differentiation during maturation of human blood monocytes to macrophages

    Eur J Haematol

    (1991)
  • E. Garabuczi et al.

    Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells

    J Immunol

    (2009)
  • S.S. Akimov et al.

    Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin

    J Cell Biol

    (2000)
  • Cited by (122)

    • The gliadin p31–43 peptide: Inducer of multiple proinflammatory effects

      2021, International Review of Cell and Molecular Biology
    • Epithelial cell dysfunction in coeliac disease

      2021, International Review of Cell and Molecular Biology
      Citation Excerpt :

      Initially, these extracellular matrix alterations were attributed to CD-associated antibodies against gluten peptides and tissue transglutaminase (tTG) 2 or primary defects in fibroblasts, but the latest reports on organoids demonstrate an additional role for epithelial cells (Dieterich et al., 2020; Roncoroni et al., 2013). Interestingly, tTG2, the CD autoantigen involved in tissue repair, stabilizes extracellular matrix proteins by binding to integrins (Dieterich et al., 1997; Mehta et al., 2010; Wang and Griffin, 2012). Tissue transglutaminases are multifunctional proteins that are expressed by IECs.

    View all citing articles on Scopus
    View full text