The Outside-In Journey of Tissue Transglutaminase in Cancer

Abstract

Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca2+-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca2+ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca2+ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2’s unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein.

GPR56 signaling pathway network and its dynamics in the mesenchymal transition of glioblastoma

“…Additionally, TG2/Fibronectin integrin complex formation on the surface of cancer cell membranes was shown to regulate β‐catenin expression and loss of TG2 also decreased mesenchymal markers like MMP‐2, TWIST‐, CD44, etc. (Condello et al 2022; Sima et al 2022), thus implying a cross‐talk between GPR56—TG2 dynamics and integrin signaling associated with the cytoskeletal reorganization and cell invasion.…”

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

“…Compared to the abovementioned members of this family, TG2 is a multifunctional and ubiquitously expressed enzyme exerting transamidation (crosslinking, primary amine incorporation, and deamidation), protein disulfide isomerase (PDI), and serine/threonine kinase activities as well as G protein and cell surface adhesion functions [38][39][40]. TG2, a monomeric protein of 687 amino acids, consists of four domains: (i) an N-terminal β-sandwich that contains the binding site for fibronectin; (ii) an α/β-domain that comprises both the active site for transamidation activity with the catalytic triad (C277, H335, and D358) and the calcium-binding site; (iii) a C-terminal β-barrel domain that contains GTP/GDP-binding site; and (iv) another C-terminal β-barrel domain that can recruit and activate phospholipase C [18,41] (Figure 1A). As mentioned above, with the exception of protein 4.2, all TGs catalyze a calcium-dependent crosslinking reaction that starts with a nucleophilic attack, by the thiol of the active cysteine, of a γ-carboxamide group of a glutamine residue forming a thioester intermediate with ammonia release (Figure 1B).…”

“…In the Ca 2+ -bound conformation, TG2 adopts an open (active) form with transamidation activity. When it binds GTP, TG2 shows a closed (inactive) conformation and acts as a G-protein contributing to transmembrane signaling [18,45] (Figure 1B). These two conformations determine different and, often, opposite effects on cancer fate depending on cell type and TG2 localization [46].…”

“…Moreover, several studies have demonstrated that TG2 dysregulation may be involved in many pathological processes and degenerative disorders [5,10,11], including injury associated with ischemic stroke [12], 2 of 22 Alzheimer's disease [13], Parkinson's disease [14], and Huntington's disease [15]. Given its pleiotropic functions, it is not surprising that TG2 is involved in the initiation, survival, progression, tumor-related angiogenesis, and metastatic properties of several cancer types [16][17][18]; nervous system tumors are not an exception [19]. Interestingly, different studies reported that TG2 expression level is upregulated in CNS tumors compared to normal tissues [20][21][22][23][24][25].…”

von Willebrand factor-binding protein (vWbp)-activated Factor XIII and transglutaminase 2 (TG2) promote cross-linking between FnBPA from Staphylococcus aureus and fibrinogen

“…Many intra-and extracellular proteins have been identi ed as TG2 substrates for TG2-mediated cross-linking reactions. In the ECM, TG2 initiates cross-linking of structural proteins such as collagen, Fn, Fbg and laminin, leading to the formation of an ECM scaffold that displays an increased stability and rigidity [36,37,38].…”