Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects

Abstract

The type 2 isoenzyme is the most widely expressed transglutaminase in mammals displaying several intra- and extracellular activities depending on its location (protein modification, modulation of gene expression, membrane signalling and stabilization of cellular interactions with the extracellular matrix) in relation to cell death, survival and differentiation. In contrast with the appreciable knowledge about the regulation of the enzymatic activities, much less is known concerning its inducible expression, which is altered in inflammatory and neoplastic diseases. In this context, we first summarize the gene's basic features including single-nucleotide polymorphism characterization, epigenetic DNA methylation and identification of regulatory regions and of transcription factor-binding sites at the gene promoter, which could concur to direct gene expression. Further aspects related to alternative splicing events and to ncRNAs (microRNAs and lncRNAs) are involved in the modulation of its expression. Notably, this important gene displays transcriptional variants relevant for the protein's function with the occurrence of at least seven transcripts which support the synthesis of five isoforms with modified catalytic activities. The different expression of the TG2 (type 2 transglutaminase) variants might be useful for dictating the multiple biological features of the protein and their alterations in pathology, as well as from a therapeutic perspective.

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

“…Transglutaminase 2 (TG2) is a 78-kDa calcium-dependent enzyme of the protein-glutamine γ-glutamyl-transferase family 5 , 6 . In the presence of calcium, TG2 functions as a catalytic enzyme that modifies the protein-bound glutamine side chains, resulting in protein crosslinking through transamidation or deamidation 6 , 7 . When this protein binds to GTP intracellularly, it becomes closed conformationally and acts as a G-protein associated signaling molecule 8 .…”

The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia

“…However, the present study showed no significant association between exon 6 (E469K) of ICAM-1 polymorphism and DS. The inclusion and exclusion criteria of the patients with DS and the prescribed medicines were different between the present study and the study by Dore et al Type-2 transglutaminase (TGM2/TG2) is emerging as a multifunctional enzyme that is capable of promoting specialized enzyme functions under regulation by allosteric effectors depending on its cellular location such as angiogenesis, cell growth/differentiation, and cell death [17,18]. TGM2 acts as a G protein in signal transduction processes and is involved in the pathophysiology of various inflammatory conditions.…”

“…TGM2 acts as a G protein in signal transduction processes and is involved in the pathophysiology of various inflammatory conditions. TGM2 is associated with 329 diseases, including immune system, endocrine, metabolic, cardiovascular, epidermal, renal and hematological diseases [17]. Bradford et al genotyped eight SNPs (rs2076380, rs7270785, rs4811528, rs2284879, rs6023526, rs2268909, rs17789815 and rs1555074) related to the TGM2 gene in individuals with schizophrenia in a British population.…”

“…The proposed mechanisms include changes in the adhesion molecules, cytokine secretion, and enzymes during ATRA/ATO induced differentiation such as Intercellular Adhesion Molecule-1(ICAM-1), monocyte chemoattractant protein-1 (MCP-1/CCL2), and type-2 transglutaminase (TGM2/TG2) [10,[12][13][14]. ICAM-1 (CD54) is a single chain 76-110 kDa glycoprotein and a member of the Ig superfamily located on chromosome 19p13 [15], MCP-1/CCL2 is a CC chemokine located on chromosome 17q11 [16], and TGM2 is a 74-80 kDa protein and a member of the transglutaminase family located on chromosome 20q11-12 [17,18]. Single Nucleotide Polymorphisms (SNPs) SNPs are variations in the DNA sequence.…”

The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression

“…The expression of TG2 is tightly controlled and can be induced at the transcriptional level by cytokines and the activation of various transcription factors [40,41]. Moreover, the alternative splicing of TG2 gene ( TGM2 ) mRNA has been observed [42,43].…”