Alternative titles; symbols
HGNC Approved Gene Symbol: TGM2
Cytogenetic location: 20q11.23 Genomic coordinates (GRCh38): 20:38,127,385-38,168,475 (from NCBI)
Transglutaminases (EC 2.3.2.13) catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. The transglutaminases include factor XIII (plasma transglutaminase; 134570), keratinocyte transglutaminase (TGM1; 190195), hair follicle transglutaminase, prostate transglutaminase (TGM4; 600585), and tissue transglutaminase (TGM2). Although the overall primary structures of these enzymes are different, they all share a common amino acid sequence at the active site (YGQCW) and a strict calcium dependence for their activity. Differences in the primary structures of transglutaminases are probably responsible for their diverse biologic functions. The unique C terminus of TGM2, which is not involved in TGase activity, functions as a G protein (see GNAQ; 600998) in receptor signaling.
Gentile et al. (1991) isolated mouse and human cDNAs encoding tissue transglutaminase. The predicted 687-amino acid human protein is 84% and 81% identical to mouse and guinea pig tissue transglutaminase, respectively. In vitro translated human tissue transglutaminase has an apparent molecular mass of 85 kD by SDS-PAGE. The translated product exhibited calcium-dependent catalytic activity. Northern blot analysis revealed that tissue transglutaminase is expressed as a 3.6-kb mRNA in human endothelial cells.
Hwang et al. (1995) cloned TGM2, which they called G-alpha-h, from a heart cDNA library. Transfected COS-1 cells expressed TGM2 protein at an apparent molecular mass of about 80 kD.
Lu et al. (1995) cloned the promoter region of TGM2, ligated it to a reporter construct, and demonstrated its activity in transient transfection experiments.
By RT-PCR and immunoblot analysis, Vezza et al. (1999) demonstrated that TGM2 was expressed in platelets, megakaryocytic cell lines, and endothelial and vascular smooth muscle cells.
Antonyak et al. (2006) described a splice variant of TGM2 that encodes a 548-amino acid protein, which they called TGase-S. TGase-S contains the GTP-binding domain, transamidation domain, and Ca(2+)-binding domain of full-length TGase, but it lacks the C-terminal phospholipase C (PLC; see 604114)-binding domain.
Fesus et al. (1987) observed a significant increase of tissue transglutaminase activity and enzyme concentration in programmed cell death of hepatocytes. Immunohistochemical examination showed transglutaminase within apoptotic hepatocytes, suggesting a role for the enzyme in apoptosis.
In neonatal rat liver cells stimulated with epidermal growth factor (EGF; 131530), Piacentini et al. (1991) found that the proliferative phase was paralleled by a 10-fold increase in tissue transglutaminase mRNA levels. During the phase of involution, there were sequential increases in enzyme activity and increased levels of insoluble apoptotic bodies. Immunostaining localized the TGM2 protein within apoptotic bodies. The findings suggested that tissue transglutaminase leads to the formation of a detergent-insoluble cross-linked protein scaffold in cells undergoing apoptosis. This scaffold could stabilize cell membranes and prevent nonspecific release of harmful intracellular components, such as lysosomal enzymes. In human neuroblastoma cells, Melino et al. (1994) showed that overexpression of tissue transglutaminase resulted in a large increase in cell death rate with changes characteristic of cells undergoing apoptosis. Transfection of cells with TGM2 cDNA in antisense orientation resulted in a pronounced decrease in apoptosis. The authors concluded that tissue transglutaminase-dependent irreversible cross-linking of intracellular protein is an important biochemical event in apoptotic cells.
Nakaoka et al. (1994) demonstrated that membranes of COS-1 cells cotransfected with the cDNAs for rat liver Tgm2 and hamster Adra1b (104220) adrenergic receptor showed both TGase activity and agonist-dependent inositol phosphate accumulation. TGase activity was blocked by a TGase inhibitor, a nonhydrolyzable GTP analog, and alpha-1 adrenergic receptor activation. The nucleotide exchange activity of rat liver Tgm2 was comparable to that of G-alpha-q. Nakaoka et al. (1994) hypothesized that, since receptor activation stimulates the binding of GTP to TGM2, activation may be a switch that allows TGM2 to act as a signaling molecule rather than a TGase.
Using C-terminal deletion mutants, Hwang et al. (1995) mapped the region of TGM2 involved in ADRA1 and PLC binding. Deletion of up to 40 C-terminal amino acids had no effect on GTP binding and TGase activity. The Ca(2+)-stimulated TGase activity was, however, inhibited by excess GTP, confirming that GTP is a negative regulator of the TGase activity of TGM2. All mutants, as well as full-length TGM2, elevated basal PLC activity when cotransfected with ADRA1, but truncation of the final 30 or 40 C-terminal amino acids resulted in loss of agonist-induced PLC activation. Further mutation analysis determined that an 8-amino acid region near the C terminus, val665 to lys672, mediated PLC interaction and stimulation.
Chen et al. (1996) found that mutation of the active site cysteine (cys277) in TGM2 resulted in the expected loss of TGase activity in transfected COS-1 cells, but it had no effect on receptor-stimulated inositol phosphate turnover when TGM2 was cotransfected with ADRA1B. TGM2 supported receptor-mediated inositol phosphate turnover when it was cotransfected with ADRA1B or ADRA1D (104219), but not with ADRA1A (104221).
Dieterich et al. (1997) demonstrated that tissue transglutaminase is the autoantigen involved in celiac disease (212750).
Vezza et al. (1999) presented evidence that TGM2 interacts with thromboxane A2 receptor (TBXA2R; 188070). Following cotransfection in COS-7 cells, 2 splice variants of TBXA2R, designated TP-alpha and TP-beta, immunoprecipitated with rat Tgm2. Agonist activation of TP-alpha, but not TP-beta, stimulated PLC-mediated inositol phosphate production.
Proliferative vitreoretinopathy (193235) is characterized by the development of epi- and subretinal fibrocellular membranes containing modified retinal pigment epithelial (RPE) cells among others. Priglinger et al. (2003) found that tissue transglutaminase was present and functionally active in proliferative vitreoretinopathy membranes. The amount and activity of tissue transglutaminase appeared to be related to the differentiation state of the RPE cells and their stimulation by transforming growth factor beta-2 (TGFB2; 190220), a growth factor known to be increased in the vitreous of proliferative vitreoretinopathy.
To elucidate the role of transglutaminase-2 in Huntington disease (HD; 143100), Mastroberardino et al. (2002) generated a transgenic HD mouse model (R6/1) that was also null for TGM2 (Tgm2 -/-). Comparisons of transglutaminase activity among different mouse lines showed that Tgm2 is the predominant transglutaminase active in the brain. The deletion of Tgm2 led to significant ameliorations in generalized and brain weight loss in the HD mice. Tgm2 ablation led to a large reduction in overall cell death and to an increased number of neuronal intranuclear inclusions, suggesting that Tgm2 crosslinking is not directly involved in the assembly of inclusions. Moreover, the findings suggested a protective role for neuronal aggregates. Tgm2 -/- HD mice showed a significant improvement in motor behavior and survival. The results suggested that TGM2 plays a role in the regulation of neuronal cell death in HD.
Antonyak et al. (2006) found that, in contrast to the cytoprotective effect of full-length human TGase, the TGase-S isoform was cytotoxic when overexpressed in mammalian cells. Mutation analysis showed that the apoptotic activity of TGase-S was not dependent on its transamidation activity. TGase-S formed inappropriate oligomers in cells before cell death, suggesting a novel mechanism for its apoptotic effects.
By fluorescence in situ hybridization (FISH) with a recombinant lambda-phage containing the full cDNA coding sequence, Gentile et al. (1994) showed that the tissue transglutaminase gene is located on chromosome 20q12. Wang et al. (1994) used PCR amplification of DNAs isolated from a panel of human/rodent somatic cell hybrids and FISH to map both the TGM2 and the TGM3 (600238) gene to 20q11.2; FISH showed overlap of the signal into band 20q12. It appeared that TGM3 may be distal to TGM2. It is noteworthy that the gene structure and amino acid sequence of TGM2 and TGM3 are more closely related to each other than to those of other members of the transglutaminase family.
To clarify the role of TGase2 in apoptosis, De Laurenzi and Melino (2001) generated TGase2 -/- mice by homologous recombination. Although RT-PCR and Western blot analysis demonstrated complete absence of TGase2, minimal residual TGase activity was measured in liver and thymus extracts. PCR analysis of mRNA extracted from the same tissues demonstrated expression of TGase1. The TGase2 -/- mice showed no major developmental abnormalities, and histologic examination of the major organs appeared normal. Induction of apoptosis ex vivo and in vitro showed no significant differences. De Laurenzi and Melino (2001) concluded that TGase2 is not a crucial component of the main pathway of the apoptotic program, and that residual enzymatic activity, due to TGase1 or other as yet unidentified TGases, may compensate for the lack of TGase2.
Because the TGase2 -/- mice generated by De Laurenzi and Melino (2001) did not show an overt apoptosis-related phenotype during fetal life, Szondy et al. (2003) investigated the role of TGase2 in the in vivo apoptosis program in distinct biologic context by using the thymus and liver as models for study. They presented data indicating that the lack of TGase2 affects both the killing and the clearance of dying cells. The disturbance of these events results from a deficiency in TGF-beta activation and is associated with the development of splenomegaly, autoantibodies, and glomerulonephritis in TGase2 -/- mice.
Zhang et al. (2003) generated a transgenic mouse model overexpressing TGM2 in cardiomyocytes and found that the mice had an age-dependent left ventricular hypertrophy and cardiac decompensation, characterized by cardiomyocyte apoptosis and fibrosis and a delayed impact on survival. Expression of COX2 (600262), thromboxane synthase (274180), and the thromboxane receptor (188070) were increased coincident with the emergence of the cardiac phenotype. The COX2-dependent increase in thromboxane A2 augmented cardiac hypertrophy, whereas formation of PGI2 by the same isozyme, as well as administration of COX2 inhibitors, rescued the cardiac phenotype. Zhang et al. (2003) concluded that TGM2 activation regulates expression of COX2, and that its products may differentially modulate cell death or survival of cardiomyocytes.
Antonyak, M. A., Jansen, J. M., Miller, A. M., Ly, T. K., Endo, M., Cerione, R. A. Two isoforms of tissue transglutaminase mediate opposing cellular fates. Proc. Nat. Acad. Sci. 103: 18609-18614, 2006. [PubMed: 17116873] [Full Text: https://doi.org/10.1073/pnas.0604844103]
Chen, S., Lin, F., Iismaa, S., Lee, K. N., Birckbichler, P. J., Graham, R. M. Alpha-1-adrenergic receptor signaling via Gh is subtype specific and independent of its transglutaminase activity. J. Biol. Chem. 271: 32385-32391, 1996. [PubMed: 8943303] [Full Text: https://doi.org/10.1074/jbc.271.50.32385]
De Laurenzi, V., Melino, G. Gene disruption of tissue transglutaminase. Molec. Cell. Biol. 21: 148-155, 2001. [PubMed: 11113189] [Full Text: https://doi.org/10.1128/MCB.21.1.148-155.2001]
Dieterich, W., Ehnis, T., Bauer, M., Donner, P., Volta, U., Riecken, E. O., Schuppan, D. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med. 3: 797-801, 1997. [PubMed: 9212111] [Full Text: https://doi.org/10.1038/nm0797-797]
Fesus, L., Thomazy, V., Falus, A. Induction and activation of tissue transglutaminase during programmed cell death. FEBS Lett. 224: 104-108, 1987. [PubMed: 2890537] [Full Text: https://doi.org/10.1016/0014-5793(87)80430-1]
Gentile, V., Davies, P. J. A., Baldini, A. The human tissue transglutaminase gene maps on chromosome 20q12 by in situ fluorescence hybridization. Genomics 20: 295-297, 1994. [PubMed: 7912692] [Full Text: https://doi.org/10.1006/geno.1994.1170]
Gentile, V., Saydak, M., Chiocca, E. A., Akande, O., Birckbichler, P. J., Lee, K. N., Stein, J. P., Davies, P. J. A. Isolation and characterization of cDNA clones to mouse macrophage and human endothelial cell tissue transglutaminases. J. Biol. Chem. 266: 478-483, 1991. [PubMed: 1670766]
Hwang, K.-C., Gray, C. D., Sivasubramanian, N., Im, M.-J. Interaction site of GTP binding Gh (transglutaminase II) with phospholipase C. J. Biol. Chem. 270: 27058-27062, 1995. [PubMed: 7592956] [Full Text: https://doi.org/10.1074/jbc.270.45.27058]
Lu, S., Saydak, M., Gentile, V., Stein, J. P., Davies, P. J. A. Isolation and characterization of the human tissue transglutaminase gene promoter. J. Biol. Chem. 270: 9748-9756, 1995. [PubMed: 7730352] [Full Text: https://doi.org/10.1074/jbc.270.17.9748]
Mastroberardino, P. G., Iannicola, C., Nardacci, R., Bernassola, F., de Laurenzi, V., Melino, G., Moreno, S., Pavone, F., Oliverio, S., Fesus, L., Piacentini, M. 'Tissue' transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease. Cell Death Differ. 9: 873-880, 2002. [PubMed: 12181738] [Full Text: https://doi.org/10.1038/sj.cdd.4401093]
Melino, G., Annicchiarico-Petruzzelli, M., Piredda, L., Candi, E., Gentile, V., Davies, P. J. A., Piacentini, M. Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells. Molec. Cell. Biol. 14: 6584-6596, 1994. [PubMed: 7935379] [Full Text: https://doi.org/10.1128/mcb.14.10.6584-6596.1994]
Nakaoka, H., Perez, D. M., Baek, K. J., Das, T., Husain, A., Misono, K., Im, M.-J., Graham, R. M. Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science 264: 1593-1596, 1994. [PubMed: 7911253] [Full Text: https://doi.org/10.1126/science.7911253]
Piacentini, M., Autuori, F., Dini, L., Farrace, M. G., Ghibelli, L., Piredda, L., Fesus, L. 'Tissue' transglutaminase is specifically expressed in neonatal rat liver cells undergoing apoptosis upon epidermal growth factor-stimulation. Cell Tissue Res. 263: 227-235, 1991. [PubMed: 1672508] [Full Text: https://doi.org/10.1007/BF00318764]
Priglinger, S. G., May, C. A., Neubauer, A. S., Alge, C. S., Schoenfeld, C.-L., Kampik, A., Welge-Lussen, U. Tissue transglutaminase as a modifying enzyme of the extracellular matrix in PVR membranes. Invest. Ophthal. Vis. Sci. 44: 355-364, 2003. [PubMed: 12506096] [Full Text: https://doi.org/10.1167/iovs.02-0224]
Szondy, Z., Sarang, Z., Molnar, P., Nemeth, T., Piacentini, M., Mastroberardino, P. G., Falasca, L., Aeschlimann, D., Kovacs, J., Kiss, I., Szegezdi, E., Lakos, G., Rajnavolgyi, E., Birckbichler, P. J., Melino, G., Fesus, L. Transglutaminase 2 -/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc. Nat. Acad. Sci. 100: 7812-7817, 2003. [PubMed: 12810961] [Full Text: https://doi.org/10.1073/pnas.0832466100]
Vezza, R., Habib, A., FitzGerald, G. A. Differential signaling by the thromboxane receptor isoforms via the novel GTP-binding protein, Gh. J. Biol. Chem. 274: 12774-12779, 1999. [PubMed: 10212262] [Full Text: https://doi.org/10.1074/jbc.274.18.12774]
Wang, M., Kim, I.-G., Steinert, P. M., McBride, O. W. Assignment of the human transglutaminase 2 (TGM2) and transglutaminase 3 (TGM3) genes to chromosome 20q11.2. Genomics 23: 721-722, 1994. [PubMed: 7851911] [Full Text: https://doi.org/10.1006/geno.1994.1571]
Zhang, Z., Vezza, R., Plappert, T., McNamara, P., Lawson, J. A., Austin, S., Pratico, D., Sutton, M. S., FitzGerald, G. A. COX-2-dependent cardiac failure in Gh/tTG transgenic mice. Circ. Res. 92: 1153-1161, 2003. [PubMed: 12702643] [Full Text: https://doi.org/10.1161/01.RES.0000071749.22027.45]