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Gene Review

TGM2  -  transglutaminase 2

Homo sapiens

Synonyms: G-ALPHA-h, GNAH, HEL-S-45, Protein-glutamine gamma-glutamyltransferase 2, TG(C), ...
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Disease relevance of TGM2


Psychiatry related information on TGM2


High impact information on TGM2

  • Notably, tTG can also cross-link glutamine residues of peptides to lysine residues in other proteins including tTG itself [10]
  • There are more than 150 identified substrates for TG2 - a searchable list of the substrates for TG2 crosslinking, kinase, deamidase and protein disulphide isomerase activities are included in the TRANSDAB   database [11].
  • These complexes may permit gluten-reactive T cells to provide help to tTG-specific B cells by a mechanism of intramolecular help, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that is a characteristic feature of active CD [10]
  • Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75 [12]
  • Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease [13]
  • Identification of tissue transglutaminase as the autoantigen of celiac disease [14]

Chemical compound and disease context of TGM2


Biological context of TGM2


Anatomical context of TGM2


Associations of TGM2 with chemical compounds

  • Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin [23]
  • Therefore, in HD, as well as in other polyglutamine diseases, tTG is unlikely to play a role in the formation of aggregates [25]
  • Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity [26]
  • TG2-/- mouse chondrocytes demonstrate markedly inhibited progression to hypertrophic differentiation in response to both retinoic acid and the chemokine CXCL1 [24]
  • Tissue transglutaminase (tTG) is a calcium-dependent enzyme that catalyzes the posttranslational modification of proteins by transamidation of specific polypeptide-bound glutamine residues [27]
  • These findings suggested that tTG may play an important role in integrin-mediated adhesion of MSCs in implanted tissues [28]
  • The substrate preference of TG2 was studied. The spatial environment of the favored glutamine and lysine residues was analyzed and the presence of specific amino acid patterns could be identified.By studying the sequence of TG2 substrate proteins lacking available crystal structure, the strong favorable influence on substrate selection of the presence of substrate glutamine and lysine residues in intrinsically disordered regions could also be revealed [29]

Physical interactions of TGM2

  • Further, truncated huntingtin coimmunoprecipitated with tTG, and this association increased when tTG was activated [30]
  • Tissue transglutaminase (tTG) has recently been established as a novel cell surface adhesion protein that binds with high affinity to fibronectin in the pericellular matrix [31]
  • Transglutaminase 2 (TG2) is a GTP-binding protein with transglutaminase activity [32]
  • RESULTS: Tissue transglutaminase antibody binding patterns were identical with the extracellular binding patterns seen with celiac patient sera [33]
  • Using co-immunoprecipitation and immunofluorescent staining experiments, we observed that tTG forms a complex with VEGFR-2 on the cell surface and within the cytoplasm of EC [34]
  • [34]Besides the modified proteins TG2 is able to interact with a variety of different proteins - TRANSDAB   lists more than 40 interaction partners for TG2 [11]

Enzymatic interactions of TGM2


Co-localisations of TGM2

  • In contrast, in cells expressing truncated mutant huntingtin (Q62) there were numerous complexes of truncated mutant huntingtin and many of these complexes co-localized with tTG [30]
  • Double staining demonstrated that elafin was co-localized with tTG [38]

Regulatory relationships of TGM2

  • When a YFP-tagged mutant truncated huntingtin construct was transiently transfected into cells that express no detectable tTG due to stable transfection with a tTG antisense construct, there was extensive aggregate formation [25]
  • In contrast, basal in situ TG activity did not increase concurrently with RA-induced increased tTG levels [27]
  • Tissue transglutaminase directly regulates adenylyl cyclase resulting in enhanced cAMP-response element-binding protein (CREB) activation [15]
  • The remaining seven genes had unmethylated promoters, although at least one of these genes (TGM2) may be regulated by RASSF1A, which was methylated in the RCC lines [39]
  • TGF-beta2-induced cell surface tissue transglutaminase increases adhesion and migration of RPE cells on fibronectin through the gelatin-binding domain [40]
  • The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC [41]

Other interactions of TGM2


Analytical, diagnostic and therapeutic context of TGM2


  1. Transglutaminase 2: an enigmatic enzyme with diverse functions. Fesus, L., Piacentini, M. Trends Biochem. Sci. (2002) [Pubmed]
  2. Identification of 'tissue' transglutaminase binding proteins in neural cells committed to apoptosis. Piredda, L., Farrace, M.G., Lo Bello, M., Malorni, W., Melino, G., Petruzzelli, R., Piacentini, M. FASEB J. (1999) [Pubmed]
  3. Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. Greenberg, C.S., Birckbichler, P.J., Rice, R.H. FASEB J. (1991) [Pubmed]
  4. Gliadin T cell epitope selection by tissue transglutaminase in celiac disease. Role of enzyme specificity and pH influence on the transamidation versus deamidation process. Fleckenstein, B., Molberg, Ø., Qiao, S.W., Schmid, D.G., von der Mülbe, F., Elgstøen, K., Jung, G., Sollid, L.M. J. Biol. Chem. (2002) [Pubmed]
  5. Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. Belkin, A.M., Akimov, S.S., Zaritskaya, L.S., Ratnikov, B.I., Deryugina, E.I., Strongin, A.Y. J. Biol. Chem. (2001) [Pubmed]
  6. Intron-exon swapping of transglutaminase mRNA and neuronal Tau aggregation in Alzheimer's disease. Citron, B.A., SantaCruz, K.S., Davies, P.J., Festoff, B.W. J. Biol. Chem. (2001) [Pubmed]
  7. Validity of mouse models for the study of tissue transglutaminase in neurodegenerative diseases. Bailey, C.D., Graham, R.M., Nanda, N., Davies, P.J., Johnson, G.V. Mol. Cell. Neurosci. (2004) [Pubmed]
  8. Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Junn, E., Ronchetti, R.D., Quezado, M.M., Kim, S.Y., Mouradian, M.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  9. Cerebrospinal fluid tissue transglutaminase in vascular dementia. Bonelli, R.M., Aschoff, A., Jirikowski, G. J. Neurol. Sci. (2002) [Pubmed]
  10. Molecular basis of celiac disease. Sollid, L.M. Annu. Rev. Immunol. (2000) [Pubmed]
  11. Transdab wiki: the interactive transglutaminase substrate database on web 2.0 surface. Csosz, E., Meskó, B., Fésüs, L. Amino. Acids. (2009) [Pubmed]
  12. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Anderson, R.P., Degano, P., Godkin, A.J., Jewell, D.P., Hill, A.V. Nat. Med. (2000) [Pubmed]
  13. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Molberg, O., Mcadam, S.N., Körner, R., Quarsten, H., Kristiansen, C., Madsen, L., Fugger, L., Scott, H., Norén, O., Roepstorff, P., Lundin, K.E., Sjöström, H., Sollid, L.M. Nat. Med. (1998) [Pubmed]
  14. Identification of tissue transglutaminase as the autoantigen of celiac disease. Dieterich, W., Ehnis, T., Bauer, M., Donner, P., Volta, U., Riecken, E.O., Schuppan, D. Nat. Med. (1997) [Pubmed]
  15. Tissue transglutaminase directly regulates adenylyl cyclase resulting in enhanced cAMP-response element-binding protein (CREB) activation. Tucholski, J., Johnson, G.V. J. Biol. Chem. (2003) [Pubmed]
  16. The role of tissue transglutaminase in 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in differentiated human SH-SY5Y neuroblastoma cells. Beck, K.E., De Girolamo, L.A., Griffin, M., Billett, E.E. Neurosci. Lett. (2006) [Pubmed]
  17. Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells. Antonyak, M.A., Miller, A.M., Jansen, J.M., Boehm, J.E., Balkman, C.E., Wakshlag, J.J., Page, R.L., Cerione, R.A. J. Biol. Chem. (2004) [Pubmed]
  18. Transglutaminase-mediated cross-linking of a peptic fraction of omega-5 gliadin enhances IgE reactivity in wheat-dependent, exercise-induced anaphylaxis. Palosuo, K., Varjonen, E., Nurkkala, J., Kalkkinen, N., Harvima, R., Reunala, T., Alenius, H. J. Allergy Clin. Immunol. (2003) [Pubmed]
  19. Immunohistochemical evaluation of transglutaminase C in tumours of salivary glands. Lee, C.H., Lee, S.K., Chi, J.G., Park, S.C., Chung, S.I., Saitoh, M., Shrestha, P., Mori, M. Eur. J. Cancer, B, Oral Oncol. (1996) [Pubmed]
  20. Structure and organization of the human transglutaminase 3 gene: evolutionary relationship to the transglutaminase family. Kim, I.G., Lee, S.C., Lee, J.H., Yang, J.M., Chung, S.I., Steinert, P.M. J. Invest. Dermatol. (1994) [Pubmed]
  21. Assignment of the human transglutaminase 2 (TGM2) and transglutaminase 3 (TGM3) genes to chromosome 20q11.2. Wang, M., Kim, I.G., Steinert, P.M., McBride, O.W. Genomics (1994) [Pubmed]
  22. Organization and chromosomal mapping of mouse Gh/tissue transglutaminase gene (Tgm2). Nanda, N., Iismaa, S.E., Copeland, N.G., Gilbert, D.J., Jenkins, N., Graham, R.M., Sutrave, P. Arch. Biochem. Biophys. (1999) [Pubmed]
  23. Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. Akimov, S.S., Krylov, D., Fleischman, L.F., Belkin, A.M. J. Cell Biol. (2000) [Pubmed]
  24. External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification. Johnson, K.A., Terkeltaub, R.A. J. Biol. Chem. (2005) [Pubmed]
  25. Tissue transglutaminase does not contribute to the formation of mutant huntingtin aggregates. Chun, W., Lesort, M., Tucholski, J., Ross, C.A., Johnson, G.V. J. Cell Biol. (2001) [Pubmed]
  26. Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity. Liu, S., Cerione, R.A., Clardy, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  27. Modulation of the in situ activity of tissue transglutaminase by calcium and GTP. Zhang, J., Lesort, M., Guttmann, R.P., Johnson, G.V. J. Biol. Chem. (1998) [Pubmed]
  28. Tissue transglutaminase is essential for integrin-mediated survival of bone marrow-derived mesenchymal stem cells. Song, H., Chang, W., Lim, S., Seo, H.S., Shim, C.Y., Park, S., Yoo, K.J., Kim, B.S., Min, B.H., Lee, H., Jang, Y., Chung, N., Hwang, K.C. Stem. Cells (2007) [Pubmed]
  29. Substrate preference of transglutaminase 2 revealed by logistic regression analysis and intrinsic disorder examination WikiGenes. Article
  30. Tissue transglutaminase selectively modifies proteins associated with truncated mutant huntingtin in intact cells. Chun, W., Lesort, M., Tucholski, J., Faber, P.W., MacDonald, M.E., Ross, C.A., Johnson, G.V. Neurobiol. Dis. (2001) [Pubmed]
  31. Involvement of tissue transglutaminase in the stabilisation of biomaterial/tissue interfaces important in medical devices. Heath, D.J., Christian, P., Griffin, M. Biomaterials (2002) [Pubmed]
  32. Overexpression of transglutaminase 2 accelerates the erythroid differentiation of human chronic myelogenous leukemia K562 cell line through PI3K/Akt signaling pathway. Kang, S.K., Lee, J.Y., Chung, T.W., Kim, C.H. FEBS Lett. (2004) [Pubmed]
  33. Tissue transglutaminase is the target in both rodent and primate tissues for celiac disease-specific autoantibodies. Korponay-Szabó, I.R., Sulkanen, S., Halttunen, T., Maurano, F., Rossi, M., Mazzarella, G., Laurila, K., Troncone, R., Mäki, M. J. Pediatr. Gastroenterol. Nutr. (2000) [Pubmed]
  34. Complex formation between tissue transglutaminase II (tTG) and vascular endothelial growth factor receptor 2 (VEGFR-2): Proposed mechanism for modulation of endothelial cell response to VEGF. Dardik, R., Inbal, A. Exp. Cell Res. (2006) [Pubmed]
  35. Regulation of human tissue transglutaminase function by magnesium-nucleotide complexes. Identification of distinct binding sites for Mg-GTP and Mg-ATP. Lai, T.S., Slaughter, T.F., Peoples, K.A., Hettasch, J.M., Greenberg, C.S. J. Biol. Chem. (1998) [Pubmed]
  36. Phosphorylation of histones by tissue transglutaminase. Mishra, S., Saleh, A., Espino, P.S., Davie, J.R., Murphy, L.J. J. Biol. Chem. (2006) [Pubmed]
  37. Tissue transglutaminase catalyzes the formation of alpha-synuclein crosslinks in Parkinson's disease. Andringa, G., Lam, K.Y., Chegary, M., Wang, X., Chase, T.N., Bennett, M.C. FASEB J. (2004) [Pubmed]
  38. Expression of tissue transglutaminase and elafin in human coronary artery: implication for plaque instability. Sumi, Y., Inoue, N., Azumi, H., Seno, T., Okuda, M., Hirata, K., Kawashima, S., Hayashi, Y., Itoh, H., Yokoyama, M. Atherosclerosis (2002) [Pubmed]
  39. Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Ibanez de Caceres, I., Dulaimi, E., Hoffman, A.M., Al-Saleem, T., Uzzo, R.G., Cairns, P. Cancer Res. (2006) [Pubmed]
  40. TGF-beta2-induced cell surface tissue transglutaminase increases adhesion and migration of RPE cells on fibronectin through the gelatin-binding domain. Priglinger, S.G., Alge, C.S., Neubauer, A.S., Kristin, N., Hirneiss, C., Eibl, K., Kampik, A., Welge-Lussen, U. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  41. Tissue transglutaminase regulates matrix metalloproteinase-2 in ovarian cancer by modulating cAMP-response element-binding protein activity. Satpathy, M., Shao, M., Emerson, R., Donner, D.B., Matei, D. J. Biol. Chem. (2009) [Pubmed]
  42. The p53 oncoprotein is a substrate for tissue transglutaminase kinase activity. Mishra, S., Murphy, L.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  43. Transforming growth factor-beta (TGF-beta) and tissue transglutaminase expression in the small intestine in children with coeliac disease. Hansson, T., Ulfgren, A.K., Lindroos, E., DannAEus, A., Dahlbom, I., Klareskog, L. Scand. J. Immunol. (2002) [Pubmed]
  44. Elafin and its precursor trappin-2 still inhibit neutrophil serine proteinases when they are covalently bound to extracellular matrix proteins by tissue transglutaminase. Guyot, N., Zani, M.L., Maurel, M.C., Dallet-Choisy, S., Moreau, T. Biochemistry (2005) [Pubmed]
  45. Characterization of tissue transglutaminase in human osteoblast-like cells. Heath, D.J., Downes, S., Verderio, E., Griffin, M. J. Bone Miner. Res. (2001) [Pubmed]
  46. Differential expression of multiple transglutaminases in human colon: impaired keratinocyte transglutaminase expression in ulcerative colitis. D'Argenio, G., Calvani, M., Della Valle, N., Cosenza, V., Di Matteo, G., Giorgio, P., Margarucci, S., Petillo, O., Jori, F.P., Galderisi, U., Peluso, G. Gut (2005) [Pubmed]
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