Abstract
Of the eight catalytic transglutaminases (TGs), transglutaminase 2 (TG2) has been the most comprehensively studied due to its ubiquitous expression in multiple cell types. Despite the observed critical role for this enzyme in multiple biological processes in vitro, TG2 knockout mouse models have shown no severe developmental phenotypes, suggesting compensation by other TGs. To begin characterization of the compensating mechanisms, we analyzed total transamidating activity and expression patterns of all catalytically active TGs in seven different tissues/organs from wild-type and TG2 knockout mice. Inhibitory analysis with TG2-specific inhibitor KCC-009 suggests that relative contribution of TG2 in total transamidating activity differs in various tissues. Accordingly, our data indicate tissue-specific mechanisms of compensation for the loss of TG2, including transcriptional compensation in heart and liver versus functional compensation in aorta, kidney and skeletal/cartiagenous tissues. On the contrary, no compensation has been detected in skeletal muscle, suggesting a limited role for the TG2-mediated transamidation in normal development of this tissue.
Similar content being viewed by others
Abbreviations
- TG:
-
Transglutaminase
- FXIIIa:
-
Factor XIIIa
- TG1-7:
-
Transglutaminase 1–7
- WT:
-
Wild type
- TG−/− :
-
Transglutaminase 2 null
References
Aeschlimann D, Wetterwald A, Fleisch H, Paulsson M (1993) Expression of tissue transglutaminase in skeletal tissues correlates with events of terminal differentiation of chondrocytes. J Cell Biol 120:1461–1470. doi:10.1083/jcb.120.6.1461
Akimov SS, Krylov D, Fleischmann LF, Belkin AM (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148:825–838. doi:10.1083/jcb.148.4.825
Ameye L, Young MF (2002) Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers–Danlos syndrome, muscular dystrophy and corneal diseases. Glycobiology 12(9):107R–1167R. doi:10.1093/glycob/cwf065
Bakker EN, Pistea A, Spaan JA, Rolf T, de Vries CJ, van Rooijen N, Candi E, VanBavel E (2006) Flow-dependent remodeling of small arteries in mice deficient for tissue-type transglutaminase: possible compensation by macrophage-derived factor XIII. Circ Res 99:86–92. doi:10.1161/01.RES.0000229657.83816.a7
Baumgartner W, Golenhofen N, Weth A, Hiiragi T, Saint R, Griffin M, Drenckhahn D (2004) Role of transglutaminase 1 in stabilisation of intercellular junctions of the vascular endothelium. Histochem Cell Biol 122:17–25. doi:10.1007/s00418-004-0668-y
Candi E, Oddi S, Paradisi A, Terrinoni A, Ranalli M, Teofoli P, Citro G, Scarpato S, Puddu P, Melino G (2002) Expression of transglutaminase 5 in normal and pathologic human epidermis. J Invest Dermatol 119:670–677. doi:10.1046/j.1523-1747.2002.01853.x
Candi E, Paradisi A, Terrinoni A, Pietroni V, Oddi S, Cadot B, Jogini V, Meiyappan M, Clardy J, Finazzi-Agro A, Melino G (2004) Transglutaminase 5 is regulated by guanine–adenine nucleotides. Biochem J 381:313–319. doi:10.1042/BJ20031474
Choi K, Siegel M, Piper JL, Yuan L, Cho E, Strnad P, Omary B, Rich KM, Khosla C (2005) Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol 12:469–475. doi:10.1016/j.chembiol.2005.02.007
Dardik R, Leor J, Skutelsky E, Castel D, Holbova R, Schiby G, Shaish A, Dickneite G, Loscalzo J, Inbal A (2006) Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb Haemost 95:546–550. doi:10.1160/TH05-06-0409
De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol 21:148–155. doi:10.1128/MCB.21.1.148-155.2001
Fesus L, Szondy Z (2005) Transglutaminase 2 in the balance of cell death and survival. FEBS Lett 579:3297–3302. doi:10.1016/j.febslet.2005.03.063
Fisher M, Jones RA, Huang L, Haylor JL, El Nahas M, Griffin M, Johnson TS (2009) Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: a potential mechanism of tissue scarring. Matrix Biol 28:20–31. doi:10.1152/physrev.00044.2008
Greenberg C, Birckbichler PJ, Rice RH (1991) Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. J FASEB 5:3071–3077
Grenard P, Bates MK, Aeschilmann D (2001) Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15. J Biol Chem 276(35):33066–33078. doi:10.1074/jbc.M10255320
Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396. doi:10.1042/BJ20021234
Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D (2008) Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 64(3):332–343. doi:10.1002/ana.21450
Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y (2003) A novel function of tissue-type transglutaminase: protein disulphide isomerase. Biochem J 373:793–803. doi:10.1042/BJ20021084
Hiiragi T, Sasaki H, Nagafuchi A, Sabe H, Shen SC, Matsuki M, Yamanishi K, Tsukita S (1999) Transglutaminase type I and its crosslinking activity are concentrated at adherens junctions in simple epithelial cells. J Biol Chem 274:34148–34154. doi:10.1074/jbc.274.48.34148
Ho KC, Quarmby VE, French FS, Wilson EM (1992) Molecular cloning of rat prostate transglutaminase complementary DNA. The major androgen-regulated protein DP1 of rat dorsal prostate and coagulating gland. J Biol Chem 267(18):12660–12667
Hwang KC, Gray CD, Sweet WE, Moravec CS, Im MJ (1996) Adrenergic receptor coupling with Gh in the failing human heart. Circulation 94:718–726. doi:10.1161/01.CIR.94.4.718
Iismaa SE, Chung L, Wu MJ, Teller DC, Yee VC, Graham RM (1997) The core domain of the tissue transglutaminase Gh hydrolyzes GTP and ATP. Biochemistry 36:11655–11664. doi:10.1021/bi970545e
Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 89:991–1023. doi:10.1152/physrev.00044.2008
Johnson KA, Polewski M, erkeltaub RA (2008) Transglutaminase 2 is central to induction of the arterial calcification program by smooth muscle cells. Circ Res 102:529–537. doi:10.1161/CIRCRESAHA.107.154260
Kuramoto N, Takizawa T, Matsuki M, Morioka H, Robinson JM, Yamanishi K (2002) Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1. J Clin Invest 109:243–250. doi:10.1172/JCI0213563
Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Natl Rev Mol Cell Biol 4:140–156. doi:10.1038/nrm1014
Mishra S, Murphy LJ (2004) Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem 279(23):23863–23868. doi:10.1074/jbc.M311919200
Nadalutti C, Viiri KM, Kaukinen K, Maki M, Lindfors K (2011) Extracellular transglutamianse 2 has a role in cell adhesion, whereas intracellular transglutaminase is involved in regulation of endothelial cell proliferation and apoptosis. Cell Prolif 44(1):49–58. doi:10.1111/j.1365-2184.2010.00716.x
Nanda N, Iismaa SE, Owens WA, Husain A, Mackay F, Graham RM (2001) Targeted inactivation of Gh/tissue transglutaminase II. J Biol Chem 276:20673–20678. doi:10.1074/jbc.M010846200
Nurminskaya M, Kaartinen MT (2006) Transglutaminases in mineralized tissues. Front Biosci 11:1591–1606. doi:10.2741/1907
Nurminskaya M, Linsenmayer TF (1996) Identification and characterization of up-regulated genes during chondrocyte hypertrophy. Dev Dynam 206:260–271. doi:10.1002/(SICI)1097-0177(199607)206:3<260:AID-AJA4>3.0.CO;2-G
Nurminskaya M, Magee C, Nurminsky D, Linsenmayer TF (1998) Plasma transglutaminase in hypertophic chondrocytes: expression and cell-specific intracellular activation produce cell death and externalization. J Cell Biol 142:1135–1144. doi:10.1083/jcb.142.4.1135
Nurminsky D, Shanmugasundaram S, Deasey S, Michaud C, Allen S, Hendig D, Dastjerdi A, Francis-West P, Nurminskaya M (2011) Transglutaminase 2 regulates early chondrogenesis and glycosaminoglycan synthesis. Mech Dev 128:234–245. doi:10.1016/j.mod.2010.11.007
Pistea A, Bakker ENTP, Spaan JAE, Hardeman MR, van Rooijen N, VanBavel E (2008) Small artery remodeling and erythrocyte deformability in L-NAME-induced hypertension: role of transglutaminases. J Vasc Res 45:10–18. doi:10.1159/000109073
Small K, Feng JF, Lorenz J, Donnelly ET, Yu A, Im MJ, Dorn GW 2nd, Liggett SB (1999) Cardiac specific overexpression of transglutaminase II (Gh) results in a unique hypertrophy phenotype independent of phospholipase C activation. J Biol Chem 274:21292–21296. doi:10.1074/jbc.274.30.21291
Spina AM, Esposito C, Pagano M, Chiosi E, Mariniello L, Cozzolino A, Porta R, Illiano G (1999) GTPase and transglutaminase are associated in the secretion of the rat anterior prostate. Biochem Biophys Res Commun 260(2):351–356. doi:10.1006/bbrc.1999.0914
Tanaka K, Yokosaki Y, Higashikawa F, Saito Y, Eboshida A, Ochi M (2007) The integrin α5β1 regulates chondrocyte hypertrophic differentiation induced by GTP-bound transglutaminase 2. Matrix Biol 26:409–418. doi:10.1016/j.matbio.2007.04.005
Thomazy V, Fesus L (1989) Differential expression of tissue transglutaminase in human cells. An immunohistochemical study. Cell Tissue Res 255:215–224
Trigwell SM, Lynch PT, Griffin M, Hargreaves AJ, Bonner PLR (2004) An improved colorimetric assay for the measurement of transglutaminase (Type II)-ε-(γ-Glutamyl) lysine cross-linking activity. Anal Biochem 330(1):164–166. doi:10.1016/j.ab.2004.03.068
Xu L, Begum S, Hearn JD, Hynes RO (2006) GPCR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, inhibits melanoma tumor growth and metastasis. Proc Natl Acad Sci 103:9023–9028. doi:10.1073/pnas.0602681103
Acknowledgments
We would like to thank Dr. Chaitan Khosla for providing us with the TG inhibitor KCC-009 and Dr. Robert Graham for providing us with TG2−/− mice. This work was supported by NIH grants R01R01HL093305, R56DK071920 and R03AR057126 and a grant from Maryland Stem Cell Research Fund to M. Nurminskaya.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Deasey, S., Shanmugasundaram, S. & Nurminskaya, M. Tissue-specific responses to loss of transglutaminase 2. Amino Acids 44, 179–187 (2013). https://doi.org/10.1007/s00726-011-1183-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-011-1183-9