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Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications

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Abstract

This review summarises the functions of the enzyme tissue transglutaminase (TG2) in the extracellular matrix (ECM) both as a matrix stabiliser through its protein cross-linking activity and as an important cell adhesion protein involved in cell survival. The contribution of extracellular TG2 to the pathology of important diseases such as cancer and fibrosis are discussed with a view to the potential importance of TG2 as a therapeutic target. The medical applications of TG2 are further expanded by detailing the use of transglutaminase cross-linking in the development of novel biocompatible biomaterials for use in soft and hard tissue repair.

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References

  • Akimov SS, Belkin AM (2001a) Cell-surface transglutaminase promotes fibronectin assembly via interaction with the gelatin-binding domain of fibronectin: a role in TGF beta-dependent matrix deposition. J Cell Sci 114(16):2989–3000

    PubMed  CAS  Google Scholar 

  • Akimov SS, Belkin AM (2001b) Cell surface tissue transglutaminase is involved in adhesion and migration of monocytic cells on fibronectin. Blood 98(5):1567–1576

    PubMed  CAS  Google Scholar 

  • Akimov SS, Krylov D, Fleischman LF, Belkin AM (2000) Tissue transglutaminase is an integrin-binding adhesion co-receptor for fibronectin. J Cell Biol 148(4):825–838

    PubMed  CAS  Google Scholar 

  • Al-Jallad HF, Nakano Y, Chen JL, McMillan E, Lefebvre C, Kaartinen MT (2006) Transglutaminase activity regulates osteoblast differentiation and matrix mineralization in MC3T3–E1 osteoblast cultures. Matrix Biol 25(3):135–148

    PubMed  CAS  Google Scholar 

  • Balklava Z, Verderio E, Collighan R, Gross S, Adams J, Griffin M (2002) Analysis of tissue transglutaminase function in the migration of Swiss 3T3 fibroblasts: the active-state conformation of the enzyme does not affect cell motility but is important for its secretion. J Biol Chem 277(19):16567–16575

    PubMed  CAS  Google Scholar 

  • Barnes RN, Bungay PJ, Elliott BM, Walton PL, Griffin M (1985) Alterations in the distribution and activity of transglutaminase during tumor-growth and metastasis. Carcinogenesis 6(3):459–463

    PubMed  CAS  Google Scholar 

  • Belkin AM, Akimov SS, Zaritskaya LS, Ratnikov BI, Deryugina EI, Strongin AY (2001) Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. J.Biol Chem 276(21):18415–18422

    PubMed  CAS  Google Scholar 

  • Bertoni F, Barbani N, Giusti P, Ciardelli G (2006) Transglutaminase reactivity with gelatine: perspective applications in tissue engineering. Biotechnol Lett 28(10):697–702

    PubMed  CAS  Google Scholar 

  • Birckbichler PJ, Patterson MK Jr (1978) Cellular transglutaminase, growth, and transformation. Ann N Y Acad Sci 312:354–365

    PubMed  CAS  Google Scholar 

  • Bowness JM, Folk JE, Timpl R (1987) Identification of a substrate site for liver transglutaminase on the aminopropeptide of type-III collagen. J Biol Chem 262(3):1022–1024

    PubMed  CAS  Google Scholar 

  • Bowness JM, Tarr AH, Wong T (1988) Increased transglutaminase activity during skin wound-healing in rats. Biochim Biophys Acta 967(2):234–240

    PubMed  CAS  Google Scholar 

  • Broderick EP, O’Halloran DM, Rochev YA, Griffin M, Collighan RJ, Pandit AS (2005) Enzymatic stabilization of gelatin-based scaffolds. J Biomed Mater Res B Appl Biomater 72B(1):37–42

    CAS  Google Scholar 

  • Chau DYS, Collighan RJ, Griffin M (2007) Collagen: structure and modification for biomedical applications. In: Pannone P J (ed) Trends in biomaterials research. Nova Publishers, pp 143–190

  • Chau DYS, Collighan RJ, Verderio EAM, Addy VL, Griffin M (2005) The cellular response to transglutaminase-cross-linked collagen. Biomaterials 26(33):6518–6529

    PubMed  CAS  Google Scholar 

  • Chiono V, Ciardelli G, Vozzi G, Cortez J, Barbani N, Gentile P, Giusti P (2008) Enzymatically-modified melt-extruded guides for peripheral nerve repair. Eng Life Sci 8(3):226–237

    CAS  Google Scholar 

  • Collier JH, Messersmith PB (2003) Enzymatic modification of self-assembled peptide structures with tissue transglutaminase. Bioconjugate Chem 14(4):748–755

    CAS  Google Scholar 

  • Collighan R, Cortez J, Griffin M (2002) The biotechnological applications of transglutaminases. Minerva Biotechnol 14(2):143–148

    Google Scholar 

  • Collighan RJ, Li X, Parry J, Griffin M, Clara S (2004) Transglutaminases as tanning agents for the leather industry. J Am Leather Chem Ass 99(7):293–302

    CAS  Google Scholar 

  • Condello S, Caccamo D, Curro M, Ferlazzo N, Parisi G, Ientile R (2008) Transglutaminase 2 and NF-kappa B interplay during NGF-induced differentiation of neuroblastoma cells. Brain Res 1207:1–8

    PubMed  CAS  Google Scholar 

  • Damodaran G, Collighan R, Griffin M, Pandit A (2008) Tethering a laminin peptide to a crosslinked collagen scaffold for biofunctionality. J Biomed Mater A 13:13

    Google Scholar 

  • Dardik R, Krapp T, Rosenthal E, Loscalzo J, Inbal A (2007) Effect of FXIII on monocyte and fibroblast function. Cell Physiol Biochem 19(1–4):113–120

    PubMed  CAS  Google Scholar 

  • Dardik R, Loscalzo J, Inbal A (2006) Factor XIII (FXIII) and angiogenesis. J Thromb Haemost 4(1):19–25

    PubMed  CAS  Google Scholar 

  • Dolynchuk KN, Ziesmann M, Serletti JM (1996) Topical putrescine (Fibrostat) in treatment of hypertrophic scars: phase II study. Plast Reconstr Surg 97(1):117–123

    PubMed  CAS  Google Scholar 

  • Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689

    PubMed  CAS  Google Scholar 

  • Facchiano F, Facchiano A, Facchiano AM (2006) The role of transglutaminase-2 and its substrates in human diseases. Front Biosci 11:1758–1773

    PubMed  CAS  Google Scholar 

  • Fesus L, Szondy Z (2005) Transglutaminase 2 in the balance of cell death and survival. Febs Lett 579(15):3297–3302

    PubMed  Google Scholar 

  • Folk JE, Finlayson JS (1977) The epsilon-(gamma-glutamyl)lysine crosslink and the catalytic role of transglutaminases. Adv Protein Chem 31:1–133

    PubMed  CAS  Google Scholar 

  • Freund KF, Doshi KP, Gaul SL, Claremon DA, Remy DC, Baldwin JJ, Pitzenberger SM, Stern AM (1994) Transglutaminase inhibition by 2-(2-Oxopropyl)thio imidazolium derivative–mechanism of factor xiiia inactivation. Biochemistry 33(33):10109–10119

    PubMed  CAS  Google Scholar 

  • Friess W (1998) Collagen––biomaterial for drug delivery. Eur J Pharm Biopharm 45(2):113–136

    PubMed  CAS  Google Scholar 

  • Fuchsbauer HL, Gerber U, Engelmann J, Seeger T, Sinks C, Hecht T (1996) Influence of gelatin matrices cross-linked with transglutaminase on the properties of an enclosed bioactive material using beta-galactosidase as model system. Biomaterials 17(15):1481–1488

    PubMed  CAS  Google Scholar 

  • Garcia Y, Collighan R, Griffin M, Pandit A (2007) Assessment of cell viability in a three-dimensional enzymatically cross-linked collagen scaffold. J Mater Sci Mater Med 18(10):1991–2001

    PubMed  CAS  Google Scholar 

  • Garcia Y, Wilkins B, Collighan RJ, Griffin M, Pandit A (2008) Towards development of a dermal rudiment for enhanced wound healing response. Biomaterials 29(7):857–868

    PubMed  CAS  Google Scholar 

  • Gaudry CA, Verderio E, Aeschlimann D, Cox A, Smith C, Griffin M (1999a) Cell surface localization of tissue transglutaminase is dependent on a fibronectin-binding site in its N-terminal beta-sandwich domain. J Biol Chem 274(43):30707–30714

    PubMed  CAS  Google Scholar 

  • Gaudry CA, Verderio E, Jones RA, Smith C, Griffin M (1999b) Tissue transglutaminase is an important player at the surface of human endothelial cells: evidence for its externalization and its colocalization with the beta(1) integrin. Exp Cell Res 252(1):104–113

    PubMed  CAS  Google Scholar 

  • Gentile V, Cooper AJ (2004) Transglutaminases––possible drug targets in human diseases. Curr Drug Targets CNS Neurol Disord 3(2):99–104

    PubMed  CAS  Google Scholar 

  • Goodman M, Cai WB, Kinberger GA (2003) The new science of protein mimetics. Macromol Sym 201:223–236

    CAS  Google Scholar 

  • Grenard P, Bresson-Hadni S, El Alaoui S, Chevallier M, Vuitton DA, Ricard-Blum S (2001) Transglutaminase-mediated cross-linking is involved in the stabilization of extracellular matrix in human liver fibrosis. J Hepatol 35(3):367–375

    PubMed  CAS  Google Scholar 

  • Griffin M, Casadio R, Bergamini CM (2002) Transglutaminases: nature’s biological glues. Biochem J 368:377–396

    PubMed  CAS  Google Scholar 

  • Griffin M, Mongeot A, Collighan R, Saint RE, Jones RA, Coutts IG, Rathbone DL (2008) Synthesis of potent water-soluble tissue transglutaminase inhibitors. Bioorg Med Chem Lett (in press)

  • Griffin M, Smith LL, Wynne J (1979) Changes in transglutaminase activity in an experimental model of pulmonary fibrosis induced by paraquat. Br J Exp Pathol 60(6):653–661

    PubMed  CAS  Google Scholar 

  • Griffin M, Wilson J (1984) Detection of epsilon(gamma-glutamyl) lysine. Mol Cell Biochem 58(1–2):37–49

    PubMed  CAS  Google Scholar 

  • Grigoriev MY, Suspitsin EN, Togo AV, Pozharisski KM, Ivanova OA, Nardacci R, Falasca L, Piacentini M, Imyanitov EN, Hanson KP (2001) Tissue transglutaminase expression in breast carcinomas. J Exp Clin Cancer Res 20(2):265–268

    PubMed  CAS  Google Scholar 

  • Gross SR, Balklava Z, Griffin M (2003) Importance of tissue transglutaminase in repair of extracellular matrices and cell death of dermal fibroblasts after exposure to a solarium ultraviolet a source. J Invest Dermatol 121(2):412–423

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    PubMed  CAS  Google Scholar 

  • Hang J, Zemskov EA, Lorand L, Belkin AM (2005) Identification of a novel recognition sequence for fibronectin within the NH2-terminal beta-sandwich domain of tissue transglutaminase. J Biol Chem 280(25):23675–23683

    PubMed  CAS  Google Scholar 

  • Haroon ZA, Wannenburg T, Gupta M, Greenberg CS, Wallin R, Sane DC (2001) Localization of tissue transglutaminase in human carotid and coronary artery atherosclerosis: implications for plaque stability and progression. Lab Invest 81(1):83–93

    PubMed  CAS  Google Scholar 

  • 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(Pt 3):793–803

    PubMed  CAS  Google Scholar 

  • Heath DJ, Christian P, Griffin M (2002) Involvement of tissue trans glutaminase in the stabilisation of biomaterial/tissue interfaces important in medical devices. Biomaterials 23(6):1519–1526

    PubMed  CAS  Google Scholar 

  • Herman JF, Mangala LS, Mehta K (2006) Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells. Oncogene 25(21):3049–3058

    PubMed  CAS  Google Scholar 

  • Holmes TC (2002) Novel peptide-based biomaterial scaffolds for tissue engineering. Trends Biotechnol 20(1):16–21

    PubMed  CAS  Google Scholar 

  • Holmes TC, de Lacalle S, Su X, Liu G, Rich A, Zhang S (2000) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc Natl Acad Sci USA 97(12):6728–6733

    PubMed  CAS  Google Scholar 

  • Hu BH, Messersmith PB (2003) Rational design of transglutaminase substrate peptides for rapid enzymatic formation of hydrogels. J Am Chem Soc 125(47):14298–14299

    PubMed  CAS  Google Scholar 

  • Hu BH, Messersmith PB (2005) Enzymatically cross-linked hydrogels and their adhesive strength to biosurfaces. Orthod Craniofac Res 8(3):145–149

    PubMed  Google Scholar 

  • Ichinose A, Bottenus RE, Davie EW (1990) Structure of transglutaminases. J Biol Chem 265(23):13411–13414

    PubMed  CAS  Google Scholar 

  • Isobe T, Takahashi H, Ueki S, Takagi J, Saito Y (1999) Activity-independent cell adhesion to tissue-type transglutaminase is mediated by alpha 4 beta 1 integrin. Eur J Cell Biol 78(12):876–883

    PubMed  CAS  Google Scholar 

  • Ito A, Mase A, Takizawa Y, Shinkai M, Honda H, Hata K, Ueda M, Kobayashi T (2003) Transglutaminase-mediated gelatin matrices incorporating cell adhesion factors as a biomaterial for tissue engineering. J Biosci Bioeng 95(2):196–199

    PubMed  CAS  Google Scholar 

  • Jelenska M, Fesus L, Kopec M (1980) The comparative ability of plasma and tissue transglutaminases to use collagen as a substrate. Biochim Biophys Acta 616(2):167–178

    PubMed  CAS  Google Scholar 

  • Johnson KA, Terkeltaub RA (2005) External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification. J Biol Chem 280(15):15004–150012

    PubMed  CAS  Google Scholar 

  • Johnson TS, Fisher M, Haylor JL, Hau Z, Skill NJ, Jones R, Saint R, Coutts I, Vickers ME, El Nahas AM, Griffini M (2007) Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease 18(12):3078–3088

    CAS  Google Scholar 

  • Johnson TS, Griffin M, Thomas GL, Skill J, Cox A, Yang B, Nicholas B, Birckbichler PJ, Muchaneta-Kubara C, ElNahas AM (1997) The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis. J Clin Invest 99(12):2950–2960

    PubMed  CAS  Google Scholar 

  • Johnson TS, Skill NJ, El Nahas AM, Oldroyd SD, Thomas GL, Douthwaite JA, Haylor JL, Griffin M (1999) Transglutaminase transcription and antigen translocation in experimental renal scarring. J Am Soc Nephrol 10(10):2146–2157

    PubMed  CAS  Google Scholar 

  • Jones MER, Messersmith PB (2007) Facile coupling of synthetic peptides and peptide-polymer conjugates to cartilage via transglutaminase enzyme. Biomaterials 28(35):5215–5224

    PubMed  CAS  Google Scholar 

  • Jones RA, Kotsakis P, Johnson TS, Chau DY, Ali S, Melino G, Griffin M (2006) Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth. Cell Death Differ 13(9):1442–1453

    PubMed  CAS  Google Scholar 

  • Jurgensen K, Aeschlimann D, Cavin V, Genge M, Hunziker EB (1997) A new biological glue for cartilage-cartilage interfaces: tissue transglutaminase. J Bone Joint Surg-Am Vol 79A(2):185–193

    Google Scholar 

  • Kaetsu H, Hashiguchi T, Foster D, Ichinose A (1996) Expression and release of the a and b subunits for human coagulation factor XIII in baby hamster kidney (BHK) cells. J Biochem (Tokyo) 119(5):961–969

    CAS  Google Scholar 

  • Kawai Y, Wada F, Sugimura Y, Maki M, Hitomi K (2008) Transglutaminase 2 activity promotes membrane resealing after mechanical damage in the lung cancer cell line A549. Cell Biol Int 32(8):928–934

    PubMed  CAS  Google Scholar 

  • Khew ST, Yang QJ, Tong YW (2008) Enzymatically crosslinked collagen-mimetic dendrimers that promote integrin-targeted cell adhesion. Biomaterials 29(20):3034–3045

    PubMed  CAS  Google Scholar 

  • Kinberger GA, Cai W, Goodman M (2002) Collagen mimetic dendrimers. J Am Chem Soc 124(51):15162–15163

    PubMed  CAS  Google Scholar 

  • Kinberger GA, Taulane JP, Goodman M (2006) The design, synthesis, and characterization of a PAMAM-based triple helical collagen mimetic dendrimer. Tetrahedron 62(22):5280–5286

    CAS  Google Scholar 

  • Kisiday J, Jin M, Kurz B, Hung H, Semino C, Zhang S, Grodzinsky AJ (2002) Self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: implications for cartilage tissue repair. Proc Natl Acad Sci USA 99(15):9996–10001

    PubMed  CAS  Google Scholar 

  • Kleman JP, Aeschlimann D, Paulsson M, van der Rest M (1995) Transglutaminase-catalyzed cross-linking of fibrils of collagen V/XI in A204 rhabdomyosarcoma cells. Biochemistry 34(42):13768–13775

    PubMed  CAS  Google Scholar 

  • Knight CRL, Rees RC, Griffin M (1991) Apoptosis––a potential role for cytosolic transglutaminase and its importance in tumor progression. Biochim Biophys Acta 1096(4):312–318

    PubMed  CAS  Google Scholar 

  • Kotsakis P, Griffin M (2007) Tissue transglutaminase in tumour progression: friend or foe? Amino Acids 33(2):373–384

    PubMed  CAS  Google Scholar 

  • Lee KN, Arnold SA, Birckbichler PJ, Patterson MK, Fraij BM, Takeuchi Y, Carter HA (1993) Site-directed mutagenesis of human tissue transglutaminase: Cys-277 is essential for transglutaminase activity but not for GTPase activity. Biochim Biophys Acta 1202(1):1–6

    PubMed  CAS  Google Scholar 

  • Linge C, Richardson J, Vigor C, Clayton E, Hardas B, Rolfe KJ (2005) Hypertrophic scar cells fail to undergo a form of apoptosis specific to contractile collagen––the role of tissue transglutaminase. J Invest Dermatol 125(1):72–82

    PubMed  CAS  Google Scholar 

  • Liu SP, Cerione RA, Clardy J (2002) Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci USA 99(5):2743–2747

    PubMed  CAS  Google Scholar 

  • Mangala LS, Arun B, Sahin AA, Mehta K (2005) Tissue transglutaminase-induced alterations in extracellular matrix inhibit tumor invasion. Mol Cancer 4:33

    PubMed  Google Scholar 

  • Mangala LS, Fok JY, Zorrilla-Calancha IR, Verma A, Mehta K (2007) Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26(17):2459–2470

    PubMed  CAS  Google Scholar 

  • Mann AP, Verma A, Sethi G, Manavathi B, Wang HM, Fok JY, Kunnumakkara AB, Kumar R, Aggarwal BB, Mehta K (2006) Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappa B in cancer cells: delineation of a novel pathway. Cancer Res 66(17):8788–8795

    PubMed  CAS  Google Scholar 

  • McHale MK, Setton LA, Chilkoti A (2005) Synthesis and in vitro evaluation of enzymatically cross-linked elastin-like polypeptide gels for cartilaginous tissue repair. Tissue Eng 11(11–12):1768–1779

    PubMed  CAS  Google Scholar 

  • Mehta K (1994) High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells. Int J Cancer 58(3):400–406

    PubMed  CAS  Google Scholar 

  • Mian S, el Alaoui S, Lawry J, Gentile V, Davies PJ, Griffin M (1995) The importance of the GTP-binding protein tissue transglutaminase in the regulation of cell cycle progression. Febs Lett 370(1–2):27–31

    PubMed  CAS  Google Scholar 

  • Mirza A, Liu SL, Frizell E, Zhu JL, Maddukuri S, Martinez J, Davies P, Schwarting R, Norton P, Zern MA (1997) A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappa B. Am J Physiol-Gastroint Liver Physiol 35(2):G281–G288

    Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Nicholas B, Smethurst P, Verderio E, Jones R, Griffin M (2003) Cross-linking of cellular proteins by tissue transglutaminase during necrotic cell death: a mechanism for maintaining tissue integrity. Biochem J 371:413–422

    PubMed  CAS  Google Scholar 

  • O’Halloran DM, Russell JC, Griffin M, Pandit AS (2006) Characterization of a microbial transglutaminase cross-linked type II collagen scaffold. Tissue Eng 12(6):1467–1474

    CAS  Google Scholar 

  • O’Halloran D, Grad S, Stoddart M, Dockery P, Alini M, Pandit AS (2008) An injectable cross-linked scaffold for nucleus pulposus regeneration. Biomaterials 29(4):438–447

    Google Scholar 

  • Oliverio S, Amendola A, DiSano F, Farrace MG, Fesus L, Nemes Z, Piredda L, Spinedi A, Piacentini M (1997) Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis. Mol Cell Biol 17(10):6040–6048

    PubMed  CAS  Google Scholar 

  • Orban JM, Wilson LB, Kofroth JA, El-Kurdi MS, Maul TM, Vorp DA (2004) Crosslinking of collagen gels by transglutaminase. J Biomed Mater A 68A(4):756–762

    CAS  Google Scholar 

  • Piacentini M, Piredda L, Starace D, AnnicchiaricoPetruzzelli M, Mattei M, Oliverio S, Farrace MG, Melino G (1996) Differential growth of N- and S-type human neuroblastoma cells xenografted into SCID mice––correlation with apoptosis. J Pathol 180(4):415–422

    PubMed  CAS  Google Scholar 

  • Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large conformational change upon activation. Plos Biology 5(12):2788–2796

    CAS  Google Scholar 

  • Raghunath M, Hopfner B, Aeschlimann D, Luthi U, Meuli M, Altermatt S, Gobet R, BrucknerTuderman L, Steinmann B (1996) Cross-linking of the dermo-epidermal junction of skin regenerating from keratinocyte autografts––anchoring fibrils are a target for tissue transglutaminase. J Clin Invest 98(5):1174–1184

    PubMed  CAS  Google Scholar 

  • Richards RJ, Masek LC, Brown RFR (1991) Biochemical and cellular mechanisms of pulmonary fibrosis. Toxicol Pathol 19(4):526–539

    Article  PubMed  CAS  Google Scholar 

  • Shweke N, Boulos N, Jouanneau C, Vandermeersch S, Melino G, Dussaule JC, Chatziantoniou C, Ronco P, Boffa JJ (2008) Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am J Pathol 173(3):631–642

    PubMed  CAS  Google Scholar 

  • Skill NJ, Griffin M, El Nahas AM, Sanai T, Haylor JL, Fisher M, Jamie MF, Mould NN, Johnson TS (2001) Increases in renal epsilon-(gamma-glutamyl)-lysine crosslinks result from compartment-specific changes in tissue transglutaminase in early experimental diabetic nephropathy: pathologic implications. Lab Invest 81(5):705–716

    Article  PubMed  CAS  Google Scholar 

  • Sperinde JJ, Griffith LG (1997) Synthesis and characterization of enzymatically-cross-linked poly(ethylene glycol) hydrogels. Macromolecules 30(18):5255–5264

    CAS  Google Scholar 

  • Stenberg P, Roth EB, Sjoberg K (2008) Transglutaminase and the pathogenesis of coeliac disease. Eur J Intern Med 19(2):83–91

    PubMed  CAS  Google Scholar 

  • Summey BT, Graff RD, Lai TS, Greenberg CS, Lee GM (2002) Tissue transglutaminase localization and activity regulation in the extracellular matrix of articular cartilage. J Orthop Res 20(1):76–82

    PubMed  CAS  Google Scholar 

  • Takahashi H, Isobe T, Horibe S, Takagi J, Yokosaki Y, Sheppard D, Saito Y (2000) Tissue transglutaminase, coagulation factor XIII, and the pro- polypeptide of von Willebrand factor are all ligands for the integrins alpha(9)beta(1) and alpha(4)beta(1). J Biol Chem 275(31):23589–23595

    PubMed  CAS  Google Scholar 

  • Tanaka K, Yokosaki Y, Higashikawa F, Saito Y, Eboshida A, Ochi M (2007) The integrin alpha 5 beta 1 regulates chondrocyte hypertrophic differentiation induced by GTP-bound transglutaminase 2. Matrix Biol 26(6):409–418

    PubMed  CAS  Google Scholar 

  • Telci D, Griffin M (2006) Tissue transglutaminase (TG2)––a wound response enzyme. Front Biosci 11:867–882

    PubMed  CAS  Google Scholar 

  • Telci D, Wang Z, Li X, Verderio EAM, Humphries MJ, Baccarini M, Basaga H, Griffin M (2008) Fibronectin-tissue transglutaminase matrix rescues RGD-impaired cell adhesion through syndecan-4 and beta(1) integrin co-signaling. J Biol Chem 283(30):20937–20947

    PubMed  CAS  Google Scholar 

  • Tovar-Vidales T, Roque R, Clark AF, Wordinger RJ (2008) Tissue transglutaminase expression and activity in normal and glaucomatous human trabecular meshwork cells and tissues. Ophthalmol Vis Sci 49(2):622–628

    Google Scholar 

  • Ueki S, Takagi J, Saito Y (1996) Dual functions of transglutaminase in novel cell adhesion. J Cell Sci 109(Pt 11):2727–2735

    PubMed  CAS  Google Scholar 

  • Upchurch HF, Conway E, Patterson MK Jr, Birckbichler PJ, Maxwell MD (1987) Cellular transglutaminase has affinity for extracellular matrix. In Vitro Cell Dev Biol 23(11):795–800

    PubMed  CAS  Google Scholar 

  • Upchurch HF, Conway E, Patterson MK, Maxwell MD (1991) Localization of cellular transglutaminase on the extracellular matrix after wounding––characteristics of the matrix bound enzyme. J Cell Physiol 149(3):375–382

    PubMed  CAS  Google Scholar 

  • Verderio E, Coombes A, Jones RA, Li XL, Heath D, Downes S, Griffin M (2001) Role of the cross-linking enzyme tissue transglutaminase in the biological recognition of synthetic biodegradable polymers. J Biomed Mater Res 54(2):294–304

    PubMed  CAS  Google Scholar 

  • Verderio E, Gross SR, Griffin M (1999) Cell-surface tissue transglutaminase regulates matrix storage of latent TGF-beta binding protein-1 (LTBP-1) and fibronectin accumulation. Mol Biol Cell 10:370

    Google Scholar 

  • Verderio EA, Scarpellini A and Johnson TS (2008) Novel interactions of TG2 with heparan sulfate proteoglycans: reflection on physiological implications. Amino Acids (in press)

  • Verderio EAM, Johnson TS, Griffin M (2005) Transglutaminases in wound healing and inflammation. Prog Exp Tumor Res 38:89–114

    PubMed  CAS  Google Scholar 

  • Verderio EAM, Telci D, Okoye A, Melino G, Griffin M (2003) A novel RGD-independent cell adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis. J Biol Chem 278(43):42604–42614

    PubMed  CAS  Google Scholar 

  • Weiss MS, Metzner HJ, Hilgenfeld R (1998) Two non-proline cis peptide bonds may be important for factor XIII function. Febs Lett 423(3):291–296

    PubMed  CAS  Google Scholar 

  • Welge-Lussen U, May CA, Lutjen-Drecoll E (2000) Induction of tissue transglutaminase in the trabecular meshwork by TGF-beta 1 and TGF-beta 2. Invest Ophthalmol Vis Sci 41(8):2229–2238

    PubMed  CAS  Google Scholar 

  • Wilhelmus M, Andringa G, Bol J, Van Dam AM, Hoozemans J, Jongenelen C, Breve J, Boekel A, Drukarch B (2007) Tissue transglutaminase is activated and redistributed to ER-derived granules in neuroblastoma cells treated with the PD-mimicking neurotoxin MPP. Park Rel Dis 13:S135–S135

    Google Scholar 

  • Zemskov EA, Janiak A, Hang J, Waghray A, Belkin AM (2006) The role of tissue transglutaminase in cell-matrix interactions. Front Biosci 11:1057–1076

    PubMed  CAS  Google Scholar 

  • Zemskov EA, Mikhailenko I, Strickland DK, Belkin AM (2007) Cell-surface transglutaminase undergoes internalization and lysosomal degradation: an essential role for LRP1. J Cell Sci 120(18):3188–3199

    PubMed  CAS  Google Scholar 

  • Zhu Y, Tramper J (2008) Novel applications for microbial transglutaminase beyond food processing. Trends Biotechnol 26(10):559–565

    PubMed  CAS  Google Scholar 

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  1. School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK

    R. J. Collighan & M. Griffin

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  1. R. J. Collighan
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  2. M. Griffin
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Correspondence to M. Griffin.

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Collighan, R.J., Griffin, M. Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids 36, 659–670 (2009). https://doi.org/10.1007/s00726-008-0190-y

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  • DOI: https://doi.org/10.1007/s00726-008-0190-y

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