1-s2.0-S0968000402021825-main

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002534 Review

http://tibs.trends.com 0968-0004/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0004(02)02182-5

Review

Laszlo Fesus*Dept of Biochemistry andMolecular Biology,Faculty of Medicine,Medical and HealthScience Center,University of Debrecen,H-4012 Hungary.*e-mail: [email protected]

Mauro PiacentiniDept of Biology,University of RomeTor Vergata andINMI-IRCCS LazzaroSpallanzani, Rome, Italy.

The first transglutaminase was identified byHeinrich Waelsch more than 40 years ago as a liverenzyme incorporating amines into proteins [1,2]. This enzyme, transglutaminase 2 (TG2), was used to determine the catalytic mechanism of thetransglutaminases, which involves an active sitecysteine, the formation of an acyl-enzyme thioesterintermediate between this cysteine and apolypeptide-bound glutamine and the reaction of thethioester intermediate with a suitable nucleophile [3].Because of their similarities in the catalytic triad andreaction mechanism, transglutaminases(EC 2.3.2.13), papain (EC 3.4.22.2) and papain-likecysteine proteases are classified within the samesuperfamily in the Structural Classification ofProteins database (SCOP, http://scop.mrc-lmb.cam.ac.uk/scop/). In invertebrates, only a singletransglutaminase gene has been found, whereas nineevolutionary related genes (encoding bloodcoagulation FXIIIa, TG17 and the inactive epb42),clustered on five different chromosomes, have evolvedin vertebrates by successive duplications [4]. HumanTG2 is a 76-kD protein, consisting of 686 amino acids.

TG2 is a multifunctional proteinTG2 moonlightsbetween several distinctbiochemical functions at various cellular locations (for details see Fig. 1.) In addition to crosslinking,TG2 can modify proteins by amine incorporation anddeamidation, and by acting as an isopeptidase in aCa2+-dependent manner (Fig. 1). Furthermore, TG2 is externalized from cells, where it mediates the interaction of integrins with fibronectin andcrosslinks proteins of the extracellular matrix (ECM).In 1994, a novel G protein (Gh), observed in rat liverplasma membrane as a mediator of transmembrane

signalling, turned out to be TG2 [5]. TG2 binds andhydrolyzes GTP with an affinity and catalytic ratesimilar to the subunits of large heterotrimericG proteins and small Ras-type G proteins. Gh/TG2couples 1b- and 1d- adrenoreceptors, thromboxaneand oxytocin receptors to phospholipase C (PLC1),mediating inositol phosphate production in responseto agonist activation. The GDP/GTP-bound formcannot act as a transglutaminase. This inhibition issuspended by Ca2+, which serves as a switch betweenthe two distinct functions [6].

Structural explanation of biochemical functionsThe structure of TG2, crystallized in a dimer form incomplex with GDP, has been reported recently [7].Similar to another transglutaminase, FXIIIa [8], TG2has four distinct domains (Fig. 2): an N-terminal-sandwich (with fibronectin and integrin bindingsite), catalytic core (containing the catalytic triad forthe acyl-transfer reaction and a conserved Trpessential for this catalytic activity [9]) and twoC-terminal -barrel domains (the second contains aphospholipase C binding sequence [10]).

A unique guanidine nucleotide-binding site, whichhas not been found in any other protein, is located in acleft between the catalytic core and the first -barrel[7]; this sequence is coded by exon 10 of the TG2 gene,which has very poor sequence homology with thesame exons in other TGs. Some GDP/GTP-interactingresidues and those essential for GTP hydrolysis aresituated in other domains (Fig. 2), as predicted bysite-directed mutagenesis [11]. In the GDP-boundform of TG2, access to the transamidation active siteis blocked by two loops, and the active site cysteine ishydrogen-bonded to a Tyr residue [7].

The structure of the Ca2+-bound form of TG2 isunresolved. A putative Ca2+-binding site, homologousto one demonstrated in FXIIIa [12], is distorted in the TG2 structure by the bound nucleotide [7].Ca2+-binding at this site, or others [13], could weakennucleotide binding, and consequent conformationalchanges a process which involves substrate bindingand related displacement of the hydrogen-bonded Tyr[14] might make the active site accessible [15]. Therecently solved three dimensional structure of TG3 hasrevealed that it has the same domain structure as TG2,and after binding Ca2+ a channel opens to expose twocritical Trp residues that control access of substrates tothe active site [16]; similar structural changes mightoccur in TG2. It has been suggested that the two

Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase thatcatalyzes Ca2+-dependent protein modifications. It acts as a G protein intransmembrane signalling and as a cell surface adhesion mediator, thisdistinguishes it from other members of the transglutaminase family. Thesequence motifs and domains revealed in the recent TG2 structure, can each beassigned distinct cellular functions, including the regulation of cytoskeleton,cell adhesion and cell death. Ablation of TG2 in mice results in impaired woundhealing, autoimmunity and diabetes, reflecting the number and variety ofTG2 functions. An important role for the enzyme in the pathogenesis of coeliacdisease, fibrosis and neurodegenerative disorders has also been demonstrated,making TG2 an important therapeutic target.

Published online: 12 September 2002

Transglutaminase 2: an enigmaticenzyme with diverse functionsLaszlo Fesus and Mauro Piacentini

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

http://tibs.trends.com

535Review

non-proline cis peptide bonds (one close to the active sitecysteine) present in FXIIIa [17], TG2 [7] and TG3 [16]might be involved in the activation process [17].

Additional motifs of TG2 (Fig. 2) might be used to allowexternalization without a signal peptide, interactionwith integrins and fibronectin [18], and translocationto the nucleus [19] or perhaps other organelles.

The function of TG2 in cellsHow are the diverse biochemical activities of TG2related to cellular functions? The in vivo expressionpattern of the enzyme, its subcellular locations andidentified substrates (Table 1) suggest multiple roles.There are cell types (e.g. endothelial and smoothmuscle cells) which constitutively express TG2 athigh levels [20], whereas in other cell types it isinduced by distinct signalling pathways, targetingspecific response elements in the regulatory region ofthe gene. Retinoic acid (RA), TGF, NF-B and APresponsive sites and regions have been functionallyidentified all are related to induction of cellulardefence mechanisms and cellular maturation ([21]and references therein).

Review

GTP

PLC-1

Ti BS

TG2

TG2

TG2

TG2

Fibronectin

Integrins

-Cys

M

PIP2

IP3

DAG

C N Lys LysH2O

O

H

Glu Glu

CE

Incorporation ofamines into proteins

Crosslinkingof proteins

Site-specificdeamidation

Isopeptidaseactivity

Promotion ofcellmatrix interactions

Transmembranesignaling

Ca2+

Ca2+

Ca2+

C, N, E

GDP

GDP

GTP

Prima

ry amin

es

Protein-bo

und Lys

H2O

H2O

Appearance onthe cell surface

C N Lys NH3

O

H

GluGln Lys

H2OGln Glu NH3

C N R NH3

O

H

GluGln NH2-R

Oxytocin receptor,TP thromboxane A2 receptor,1B- and 1D adrenoreceptors

IVII

VIV

IVIII

II

Receptorstimulation

Fig. 1. Biochemical activities of transglutaminase 2 (TG2). TG2catalyzes Ca2+-dependent acyl-transfer reaction [3] between-carboxamide group of a specific protein-bound glutamine and eitherthe -amino group of a distinct protein-bound lysine residue (covalentprotein crosslinking; the principal in vivo activity) or primary aminessuch as polyamines and histamine. Water can replace amine donorsubstrates, leading to deamidation of the recognized glutamines. TG2,similar to factor XIIIa, has Ca2+-dependent isopeptidase activity and, at least under test tube conditions, can hydrolyse : isopeptides [55].TG2 can be exposed on the external leaflet of the plasma membrane ([40,42] and references therein). The presence of TG2outside the cell has been proposed to depend on its interaction withfibronectin and integrins [39,56,57]. TG2 binds and thereby activatesphospholipase C following stimulation of several kinds of cell surfacereceptors; its endogenous GTPase activity ensures proper regulation oftransmembrane signalling through these receptors ([11] and referencestherein). Functions of TG2 are performed in the cytosol (C), the nucleus(N), at the cell membrane (M) and in the extracellular space (E). Exceptfor its isopeptidase activity, all other functions have been shown tooccur in intact cells and/or tissues.



536 Review

At membrane locations, the role of TG2 intransmitting signals from seven-transmembranehelix receptors to phospholipase C is clearlyestablished [11]. Phospholipase C itself becomes activewhen its inhibition by GDPTG2 is suspended afterTG2 binds GTP [22]. Interaction of TG2 with specificmolecules (e.g. with sphingosylphosphocholine [23])might reduce the Ca2+ requirement for the

transglutaminase activity [24]. This activity isstrongly influenced by nitric oxide: up to 15 of the18 cysteine residues can be nitrosylated anddenitrosylated in a Ca2+-dependent manner, inhibitingand activating the enzyme, respectively [25].

TG2 activated by Ca2+ interacts with and modifiesmajor components of the cytoskeleton (Table 1). In response to RA treatment, TG2-dependenttransamidation of RhoA results in the increasedbinding of RhoA GTPase to ROCK-2 protein kinase,autophosphorylation of ROCK-2 and phosphorylationof vimentin [26] which can lead to the formation ofstress fibers and increased cell adhesion. Theseevents are prevented by TG2 inhibition. TG2 caninteract with -tubulin and with microtubule-bindingproteins [27] including tau, which can be crosslinkedby the enzyme [28].

An intriguing aspect of TG2 function is itstranslocation to the nucleus under certainconditions [24] presumably with the help ofimportin-3 [19] where it can function either as aG protein [29] or as a transamidase activated bynuclear Ca2+-signals to crosslink histones [30],retinoblastoma (Rb) [31] and SP1 (S. Kojima,pers. commun.) proteins (Table 1). This suggeststhat TG2 could have a direct role in chromatinmodifications and/or gene expression regulation.

TG2 is induced in cells undergoing apoptosis in vivo[32]. Its overexpression primes cells for suicide andinhibition of its expression by antisense strategyresults in decreased cell death [33]. It has beenreported recently that TG2 sensitizes cells forapoptosis by interacting with mitochondria [34],shifting them to a higher polarized state and alteredredox status. This might provoke activation oftransglutaminase crosslinking activity [24]. Duringthe late stage of apoptosis, the massive increase ofcytosolic Ca2+ determines the switch of TG2 to itscrosslinking configuration in all subcellularcompartments leading to extensive polymerization ofintracellular proteins (including actin [35] and Rb [31])and formation of detergent-insoluble structures [36].These protein scaffolds stabilize the structure of thedying cell before its clearance by phagocytosis,limiting the release of harmful intracellularcomponents and consequently inflammatory orautoimmune responses [37]. Under pathologicalconditions the death of cells expressing high amountsof TG2 can occur as a result of a mummificationeventcaused by extensive crosslinking of cytosolic proteinswithout signs of either apoptosis or necrosis [38].

TG2 on the cell surface and in the extracellular matrixIntegrin-bound TG2 on the cell surface provides abinding site for fibronectin, which TG2 binds withhigh affinity (Fig. 1). The TG2 binding site onintegrins probably involves sequences outside theintegrin ligand-binding pocket. It is estimated that,on the surface of different cell types, 540% of 1integrins could be complexed with TG2 and that all

Review

Ti BS

*BH3FN/Integrin *NLS1 *NLS2 PLC1GTP

C277 H335 D358W241 Y516N398D400

E447E452Y174

K173 R476R478V479M483

R580

*Ca2+

1 139 147 472460 472583 687

273KY274387KY388

3 63 144 184 227 286 332 366 447 592538Exon10 687639

NH2 COOH

C336 Y583

(a) -sandwich Catalytic core -barrel1 -barrel2

(b)

Fig. 2. Functional elements and three-dimensional structure of the human tissue-type transglutaminase(TG2) [7]. (a) The four structural domains are indicated by arrows with amino acid positions (top). Exon boundaries of the gene encoding TG2 are indicated by arrowheads with numbers correspondingto the last amino acids of each exon-encoded region. Exon 10, which contains residues forming theGDP-binding site, is marked. Functional regions and amino acid positions indicated are as follows.FN, fibronectin binding site [18], 2AEELVLE7 (cyan); integrin-binding region, N-terminal 28-kDa fragment;BH3, BH3 motif of the Bcl-2 protein family, 200PKFLKNAGRDCSRR214 [34] (green); NLS1 and NLS2, nuclearlocalization signals predicted on the basis of homology to the NLS of the NS1 non-structural protein ofinfluenza virus [19], 259DILRR263 and 597PKQKRK602 (grey); catalytic triad, Cys277-His335-Asp358 (blue) andactive site residues W241, C336 and Y516 of transamidating activity (purple ball and stick representation)involved in transition state stabilization, forming an inhibitory H-bond with Cys277 and potentialinhibition of activity by disulfide bonding of Cys277, respectively [7,9,14]; Ca2+, Ca2+-binding sitepredicted from the FXIIIa structure [12] (red); non-proline cis peptide bonds 273KY274, 387KY388 (yellow);GTP, GDP-binding and GTPase catalytic site residues (orange); PLC1, interaction site forphospholipase C1 657LHMGLHKLVVNFESDK LKAVK677 (magenta). Putative sites are labelled by anasterisk. (b) Three-dimensional structure of TG2 in complex with GDP shown from directions facingthe transamidating (left) and the GTPase (right) active sites based on the reported crystal structure [7].Functional regions indicated in (a) are coloured correspondingly. N- and C-terminals are designatedby N and C, respectively. The fibronectin binding site is not indicated because the revealed structurelacks the coordinates for the N-terminal amino acids, M1L14. The catalytic triad and the surroundingresidues of the transamidating active site, as well as amino acids contributing to the GTPase site, areshown in ball and stick representation. The bound GDP molecule is colored green. Clusters of Glu/Glnand Asp/Asn residues forming putative Ca2+-binding sites predicted on the basis of surfacepotentional analysis [13] are coloured red.



537Review

TG2 on the cell surface is present as 1:1 complexeswith integrins [39]. The interaction of TG2 withintegrins occurs primarily at the extracellulardomains of integrin subunits, does not requirecrosslinking activity [40] and facilitates adhesion,spreading and motility of cells [39,40].

The significance of TG2 function in theextracellular space goes beyond promotion of celladhesion and spreading; it is directly involved inwound healing and angiogenesis [41]. TG2 is alsoinvolved in the assembly, remodelling andstabilization of the ECM in various tissues [42]. Thisis done by crosslinking fibronectin, fibrinogen/fibrin,von Willebrand factor, vitronectin, lipoprotein a,dermatane sulfate proteoglycans, collagen V,osteonectin, laminin, nidogen and osteopontin ([42]and references therein). Furthermore, the secretedenzyme contributes to the covalent modification andactivation of several growth factors [43] includingTGF [44], which promotes transcriptional regulationof ECM genes and of TG2 itself [45].

Consequences of TG2 deletionKnowing the multifunctionality and unique cellularbiochemistry of TG2, it came as a surprise to learnthat homozygous deletion of TG2 does not result in anembryonic lethal phenotype [46,47]. The homozygousnull animals are viable, of normal size and weight,and born with mendelian frequency. No obviousalterations have been observed in apoptosis, thestructure of the ECM or heart function (in which theG protein activity of TG2 thought to be important).The most probable explanation for the lack of severephenotypes is that other transglutaminases inmammalian tissues can compensate for the loss of TG2. However, the other mammaliantransglutaminases do not bind GDP/GTP and, withthe exception of FXIIIa, they have not been found onthe cell surface. Therefore, alterations are expected

in TG2/ mice, especially under certain stresses andpathological conditions. In fact, decreased adherenceof primary fibroblasts [47] and impaired woundhealing related to altered cytoskeletal dynamics offibroblasts [R. Graham, pers. commun.] have beenobserved in these mice, consistent with the suggestedextra- and intra-cellular functions of TG2. Theparticipation of TG2 in apoptosis could explain thefindings that on increasing the frequency of cell death in the knock out mice, clearance of apoptoticcells by phagocytosis is defective in the thymus andthe liver and inflammatory as well as autoimmunereactions develop (Z. Szondy, pers. commun.).TG2-deficient mice also show glucose intolerance and hyperglycaemia because of reduced insulinsecretion, a phenomenon similar to a subtype ofdiabetes called MODY (for maturity-onset diabetes of the young)[48]. In humans, no definitive TG2deficiency has been observed so far, and therefore theabove findings clearly point to possible areas forfuture clinical investigation.

Pathogenic role of the enzyme in diseaseCoeliac disease is a malabsorbtion syndromecharacterized by almost total atrophy of villi in thejejunum on exposure to dietary glutens. TG2 is involvedin generating T cell stimulatory gluten peptidesthrough deamidation of specific glutamines [49,50].In HLA-DQ2 or HLA-DQ8 settings, the TG2-formeddisease-triggering epitopes provoke a pathologicalimmune response that destroys the jejunalepithelium. In parallel, a T-cell-mediatedautoimmune response is initiated, producingIgA-type autoantibodies against TG2 [51], thedetection of which has become a widely useddiagnostic marker of coeliac disease. Dysregulationof the suggested functions of TG2 in variouspathological settings might significantly contributeto the development of fibrosis in susceptible organssuch as the lung, liver and kidney ([52] andreferences therein).

Huntington disease (HD) is a neurodegenerativediseases caused by the expansion of CAG trinucleotiderepeats in the gene encoding huntingtin (htt). Thisresults in a large number of contiguous glutamineresidues in the htt protein. Accumulations ofubiquitinated htt aggregate in the nucleus andprogressive loss of neuronal cells is observed. One ofthe proposed mechanisms of htt aggregation is basedon the action of TG2 because expanded polyglutaminerepeats are excellent glutaminyl-donor substrates forTG2-catalyzed cross-linking ([24] and referencestherein). By crossing HD R6/1 transgenic mice withTG2/ mice, a reduction in cell death was observed inR6/1/TG2/ compared with TG2/ mice, together withthe potentiation of the formation of htt aggregatesand significant improvement in both motorperformance and survival [53], suggesting that theinvolvement of TG2 in the loss of neurons in HD is notrelated to the formation of htt aggregates.

Review

Table 1. Intracellular localization of TG2 and examples of its proteinpartnersa

Subcellular compartment Interacting proteins Substrates

Cytosol RhoA [26], DLK [58]Plasma membrane Receptors, PLC1 [11] LTGF- [59]

Integrins [39, 40] Ankyrinb, LC1 [60]CytoskeletonMicrofilaments Actin [35], Myosin [61]

Spectrinb, Thymosin [62] Troponin Tb,

Intermediate filaments Keratinb, Vimentinb

Neurofilaments [63]Microtubules Tubulin- [27] S100A7, S100A10,

S100A11 [64]; Tau [28]Nuclear Importin 3 [19] Histonesb

pRB [31]

aAbbreviations: DLK, dual leucine zipper-bearing kinase; LTGF, latent tumor growth factor; LC1,lipocortin; S100As, family of 1014 kDa EF hand containing calcium-binding proteins; pRB,retinoblastoma protein; PLC, phospholipase.bFor references see [65].

2



538 Review

Intronexon swapping of TG2 mRNA in the brainsof patients with Alzheimer disease results in theappearance of an alternatively spliced short form ofTG2, which lacks GDP/GTP binding residues andthereby has increased crosslinking activity [54]. The latter has been connected to the formation ofneurofibrillary tangles and death of neuronal cells [24].

ConclusionTG2 is emerging as a well-characterized,multifunctional molecular player in various cellularprocesses, ranging from intracellular signalling toapoptosis and pathological conditions such asautoimmune and Huntington diseases. The evidenceaccumulated in recent years points to the enzymehaving a general protective and stabilizing role incells and tissues; in fact, in the absence of the enzymemice show impaired wound healing, autoimmunityand diabetes. However, under pathological condition,the uncontrolled activation of TG2 can turn its

protective function into a pathological one. Infibrogenesis, coeliac and Huntington disease, theenzyme contributes to the formation of fibrotictissues with scars, creates stimulatory epitopes forthe immune system and determines excessive celldeath, respectively. Despite these major advance,basic issues remain to be elucidated. These includethe intracellular regulation of TG2, both in itscrosslinking and signalling configuration, thephysiological significance of its nuclear function(s),and the mechanism of externalization. Anotherquestion is the extent to which its functions can bereplaced by other transglutaminase(s). Consideringthe emerging possibility of TG2-based therapies potentially made available by the detailed structuraland functional characterization of the enzyme inrecent years for fibrosis, Huntington and coeliacdiseases, it is easy to predict that tissuetransglutaminase will make further headlines in the future.

Review

AcknowledgementsThis work was partiallysupported by grants(Apoptosis Mechanismsand Apoclear) from theEuropean Community, byfunds from the HungarianNational Research Fund(OTKA) and HungarianMinistry of Health (ETT),from AIRC and RicercaCorrente and Finalizzatafrom the Italian Ministryof Health. We thank Zoltan Nemes and ZsoltKeresztessy (University ofDebrecen) for their helpfulsuggestions.

References1 Sarkar, N.K. et al. (1957) An enzymically

catalyzed incorporation of amines into proteins.Biochim. Biophys. Acta 25, 451452

2 Lorand, L. (2002) Transglutaminase.Remembering Heinrich Waelsch. Neurochem. Int.40, 712

3 Folk, J.E. and Finlayson, J.S. (1977) The epsilon-(gamma-glutamyl)lysine crosslink and thecatalytic role of transglutaminases. Adv. ProteinChem. 31, 1133

4 Grenard, P. et al. (2001) Evolution oftransglutaminase genes: identification of atransglutaminase gene cluster on humanchromosome 15q15. J. Biol. Chem. 276,3306633078

5 Nakaoka, H. et al. (1994) Gh: a GTP-bindingprotein with transglutaminase activity andreceptor signaling function. Science 264,15931596

6 Achyuthan, K.E. et al. (1987) Identification of aguanosine triphosphate-binding site on guineapig liver transglutaminase. Role of GTP andcalcium ions in modulating activity. J. Biol. Chem.262, 19011906

7 Liu, S. et al. (2002) Structural basis for theguanine nucleotide-binding activity of tissuetransglutaminase and its regulation oftransamidation activity. Proc. Natl. Acad. Sci.U. S. A. 99, 27432747

8 Yee, V.C. et al. (1994) Three-dimensionalstructure of a transglutaminase: human bloodcoagulation factor XIII. Proc. Natl. Acad. Sci.U. S. A. 91, 72967300

9 Murthy, S.N. et al. (2002) Conserved tryptophanin the core domain of transglutaminase essentialfor catalytic activity. Proc. Natl. Acad. Sci. U. S. A.99, 27382742

10 Hwang, K-C. et al. (1995) Interaction site ofGTP binding Gh (transglutaminase II) withphospholipase C. J. Biol. Chem. 270, 2705827062

11 Iismaa, S.E. et al. (2000) GTP binding andsignaling by Gh/transglutaminase II involvesdistinct residues in a unique GTP-binding pocket.J. Biol. Chem. 275, 1825918265

12 Fox, B.A. et al. (1999) Identification of the calciumbinding site and a novel ytterbium site in blood

coagulation factor XIII by X-ray crystallography.J. Biol. Chem. 274, 49174923

13 Ambrus, A. et al. (2001) Calcium binding oftransglutaminases: A 43Ca NMR study combinedwith surface polarity analysis. J. Biomol. Struct.Dyn. 19, 5974

14 Noguchi, K. et al. (2001) Crystal structure of redsea bream transglutaminase. J. Biol. Chem. 276,1205512059

15 Mariani, P. et al. (2000) Ligand-inducedconformational changes in tissuetransglutaminase: Monte Carlo analysis ofsmall-angle scattering data. Biophys. J. 78,32403251

16 Ahvazi, B. et al. (2002) Three-dimensionalstructure of the human transglutaminase 3enzyme: binding of calcium ions changesstructure for activation. EMBO J. 21, 20552067

17 Weiss, M.S. et al. (1998) Two non-proline cispeptide bonds may be important for factor XIIIfunction. FEBS Lett. 423, 291296

18 Gaudry, C.A. et al. (1999) Cell surface localizationof tissue transglutaminase is dependent on afibronectin-binding site in its N-terminal-sandwich domain. J. Biol. Chem. 274,3070730714

19 Peng, X. et al. (1999) Interaction of tissuetransglutaminase with nuclear transport proteinimportin-3. FEBS Lett. 5, 3539

20 Thomzy, V. and Fesus, L. (1989) Differentialexpression of tissue transglutaminase in humancells: an immunohistochemical study. Cell TissueRes. 255, 215224

21 Szegezdi, E. et al. (2000) Apoptosis-linked in vivoregulation of the tissue transglutaminase genepromoter. Cell Death Differ. 7, 12251233

22 Murthy, S.N. et al. (1999) Interaction ofG(h)/transglutaminase with phospholipase C1and with GTP. Proc. Natl. Acad. Sci. U. S. A. 96,1181511819

23 Lai, T.S. et al. (1997) Sphingosylphosphocholinereduces the calcium ion requirement foractivating tissue transglutaminase. J. Biol.Chem. 272, 1629516300

24 Lesort, M. et al. (2000) Tissue transglutaminase: apossible role in neurodegenerative diseases.Prog. Neurobiol. 61, 439463

25 Lai, T.S. et al. (2001) Calcium regulatesS-nitrosylation, denitrosylation, and activity oftissue transglutaminase. Biochemistry 40,49044910

26 Singh, U.S. et al. (2001) Role of transglutaminase IIin retinoic acid-induced activation ofRhoA-associated kinase-2. EMBO J. 20, 24132423

27 Piredda, L. et al. (1999) Identification of tissuetransglutaminase binding proteins in neural cellscommitted to apoptosis. FASEB J. 13, 355364

28 Murthy, S.N. et al. (1998) Cross-linking sites ofthe human tau protein, probed by reactions withhuman transglutaminase. J. Neurochem. 71,26072614

29 Singh, U.S. et al. (1995) Identification andbiochemical characterization of an 80 kilodaltonGTP-binding/transglutaminase from rabbit livernuclei. Biochemistry 34, 1586315874

30 Ballestar, E. et al. (2001) Conformational changesin the nucleosome followed by the selectiveaccessibility of histone glutamines in thetransglutaminase reaction: effects of saltconcentrations. Biochemistry 40, 19221929

31 Oliverio, S. et al. (1997) Tissue transglutaminase-dependent posttranslational modification of theretinoblastoma gene product in promonocytic cellsundergoing apoptosis. Mol. Cell. Biol. 17,60406048

32 Fesus, L. et al. (1987) Induction and activation oftissue transglutaminase during programmed celldeath. FEBS Lett. 224, 104108

33 Oliverio, S. et al. (1999) Inhibition of tissuetransglutaminase increases cell survival bypreventing apoptosis. J. Biol. Chem. 274,3412334128

34 Piacentini, M. et al. (2002) Transglutaminaseoverexpression sensitizes neuronal cell lines toapoptosis by increasing mitochondrial membranepotential and cellular oxidative stress.J. Neurochem. 81, 10611072

35 Nemes, Z. et al. (1997) Identification ofcytoplasmic actin as an abundant glutaminylsubstrate for tissue transglutaminase in HL-60and U937 cells undegoing apoptosis. J. Biol.Chem. 33, 2057720583

36 Fesus, L. et al. (1989) Apoptotic hepatocytesbecome insoluble in detergents and chaotropic



539Review

agents as a result of transglutaminase action.FEBS Lett. 245, 150154

37 Piredda, L. et al. (1997) Lack of tissuetransglutaminase protein cross-linking leads toleakage of macromolecules from dying cells:relationship to development of autoimmunity inMRLlpr/lpr mice. Cell Death Differ. 4, 463472

38 Griffin, M. and Verderio, E. (2000) Tissuetransglutaminase in cell death. In Programmedcell death in animals and plants (Bryant, J.A.,Hughes, S.G. and Galand, J.M., eds), pp. 223238,Bios Scientific Publications

39 Akimov, S.S. and Belkin, A.M. (2001) Cell-surfacetransglutaminase promotes fibronectin assemblyvia interaction with the gelatin-binding domain offibronectin: a role in TGF-dependent matrixdeposition. J. Cell Sci. 114, 29893000

40 Balklava, Z. et al. (2002) Analysis of tissuetransglutaminase function in the migration ofSwiss fibroblasts. The active-state conformationof the enzyme does not affect cell motility but it isimportant for its secretion. J. Biol. Chem. 277,1656716575

41 Haroon, Z.A. et al. (1999) Tissuetransglutaminase is expressed, active, anddirectly involved in rat dermal wound healing andangiogenesis. FASEB J. 13, 17871795

42 Aeschlimann, D. and Thomazy, V. (1999) Proteincrosslinking in assembly and remodelling ofextracellular matrices: The role oftransglutaminases. Connect. Tissue Res. 41, 127

43 Sakai, K. et al. (2001) Tissue transglutaminasefacilitates the polymerization of insulin-likegrowth factor-binding protein-1 (IGFBP-1) andleads to loss of IGFBP-1s ability to inhibit insulin-like growth factor-I-stimulated protein synthesis.J. Biol. Chem. 276, 87408745

44 Nunes, I. et al. (1997) Latent transforming growthfactor binding protein domains involved inactivation and transglutaminase-dependentcross-linking of latent transforming growthfactor-beta. J. Cell Biol. 136, 11511163

45 Ritter, S.J. and Davies, P.J. (1998) Identificationof a transforming growth factor-beta/bonemorphogenic protein 4 (TGF-beta/BMP4)response element within the mouse tissuetransglutaminase gene promoter. J. Biol. Chem.263, 45864592

46 De Laurenzi, V. and Melino, G. (2001) Genedisruption of tissue transglutaminase. Mol. Cell.Biol. 21, 148155

47 Nanda, N. et al. (2001) Targeted inactivation ofGh/tissue transglutaminase II. J. Biol. Chem. 276,2067320678

48 Bernassola, M. et al. Role of transglutaminase 2 inglucose tolerance. FASEB J. (in press)

49 Anderson, R.P. et al. (2000) In vivo antigenchallenge in coeliac disease identifies a singletransglutaminase-modified peptide as thedominant A-gliadin T-cell epitope. Nat. Med. 6,337342

50 Willemijn, L. et al. (2002) Specificity of tissuetransglutaminase explains cereal toxicity incoeliac disease. J. Exp. Med. 195, 643649

51 Dietrich, W. et al. (1997) Identification of tissuetransglutaminase as the autoantigene of celiacdisease. Nat. Med. 3, 797801

52 Skill, N.J. et al. (2001) Increases in renal(-glutamyl)lysine crosslinks result fromcompartment-specific changes in tissuetransglutaminase in early experimental diabeticnephropathy: pathologic implications.Lab. Invest. 81, 705716

53 Mastroberardino, P.G. et al. (2002) Tissuetransglutaminase ablation reduces neuronaldeath and prolongs survival in a mouse model ofHuntingtons disease. Cell Death Differ. 9,873880

54 Citron, B.A. et al. (2001) Intron-exon swapping oftransglutaminase mRNA and neuronal tauaggregation in Alzheimers disease. J. Biol. Chem.276, 32953301

55 Parameswaran, K.N. et al. (1997) Hydrolysis of: isopeptides by cytosolic transglutaminases and

by coagulation factor XIIIa. J. Biol. Chem. 272,1031110317

56 Radek, J.T. et al. (1993) Affinity of humanerythrocyte transglutaminase for a 42-kDagelatin-binding fragment of human plasmafibronectin. Proc. Natl. Acad. Sci. U. S. A. 90,31523156

57 Isobe, T. et al. (1999) Activity-independent celladhesion to tissue-type transglutaminase ismediated by 41 integrin. Eur. J. Cell Biol. 78,876883

58 Hebert, S.S. et al. (2000) The mixed lineage kinaseDLK is oligomerized by tissue transglutaminaseduring apoptosis. J. Biol. Chem. 275,3248232490

59 Kojima, S. et al. (1993) Requirement fortransglutaminase in the activation of latenttransforming growth factor-beta in bovineendothelial cells. J. Cell Biol. 121, 439448

60 McKanna, J.A. (1995) Lipocortin 1 in apoptosis:mammary regression. Anat. Rec. 242, 110

61 Eligula, L. et al. (1998) Transglutaminase-induced cross-linking between subdomain 2 of G-actin and the 636642 lysine-rich loop of myosin subfragment 1. Biophys. J. 74,953963

62 Huff, T. et al. (1999) Thymosin beta(4) serves as aglutaminyl substrate of transglutaminase.Labelling with fluorescent dansylcadaverine doesnot abolish interaction with G-actin. FEBS Lett.464, 1420

63 Grierson, A.J. et al. (2001) Three differenthuman tau isoforms and rat neurofilament light,middle and heavy chain proteins are cellularsubstrates for transglutaminase. Neurosci. Lett.298, 912

64 Ruse, M. et al. (2001) S100A7, S100A10, andS100A11 are transglutaminase substrates.Biochemistry 40, 31673173

65 Piacentini, M. and Colizzi, V. (1999) Tissuetransglutaminase: apoptosis versusautoimmunity. Immunol. Today 20, 130134

Review

Free journals for developing countries

The WHO and six medical journal publishers have launched the Access to Research Initiative, which enables institutionsin ~70 developing countries to gain free access to biomedical literature through the Internet.

The science publishers Blackwell, Elsevier Science, the Harcourt Worldwide STM group, Wolters Kluwer InternationalHealth and Science, SpringerVerlag and John Wiley were approached by the WHO and the British Medical Journal in

2001. Initially, >1000 journals will be available for free or at significantly reduced prices to universities, medical schools,research and public institutions in developing countries. The second stage involves extending this initiative to

institutions in other countries.Gro Harlem Brundtland, director-general for the WHO, said that this initiative was perhaps the biggest step ever taken

towards reducing the health information gap between rich and poor countries.See http://www.healthinternetwork.net for more information.

1-s2.0-S0968000402021825-main

Documents

Transcript of 1-s2.0-S0968000402021825-main