Tissue transglutaminase in normal and abnormal wound healing: Review article

Verderio, Elisabetta; Johnson, Timothy S.; Griffin, Martin

doi:10.1007/s00726-004-0094-4

Cited by 160 publications

(152 citation statements)

References 98 publications

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“…TG2 is now recognized as a wound response enzyme, which, under stress conditions, is up-regulated, leading to its secretion into the extracellular matrix (23,24). In TG2 KO animals, wound healing is delayed (23), whereas overexpression of the enzyme can lead to fibrosis (44).…”

Section: Discussionmentioning

confidence: 99%

“…In TG2 KO animals, wound healing is delayed (23), whereas overexpression of the enzyme can lead to fibrosis (44). Once secreted into the extracellular matrix, TG2 forms a heterocomplex with its high affinity binding partner FN, which is thought to mediate down-regulation of its transamidating activity and make it more resistant to proteolytic degradation (7).…”

Section: Discussionmentioning

confidence: 99%

“…We also illustrated how this compensation mechanism is particularly important for cell survival during situations involving matrix remodeling (e.g. wounding and scarring, angiogenesis, and tumor metastasis), where high levels of TG2 and RGD peptides are released during the matrix remodeling process (23)(24)(25).…”

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confidence: 99%

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RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

Wang

Collighan

Gross

et al. 2010

Journal of Biological Chemistry

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Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, weshow that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and ␤1 integrin co-signaling pathway. By using ␣5 null cells, ␤1 integrin functional blocking antibody, and a ␣5␤1 integrin targeting peptide A5-1, we demonstrate that the ␣5 and ␤1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKC␣ is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains. Fibronectin (FN)3 mediates the cell adhesion process by interacting with cell surface receptors through its different cell binding sites. It is essential to embryogenesis and found associated with the extracellular matrix in large quantities during wound healing and angiogenesis. The amino acid sequence Arg-Gly-Asp (RGD) found within FN and many other matrix proteins is the most widely occurring cell-adhesive motif (1). It is the most important recognition site for about half of all known integrins, such as ␣5␤1, ␣V␤1, ␣V␤3, and ␣V␤5 (2). However, this cell adhesion process can easily be inhibited by the presence of competitive peptides containing the RGD sequence, often leading to apoptosis (anoikis) (3, 4). Such peptides are commonly released during matrix remodeling, a process that is essential to both wound healing and angiogenesis (5-7). Of the integrins, ␣5␤1 integrin is probably the major cell surface integrin that interacts with the RGDcell binding site on FN, initiating the cell adhesion process (8), whereas the binding of ␣v␤3 integrin to the RGD domain can also support cell adhesion on FN (9). In addition to the RGDcell binding domains, the heparin binding sites within FN have also been reported to be involved in cell adhesion because, although cell binding to the RGD-cell binding domains of FN can initiate the cell adhesion process, it is not sufficient to fully support actin cytoskeleton formation, an observation tha...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

Wang

Collighan

Gross

et al. 2010

Journal of Biological Chemistry

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“…It acts to cross-link a wide variety of extracellular matrix proteins (28), it is up-regulated during wound healing (37)(38)(39)(40), and has been implicated in several steps of wound healing (39). Levels of active TG2 are up-regulated at the tumor-stroma interface (34).…”

Section: Gpr56 Is a Gpcr Implicated In Multiple Biologicalmentioning

confidence: 99%

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

Begum

Hearn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

254

297

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The survival and growth of tumor cells in a foreign environment is considered a rate-limiting step during metastasis. To identify genes that may be essential for this process, we isolated highly metastatic variants from a poorly metastatic human melanoma cell line and performed expression analyses of metastases and primary tumors from these cells. GPR56 is among the genes markedly downregulated in the metastatic variants. We show that overexpression of GPR56 suppresses tumor growth and metastasis, whereas reduced expression of GPR56 enhances tumor progression. Levels of GPR56 do not correlate with growth rate in vitro, suggesting that GPR56 may mediate growth suppression by interaction with a component in the tumor microenvironment in vivo. We show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. We discuss the mechanisms whereby GPR56-TG2 interactions may suppress tumor growth and metastasis. (ii) some of the detached cells enter the circulation via blood vessels or lymphatics (intravasation); (iii) a fraction of the cells in the circulation arrest and transmigrate through blood vessels or lymphatics and invade into a distant tissue or organ (extravasation); (iv) some of the invading cells survive and proliferate in the new environment as metastases. To produce any clinically relevant metastases, a tumor cell must complete all these steps.Abundant clinical and experimental data suggest that the survival and growth step (step iv) is a rate-limiting step during metastasis (1, 2). Frequently, tumor cells are able to enter the circulation and settle in many organs but are not able to proliferate or are only able to proliferate in certain organs. Experimental metastasis assays have been developed to study these steps of metastasis. In these assays, a pool of poorly metastatic tumor cells is injected into the circulation of immunodeficient mice and gives rise to metastases at low frequency. Cells in these rare metastases can be selected from the original pool as variants which, through genetic or epigenetic changes, have gained the ability to invade, survive, and grow in a foreign environment. When these cells are isolated and amplified in vitro, they largely maintain their enhanced metastatic potential. Genes involved in metastasis can then be identified by comparing the gene expression profiles between the highly metastatic variants and the poorly metastatic pool through microarray analyses. With this method, RhoC has previously been discovered to play important roles during melanoma metastasis to lung (3), and a five-gene signature has been discovered to be essential for breast cancer metastasis to bone (4).In this article, we report that a member of a newly described family of G protein-coupled receptors (GPCRs), GPR56, contributes to suppression of melanoma metastasis and tumor growth. This suppression is not cell-autonomous, because cells with altered levels of GPR56 grow at similar rates ...

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“…In addition, tTG is also associated with the immediate defense against injury or infections, as well as with the pathogenesis of several chronic inflammatory diseases, including RA and multiple sclerosis [19]. It is well established that tTG promotes wound healing [20,21] and regulates the extracellular matrix formation and mineralization [22,23]. Recently, the presence of increased levels of anti-tTG IgG and IgA Ab in the blood and synovial fluid of patients with RA has been reported [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Dzhambazov

Lindh

Engström³

et al. 2009

Eur J Immunol

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The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q 267 ) and modified (E 267 ) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.Key words: Collagen-induced arthritis . CII-peptide . Posttranslational modifications .T cells . Tissue transglutaminase IntroductionPosttranslational modifications of proteins are being recognized as increasingly important for the initiation and pathogenesis of autoimmune diseases. Such modifications could lead to breaking of the immunological tolerance to self proteins by creation of new epitopes within the target antigen. Rheumatoid arthritis (RA) is an autoimmune disease involving an inflammatory attack on peripheral cartilaginous joints characterized by leukocyte infiltration, secretion of inflammatory cytokines and auto-Ab, and subsequent cartilage destruction, irreversible bone erosion and joint deformation. Major candidate autoantigens in RA that are locally expressed in the joint are type II collagen (CII), fibrin, and proteoglycans. CII is of particular interest, since T-and B-cell autoimmune responses to this protein leads to collagen-induced arthritis (CIA) in mice [1], rats [2] and primates [3,4], which shares many phenotypic features with RA. The shared immunodominant T-cell epitope in CIA and RA has been identified as . Amino acids of this immunodominant core can be posttranslationally modified either by enzymatic processes or spontaneously. It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or 2412phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthri...

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Tissue transglutaminase in normal and abnormal wound healing: Review article

Cited by 160 publications

References 98 publications

RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

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