Tissue transglutaminase (TG2) - a wound response enzyme

Telci, Dilek; Griffin, Martin

doi:10.2741/1843

Cited by 115 publications

(96 citation statements)

References 98 publications

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“…TG2 is translocated to the plasma membrane and was subsequently deposited into the ECM via a non-classical secretory mechanism reportedly dependent on active site conformation and on an intact N-terminal ␤-sandwich domain (4, 5) as well as on its possible association with integrins (6). Deposition of the enzyme into the ECM after cell damage and stress is important in the remodeling and/or stabilization of the several ECM proteins, such as FN (7,8). FN is particularly interesting since TG2 binds to this ECM protein with high affinity promoting wideranging effects on cell-matrix interactions, including the regulation of cell adhesion and migration, matrix assembly, and adhesion-dependent signaling (6,7,9).…”

Section: Tissue Transglutaminase (Tg2)mentioning

confidence: 99%

“…Deposition of the enzyme into the ECM after cell damage and stress is important in the remodeling and/or stabilization of the several ECM proteins, such as FN (7,8). FN is particularly interesting since TG2 binds to this ECM protein with high affinity promoting wideranging effects on cell-matrix interactions, including the regulation of cell adhesion and migration, matrix assembly, and adhesion-dependent signaling (6,7,9).Cell adhesion to FN involves a series of coordinated signaling events orchestrated by numerous transmembrane receptors including the integrins and the superfamily of cell-surface proteoglycans (10, 11). The identity of the receptor-ligand pairing defines the composition of focal adhesions and the participants of intracellular signaling (10).…”

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confidence: 99%

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Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 Integrin Co-signaling

Telci

Wang

et al. 2008

Journal of Biological Chemistry

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Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase C␣ (PKC␣) and its subsequent interaction with ␤ 1 integrin since disruption of PKC␣ binding to ␤ 1 integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKC␣ leading to its association with ␤ 1 integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation. Tissue transglutaminase (TG2)2 belongs to a family of enzymes that in the presence of Ca 2ϩ catalyze the post-translational modification of proteins either by covalent cross-linking or through the incorporation of primary amines. TG2 has a GTP binding/hydrolysis site that negatively modulates the Ca 2ϩ -dependent transamidating activity of the enzyme by obstructing access to the active site (1). As a consequence, the enzyme is likely to be inactive under normal Ca 2ϩ homeostasis. TG2 localizes mainly in the cytoplasm, yet recent reports also suggest its presence in the nucleus, mitochondria, at the cell surface, and in the extracellular matrix (ECM) (1-3). TG2 is translocated to the plasma membrane and was subsequently deposited into the ECM via a non-classical secretory mechanism reportedly dependent on active site conformation and on an intact N-terminal ␤-sandwich domain (4, 5) as well as on its possible association with integrins (6). Deposition of the enzyme into the ECM after cell damage and stress is important in the remodeling and/or stabilization of the several ECM proteins, such as FN (7,8). FN is particularly interesting since TG2 binds to this ECM protein with high affinity promoting wideranging effects on cell-matrix interactions, including the regulation of cell adhesion and migration, matrix assembly, and adhesion-dependent signaling (6,7,9).Cell adhesion to FN involves a series of coordinated signaling events orchestrated by numerous transmembrane receptors including the integrins and the superfamily of cell-surface proteoglycans (10, 11). The identity of the receptor-ligand pairing defines the composition of f...

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Section: Tissue Transglutaminase (Tg2)mentioning

confidence: 99%

mentioning

confidence: 99%

Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 Integrin Co-signaling

Telci

Wang

et al. 2008

Journal of Biological Chemistry

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165

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“…In this paper, we have extended this work to explore the involvement of the RGD-independent adhesion mediated by TG-FN matrix in fibronectin matrix assembly, an event central to matrix remodeling and key to the process of many physiological and pathological situations where TG2 is found (26). We also explore the involvement of other cell surface receptors in addition to ␤1 integrin and syndecan-4, including syndecan-2 and ␣5, ␣4, and ␤3 integrins, in this process.…”

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confidence: 99%

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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“…In addition, TG2 can bind and hydrolyse GTP and displays protein disulphide isomerase activity as well as a protein kinase activity (Park et al 2010). Given the pleiotropic functions of this protein, TG2 has been implicated in a variety of events including the suppression of cell proliferation, cell differentiation, signal transduction, apoptosis, and wound healing (Fesus and Piacentini 2002;Telci and Griffin 2006). The role played by TG2 in the cell response to redox state imbalance has been reviewed by Caccamo et al (2012).…”

Section: Editorialmentioning

confidence: 99%

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

Agostinelli

2014

Amino Acids

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Tissue transglutaminase (TG2) - a wound response enzyme

Cited by 115 publications

References 98 publications

Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 Integrin Co-signaling

Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β1 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

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

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