Regulation of Cell Surface Tissue Transglutaminase: Effects on Matrix Storage of Latent Transforming Growth Factor-β Binding Protein-1

Verderio, Elisabetta; Gaudry, Claire A.; Gross, Stephane R.; Smith, Colin G.; Downes, S.; Griffin, Martin

doi:10.1177/002215549904701108

Cited by 97 publications

(96 citation statements)

References 39 publications

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“…Cell surface TG2 involvement in fibronectin deposition in an integrin-dependent but transamidating-independent manner has been reported previously (46). In contrast, in other reports (47,48), the cross-linking activity of TG2 was also reported to be required in FN assembly and deposition. We therefore first ruled out that the mechanism used by fibronectin matrixbound TG2 for both cell adhesion and FN fibril formation was different from that used by cell surface TG2 (46) by demonstrating that MEF cells overexpressing cell surface TG2 were unable to compensate for RGD-mediated loss of cell adhesion.…”

Section: Discussionmentioning

confidence: 59%

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: 59%

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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“…We have recently reported that tTg requires an intact fibronectin binding site for it to achieve its cell surface localization (Gaudry et al, 1999a). We have also demonstrated a close association of tTg and fibronectin with the latent TGF-␤1 binding protein at the surface of cells (Verderio et al, 1999). Changes in fibronectin secretion and deposition, therefore, could be important in determining the extracellular localization of the enzyme, which, in turn, is coupled to the storage and activation of TGF-␤1 in the diseased kidney, especially because an increase in renal fibronectin content is a key feature of progressive DN (Murphy et al, 1999).…”

Section: Skill Et Almentioning

confidence: 68%

“…It is quite conceivable that tTg can cause excess deposition of ECM components because it has been shown in vitro to cause fibril formation in the absence of lysyl oxidase (Kleman et al, 1995;Johnson et al, 1999), and when overexpressed in fibroblasts causes increased deposition of fibronectin and latent TGF-␤1 (Verderio et al, 1999). Moreover, we have previously shown in vitro that tTg cross-linking can interfere with matrix metalloproteinase action on collagen fibril formation, stabilizing the collagen fibril to degradation .…”

Section: Skill Et Almentioning

confidence: 91%

“…Second, extracellular cross-linking of the ECM; fibronectin (Lorand et al, 1988), collagens I, III, IV (Bowness et al, 1987), and IX (Kleman et al, 1995), laminin, and nidogen (Aeschlimann and Paulsson, 1991) are tTg substrates. Such cross-linking of the ECM components could contribute to increased ECM deposition given the ability of tTg to crosslink collagen fibrils (even in the absence of lysyl oxidase) (Kleman et al, 1995) and also stabilize the ECM by conferring a resistance to proteolytic enzymes Verderio et al, 1999). Finally, the requirement of tTg for the matrix storage (Verderio et al, 1999) and subsequent activation of the profibrogenic growth factor TGF-␤1 could potentiate disease progression (Nunes et al, 1997).…”

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confidence: 99%

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Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

Skill

Griffin

Nahas

et al. 2001

Laboratory Investigation

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SUMMARY:Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, ⑀-(␥-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney ⑀-(␥-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (ϩ337%) and peaked at Day 120 (ϩ650%) (p Ͻ 0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p Ͻ 0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular ⑀-(␥-glutamyl) lysine (ϩ361%); however, in the glomeruli this was associated with increases in Tg activity (ϩ228%) and tTg antigen by Western blotting (ϩ215%). Importantly, the ratio of glomerular ⑀-(␥-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca 2ϩ and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN. (Lab Invest 2001, 81:705-716).

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“…Levels of active TG2 are up-regulated at the tumor-stroma interface (34). TG2 promotes incorporation of TGF␤ into matrix and its activation (41) and is, itself, up-regulated by TGF␤ (42). TGF␤ also up-regulates levels of extracellular matrix and integrins (43), and TGF␤ is a well known suppressor of tumor growth and progression (44).…”

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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Regulation of Cell Surface Tissue Transglutaminase: Effects on Matrix Storage of Latent Transforming Growth Factor-β Binding Protein-1

Cited by 97 publications

References 39 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

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

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

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