Dissecting the interaction between transglutaminase 2 and fibronectin

Cardoso, Inês; Østerlund, Eva Christina; Stamnæs, Jorunn; Iversen, Rasmus; Andersen, Jan Terje; Jørgensen, Thomas J. D.; Sollid, Ludvig M.

doi:10.1007/s00726-016-2296-y

Cited by 26 publications

(48 citation statements)

References 47 publications

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“…Previous studies identified the β hairpin loop as the FN-binding region (amino acids 88–106) (7). However, more recent analyses using hydrogen/deuterium exchange and mass spectrometry point to residues K30, R116, and H134 in the N-terminus as being critical to forming a complex with the 42 kDa gelatin-binding domain of FN (8). On the surface of cells, the complex between TG2 and FN is further supported and stabilized by direct interactions of both proteins with integrins, the major receptors involved in cellular adhesion to the ECM.…”

Section: Introductionmentioning

confidence: 99%

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

et al. 2018

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Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.

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Section: Introductionmentioning

confidence: 99%

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

et al. 2018

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“…We also tested a chimeric variant of TG2 where the entire TG2 N‐terminal domain is exchanged with the corresponding amino acid residues of TG3 . This protein no longer binds FN and is not recognized by the celiac mAbs targeting any of the four major epitopes . Importantly, both these proteins showed comparable binding to the small intestinal tissue ECM as observed for full‐length WT TG2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transglutaminase 2 strongly binds to an extracellular matrix component other than fibronectin via its second C‐terminal beta‐barrel domain

et al. 2016

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Transglutaminase 2 (TG2) is a ubiquitous crosslinking enzyme present in both intra-and extracellular in many cell types and tissues. TG2 is upregulated upon cellular stress or injury, and extracellular TG2 is implicated in several human diseases, including celiac disease. However, incomplete knowledge about extracellular TG2 biology limits our understanding of how TG2 is involved in disease. Here, we demonstrate that binding of TG2 to the ECM of small intestinal tissue sections is the sum of binding to fibronectin (FN) via its N-terminal domain and binding to an abundant, novel extracellular matrix (ECM) interaction partner via its second C-terminal beta-barrel domain. The latter interaction dominates and gives rise to the characteristic reticular staining pattern of extracellular TG2. Of relevance for celiac disease, we show that self-multimerized TG2 does not efficiently deposit in the intestinal ECM, and TG2 complexes may thus become free-floating antigens in tissues in contrast to monomeric TG2 that would readily become sequestered by the ECM. Upon injection of monoclonal antibody targeting the FNbinding site, we observe antibody deposition on extracellular TG2 in cryosections, suggesting that the FN-binding site of TG2 is exposed in vivo. This would explain how and why celiac autoantibodies recognizing the FNbinding site of TG2 can bind TG2 in vitro, in situ as well as in vivo.

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“…The above models clearly point to the TG2 interaction region reported by Cardoso et al (32), and we therefore ran a second set of simulations, with Haddock (https://haddock.science.uu.nl/) (49), driven by the experimental information. For the docking simulations with Haddock, the TG2 open conformation was used vs. the same fibronectin fragment used above (residues 516-602, PDB ID: 3GXE).…”

Section: Docking Simulationsmentioning

confidence: 96%

“…From this set of results, we filtered out all the solutions that did not match the previously reported (15,32,47) and current experimental data. Toward this goal, we analyzed the interface of the models and selected for further analyses only models featuring more than 50 interatomic contacts (using a cutoff of 5Å) between the N-terminal region of TG2 (residues 1-230) and the FN I 8 module.…”

Section: Docking Simulationsmentioning

confidence: 99%

“…However, the finding that it maps within the N-terminal 28-kDa proteolytic fragment of the molecule (28,29) in a hairpin structure protruding from its surface and extending from aa 88 to 106 led to the design and testing of small molecules with promising, although suboptimal, effects in vitro (30). More recent work has indicated that residues outside the TG2 N-terminal domain can also participate in FN binding (31,32), thus making the precise definition of the TG2 residues involved in the interaction an open question.…”

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confidence: 99%

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Mapping the minimum domain of the fibronectin binding site on transglutaminase 2 (TG2) and its importance in mediating signaling, adhesion, and migration in TG2‐expressing cells

et al. 2018

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The interaction between the enzyme transglutaminase 2 (TG2) and fibronectin (FN) is involved in the cell‐matrix interactions that regulate cell signaling, adhesion, and migration and play central roles in pathologic conditions, particularly fibrosis and cancer. A precise definition of the exact interaction domains on both proteins could provide a tool to design novel molecules with potential therapeutic applications. Although specific residues involved in the interaction within TG2 have been analyzed, little is known regarding the TG2 binding site on FN. This site has been mapped to a large internal 45‐kDa protein fragment coincident with the gelatin binding domain (GBD). With the goal of defining the minimal FN interacting domain for TG2, we produced several expression constructs encoding different portions or modules of the GBD and tested their binding and functional properties. The results demonstrate that the I8 module is necessary and sufficient for TG2‐binding in vitro, but does not have functional effects on TG2‐expressing cells. Modules I7 and I9 increase the strength of the binding and are required for cell adhesion. A 15‐kDa fragment encompassing modules I7–9 behaves as the whole 45‐kDa GBD and mediates signaling, adhesion, spreading, and migration of TG2+ cells. This study provides new insights into the mechanism for TG2 binding to FN.—Soluri, M. F., Boccafoschi, F., Cotella, D., Moro, L., Forestieri, G., Autiero, I., Cavallo, L., Oliva, R., Griffin, M., Wang, Z., Santoro, C., Sblattero, D. Mapping the minimum domain of the fibronectin binding site on transglutaminase 2 (TG2) and its importance in mediating signaling, adhesion, and migration in TG2‐expressing cells. FASEB J. 33, 2327–2342 (2019). http://www.fasebj.org

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Dissecting the interaction between transglutaminase 2 and fibronectin

Cited by 26 publications

References 47 publications

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Transglutaminase 2 strongly binds to an extracellular matrix component other than fibronectin via its second C‐terminal beta‐barrel domain

Mapping the minimum domain of the fibronectin binding site on transglutaminase 2 (TG2) and its importance in mediating signaling, adhesion, and migration in TG2‐expressing cells

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