Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β

Abstract

The matrix glycoprotein tenascin-X regulates the bioavailability of mature TGF-β through an α11β1 integrin–dependent mechanism that promotes epithelial-to-mesenchymal transition.

Tenascin-X: beyond the architectural function

“…83 We recently demonstrated that full-length TN-X interacted with the latent LAP ¢ TGF-b complex in vitro and in vivo. 66 This interaction resides in the C-terminal FBG-like domain of TN-X. More importantly, we found that the FBG-like domain of TN-X was able to activate the latent TGF-b in different cell types in order to induce a TGF-b/Smad intracellular signal.…”

“…1A and 3): (i) a conformational heparin-binding site comprising 2 FNIII modules (FNIII b10 and b11 domains) being a natural ligand for heparan-sulfate proteoglycan receptors 65 ; (ii) a cryptic RGD-containing cell adhesion site located between the contiguous FNIII b9 and b10 domains being a ligand for the avb3 integrin 61 ; and (iii) the C-terminal FBG-like domain, which is the major cell adhesion site of the whole molecule and involves the a11b1 integrin receptor. 61,66 The next challenge will be to determine the involvement of those receptors, and their corresponding binding sites, in the anti-adhesive properties of TN-X.…”

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

“…TSP-1 can also transactivate EGFR and is involved in the regulation of VEGF, FGF, and PDGF signalling (12). Tenascin-X was also recently identified as an activator of TGFβ (13). SPARC similarly regulates signalling by a number of growth factors, both directly and indirectly, including TGFβ, VEGF, PDGF, FGF and HGF (14,15).…”

Tenascins in fibrotic disorders—from bench to bedside

“…Activation of TGF-b might involve either various cell surface receptors, such as RGD-dependent integrins, or the ECM protein thrombospondin 1. 27 Alcaraz and colleagues have shown that tenascin X activates the latent TGF-b into an active molecule, most likely through a conformational change in the latent complex. Authors demonstrated that fibrinogen-like (FBG) domain of tenascin X physically interacts with the small latent TGF-b complex in vitro and in vivo and is crucial for the cytokine activation.…”

“…Moreover, a11b1 integrin has been identify as a cell surface receptor for tenascin X. 27 Active TGF-b transduces its signal from cell surface to nucleus via the canonical Smad-dependent pathway or the noncanonical pathways including the MAP kinase pathway or PI3K/ Akt/PKB kinase pathway. Upon TGF-b binding active receptor I and II complex is formed on the cell surface and phosphorylates the serine residues at SSXS motif of cytoplasmic Smad2 and Smad3.…”