title: Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β.
abstract: Transforming growth factor β (TGF-β) isoforms are secreted as inactive complexes formed through noncovalent interactions between the bioactive TGF-β entity and its N-terminal latency-associated peptide prodomain. Extracellular activation of the latent TGF-β complex is a crucial step in the regulation of TGF-β function for tissue homeostasis. We show that the fibrinogen-like (FBG) domain of the matrix glycoprotein tenascin-X (TNX) interacts physically with the small latent TGF-β complex in vitro and in vivo, thus regulating the bioavailability of mature TGF-β to cells by activating the latent cytokine into an active molecule. Activation by the FBG domain most likely occurs through a conformational change in the latent complex and involves a novel cell adhesion-dependent mechanism. We identify α11β1 integrin as a cell surface receptor for TNX and show that this integrin is crucial to elicit FBG-mediated activation of latent TGF-β and subsequent epithelial-to-mesenchymal transition in mammary epithelial cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Alcaraz
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Exposito
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chuvin
authors.forename: Roxane M
authors.initials: RM
authors.lastname: Pommier
authors.forename: Caroline
authors.initials: C
authors.lastname: Cluzel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Martel
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sentis
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.forename: Claire
authors.initials: C
authors.lastname: Lethias
authors.forename: Ulrich
authors.initials: U
authors.lastname: Valcourt
mesh_terms: D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D038981:Receptors, Collagen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D011498:Protein Precursors; D038981:Receptors, Collagen; D011994:Recombinant Proteins; D051785:Smad Proteins; D019063:Tenascin; D053773:Transforming Growth Factor beta1; C467800:integrin alpha11beta1; C081865:tenascin X