Latent Tgf-Beta Activation Is A Hallmark Of The Tenascin Family

Transforming growth factor-beta (TGF-beta) isoforms are secreted as inactive complexes formed through non-covalent interactions between bioactive TGF-beta entities and their N-terminal pro-domains called latency-associated peptides (LAP). Extracellular activation of latent TGF-beta within this complex is a crucial step in the regulation of TGF-beta activity for tissue homeostasis and immune cell function. We previously showed that the matrix glycoprotein Tenascin-X (TN-X) interacted with the small latent TGF-beta complex and triggered the activation of the latent cytokine into a bioactive TGF-beta. This activation most likely occurs through a conformational change within the latent TGF-beta complex and requires the C-terminal fibrinogen-like (FBG) domain of the glycoprotein. As the FBG-like domain is highly conserved among the Tenascin family members, we hypothesized that Tenascin-C (TN-C), Tenascin-R (TN-R) and Tenascin-W (TN-W) might share with TN-X the ability to regulate TGF-beta bioavailability through their C-terminal domain. Here, we demonstrate that purified recombinant full-length Tenascins associate with the small latent TGF-beta complex through their FBG-like domains. This association promotes activation of the latent cytokine and subsequent TGF-beta cell responses in mammary epithelial cells, such as cytostasis and epithelial-to-mesenchymal transition (EMT). Considering the pleiotropic role of TGF-beta in numerous physiological and pathological contexts, our data indicate a novel common function for the Tenascin family in the regulation of tissue homeostasis under healthy and pathological conditions.