Latent TGF-β Activation Is a Hallmark of the Tenascin Family

Abstract

Transforming growth factor-β (TGF-β) isoforms are secreted as inactive complexes formed through non-covalent interactions between bioactive TGF-β entities and their N-terminal pro-domains called latency-associated peptides (LAP). Extracellular activation of latent TGF-β within this complex is a crucial step in the regulation of TGF-β 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-β complex and triggered the activation of the latent cytokine into a bioactive TGF-β. This activation most likely occurs through a conformational change within the latent TGF-β 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-β bioavailability through their C-terminal domain. Here, we demonstrate that purified recombinant full-length Tenascins associate with the small latent TGF-β complex through their FBG-like domains. This association promotes activation of the latent cytokine and subsequent TGF-β cell responses in mammary epithelial cells, such as cytostasis and epithelial-to-mesenchymal transition (EMT). Considering the pleiotropic role of TGF-β 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.

COL1A1 expression induced by overexpression of both a 15‑amino acid peptide from the fibrinogen domain of tenascin‑X and integrin α11 in LX‑2 cells

“…In the present study, we identified a 15-aa peptide (referred to as hTNX-FGFFFF with an aa sequence of GGLRIPFPRDCGEEM) located at the N-terminal part of the TNX-FG domain as the minimum region responsible for the induction of COL1A1 expression. Interestingly, this minimum region in the TNX-FG domain was not overlapped with some residues in loop 9 in the TNX-FG domain reported by Aubert et al (43), indicating that the 15-aa peptide would fail to interact directly with LAP and mature TGF-β1. However, the fact that SB525334 weakly suppresses the induction of COL1A1 expression with overexpression of hTNX-FGFFFF and integrin α11β1 as shown in Fig.…”

The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation

“…It is comprised of 200 kDa hexamers and possesses 511 isoforms, since it contains nine splice variable Fn III domains in addition to the eight constant ones, and a C-terminal FBG-like domain ( 96 ). The FBG domains, highly conserved among the Tenascin family members (TNC, tenascin R, tenascin W, and tenascin X), can dock with TGF-β small latent complex and activate latent TGF-β ( 97 ). In addition to sharing domains that can be unfolded by cell forces with Fn, TNC can bind Fn directly ( 98 ).…”

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…As such, most of the TGF-β deposited in the extracellular space is inactive, although active TGF-β is observed in specific locations ( Barcellos-Hoff et al, 1994 ). Bioavailability of TGF-β is additionally regulated by TGF-β-binding proteins like fibromodulin and decorin which sequester TGF-β and prevent it from binding to specific TGF-β receptors ( Hinz, 2015 ; Khan and Marshall, 2016 ; Nastase et al, 2018 ; Aubert et al, 2021 ). Activation of latent TGF-β is a key step in the regulation of TGF-β-signaling activity.…”