1. Academic Validation
  2. BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1

BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1

  • Sci Signal. 2020 Jul 7;13(639):eaba3880. doi: 10.1126/scisignal.aba3880.
Cyril Anastasi 1 Patricia Rousselle 1 Maya Talantikite 1 Agnès Tessier 1 Caroline Cluzel 1 Alice Bachmann 1 Natacha Mariano 1 Mélissa Dussoyer 1 Lindsay B Alcaraz 2 Laëtitia Fortin 1 Alexandre Aubert 1 Frédéric Delolme 1 3 Naïma El Kholti 1 Jean Armengaud 4 Pierre Fournié 5 6 Céline Auxenfans 1 7 Ulrich Valcourt 1 2 Sandrine Vadon-Le Goff 1 Catherine Moali 8
Affiliations

Affiliations

  • 1 University of Lyon, CNRS UMR 5305, Tissue Biology and Therapeutic Engineering Laboratory (LBTI), F-69367 Lyon, France.
  • 2 University of Lyon, Centre Léon Bérard, INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), F-69373 Lyon, France.
  • 3 University of Lyon, ENS de Lyon, INSERM US8, CNRS UMS3444, SFR Biosciences, F-69366 Lyon, France.
  • 4 CEA Marcoule, Innovative Technologies for Detection and Diagnostics Laboratory (DRF/Joliot/DMTS/SPI/Li2D), F-30200 Bagnols-sur-Cèze, France.
  • 5 Purpan University Hospital, Ophthalmology Department, F-31059 Toulouse, France.
  • 6 University of Toulouse, CNRS UMR 5165, INSERM U1056, Epithelial Differentiation and Rheumatoid Autoimmunity Unit (UDEAR), F-31059 Toulouse, France.
  • 7 Hospices Civils de Lyon, Tissue and Cell Bank, F-69437 Lyon, France.
  • 8 University of Lyon, CNRS UMR 5305, Tissue Biology and Therapeutic Engineering Laboratory (LBTI), F-69367 Lyon, France. c.moali@ibcp.fr.
Abstract

Bone Morphogenetic Protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms by which BMP-1 exerts these effects are highly context dependent. Because BMP-1 overexpression induces marked phenotypic changes in two human cell lines (HT1080 and 293-EBNA cells), we investigated how BMP-1 simultaneously affects cell-matrix interactions and growth factor activity in these cells. Increasing BMP-1 led to a loss of cell adhesion that depended on the matricellular glycoprotein thrombospondin-1 (TSP-1). BMP-1 cleaved TSP-1 between the VWFC/procollagen-like domain and the type 1 repeats that mediate several key TSP-1 functions. This cleavage induced the release of TSP-1 C-terminal domains from the extracellular matrix and abolished its previously described multisite cooperative interactions with heparan sulfate proteoglycans and CD36 on HT1080 cells. In addition, BMP-1-dependent proteolysis potentiated the TSP-1-mediated activation of latent Transforming Growth Factor-β (TGF-β), leading to increased signaling through the canonical SMAD pathway. In primary human corneal stromal cells (keratocytes), endogenous BMP-1 cleaved TSP-1, and the addition of exogenous BMP-1 enhanced cleavage, but this had no substantial effect on cell adhesion. Instead, processed TSP-1 promoted the differentiation of keratocytes into myofibroblasts and stimulated production of the myofibroblast marker α-SMA, consistent with the presence of processed TSP-1 in human corneal scars. Our results indicate that BMP-1 can both trigger the disruption of cell adhesion and stimulate TGF-β signaling in TSP-1-rich microenvironments, which has important potential consequences for wound healing and tumor progression.

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