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

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.

• Authors: Cyril Anastasi, Patricia Rousselle, Maya Talantikite, Agnès Tessier, Caroline Cluzel, Alice Bachmann, Natacha Mariano, Mélissa Dussoyer, Lindsay B Alcaraz, Laëtitia Fortin, Alexandre Aubert, Frédéric Delolme, Naïma El Kholti, Jean Armengaud, Pierre Fournié, Céline Auxenfans, Ulrich Valcourt, Sandrine Vadon-Le Goff, Catherine Moali
• Journal: Science signaling (Sci Signal) Vol. 13 Issue 639 (07 07 2020) ISSN: 1937-9145 [Electronic] United States
• PMID: 32636307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Thrombospondin 1
• Transforming Growth Factor beta
• thrombospondin-1, human
• BMP1 protein, human
• Bone Morphogenetic Protein 1

Topics

• Animals
• Bone Morphogenetic Protein 1 (genetics, metabolism)
• Cell Adhesion
• Cell Line, Tumor
• Humans
• Proteolysis
• Thrombospondin 1 (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Xenopus laevis