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Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics

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Abstract

The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi:10.6019/PXD000786.

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Abbreviations

BG:

Betaglycan

BMP:

Bone Morphogenetic Protein

BSA:

Bovine Serum Albumin

BTP:

BMP-1/Tolloid-like Proteinase

DTT:

Dithiothreitol

ECM:

Extracellular Matrix

GAG:

Glycosaminoglycan

mTLD:

Mammalian Tolloid

mTLL-1:

Mammalian Tolloid-like 1

SDS-PAGE:

Sodium Dodecyl Sulfate Poly-Acrylamide Gel Electrophoresis

TGF-β:

Transforming Growth Factor-β

ZP:

Zona Pellucida

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Acknowledgments

We thank Walter Stöcker for the pIRESneo2-BMP-1 construct, Larry W. Fisher for the LF-41 antibody and Fibrogen Inc for the yeast cells expressing procollagen I. The work was funded by the Consejo Nacional de Ciencia y Tecnologia of Mexico (SALUD-2010-1-142121 to F.L.C.), the Agence Nationale de la Recherche (ANR 07 PHYSIO 022 01 to C.M. and D.J.S.H), the Région Rhône-Alpes (to C.M. and M.T.), the Canadian Institutes of Health Research (to C.M.O.), the Ligue Nationale contre le Cancer (to L.B.A.), the Université Lyon I and the Centre National de la Recherche Scientifique.

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Authors and Affiliations

  1. UMR 5305, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, CNRS/Université de Lyon, 69367, Lyon, France

    Frédéric Delolme, Cyril Anastasi, Sandrine Vadon-Le Goff, Maya Talantikite, Robin Capomaccio, Jimmy Mevaere, Laëtitia Fortin, Odile Damour, David J. S. Hulmes & Catherine Moali

  2. Centre Commun de Microanalyse des Protéines, UMS 3444, Institut de Biologie et Chimie des Protéines, 69367, Lyon, France

    Frédéric Delolme, Dominique Mazzocut & Isabelle Zanella-Cléon

  3. INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon, Centre Léon Bérard, 69373, Lyon, France

    Lindsay B. Alcaraz & Ulrich Valcourt

  4. Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, 04510, Mexico, Mexico

    Valentin Mendoza & Fernando Lopez-Casillas

  5. Banque de Tissus et Cellules, Hospices Civils de Lyon, 69437, Lyon, France

    Odile Damour

  6. Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

    Christopher M. Overall

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  1. Frédéric Delolme
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  2. Cyril Anastasi
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  16. Fernando Lopez-Casillas
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  17. Catherine Moali
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Correspondence to Catherine Moali.

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F. Delolme, C. Anastasi and L. B. Alcaraz contributed equally to the work.

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Delolme, F., Anastasi, C., Alcaraz, L.B. et al. Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics. Cell. Mol. Life Sci. 72, 1009–1027 (2015). https://doi.org/10.1007/s00018-014-1733-x

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