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Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Oncogene volume 24, pages 6925–6935 (2005)Cite this article

Abstract

Platelet-derived growth factor-B (PDGF-B) is important for normal tissue growth and maintenance and its overexpression has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Here, we show that synthesized as a precursor, proPDGF-B is converted to a mature form by proteolytic cleavage at two sites and its N-terminal cleavage is a prerequisite for processing at its C-terminus. The first cleavage occurs at residues RGRR81↓, and the second cleavage close to residues ARPVT190, just before the C-terminal amino-acid sequence crucial for PDGF-B retention to cell surface. Cotransfection of a Furin-deficient cell line LoVo-C5 with proPDGF-B and different PC members revealed that Furin, PACE4, PC5, and PC7 are candidate proPDGF-B convertases. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of proPDGF-B. The processing of proPDGF-B is blocked by site-directed mutagenesis of the RGRR81↓ sequence and by various PC inhibitors. Mutation of the PDGF-A and/or PDGF-B convertase sites, revealed that processing of both A and B chains is required for the formation of mature PDGF-B dimers and that the processing of the B chain controls the level of secreted and matrix-bound PDGF-BB forms. Our findings emphasize the importance of the convertase-directed processing of proPDGF-B at the RGRR81↓ sequence for PDGF-B maturation and secretion.

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Acknowledgements

This work was supported by the grant from the Ottawa Health Research Institute start-up fund, CIHR Grant# MOP69021, Fondation pour la Recherche Médicale and Avenir Award, Paris, France.

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Authors and Affiliations

  1. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, H2W 1R7, Quebec, Canada

    Geraldine Siegfried, Suzanne Benjannet & Nabil Seidah

  2. Regional Protein Chemistry Centre, Diseases of Ageing Unit, Ottawa Health Research Institute, Loeb Building, 725 Parkdale Ave., Ottawa, K1Y 4E9, Ontario, Canada

    Ajoy Basak, Wendy Prichett-Pejic, Nathalie Scamuffa, Liming Ma, John P Veinot & Abdel-Majid Khatib

  3. Laboratoire de Pharmacologie Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale INSERM U 716, Institut de Génétique Moléculaire, Paris, France

    Fabien Calvo & Abdel-Majid Khatib

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  1. Geraldine Siegfried
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Correspondence to Abdel-Majid Khatib.

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Siegfried, G., Basak, A., Prichett-Pejic, W. et al. Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene 24, 6925–6935 (2005). https://doi.org/10.1038/sj.onc.1208838

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