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PDGF-D is a specific, protease-activated ligand for the PDGF β-receptor

Nature Cell Biology volume 3, pages 512–516 (2001)Cite this article

Abstract

The term 'platelet-derived growth factor' (PDGF) refers to a family of disulphide-bonded dimeric isoforms that are important for growth, survival and function in several types of connective tissue cell. So far, three different PDGF chains have been identified — the classical PDGF-A and PDGF-B1,2 and the recently identified PDGF-C3. PDGF isoforms (PDGF-AA, AB, BB and CC) exert their cellular effects by differential binding to two receptor tyrosine kinases. The PDGF α-receptor (PDGFR-α) binds to all three PDGF chains, whereas the β-receptor (PDGFR-β) binds only to PDGF-B1. Gene-targeting studies using mice have shown that the genes for PDGF-A and PDGF-B, as well as the two PDGFR genes, are essential for normal development4. Furthermore, overexpression of PDGFs is linked to different pathological conditions, including malignancies, atherosclerosis and fibroproliferative diseases1. Here we have identify and characterize a fourth member of the PDGF family, PDGF-D. PDGF-D has a two-domain structure similar to PDGF-C3 and is secreted as a disulphide-linked homodimer, PDGF-DD. Upon limited proteolysis, PDGF-DD is activated and becomes a specific agonistic ligand for PDGFR-β . PDGF-DD is the first known PDGFR-β-specific ligand, and its unique receptor specificity indicates that it may be important for development and pathophysiology in several organs.

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Figure 1: Amino–acid sequence of human PDGF-D.
Figure 2: Recombinant expression, in vitro and in vivo processing, and receptor analysis of PDGF-DD.
Figure 3: Expression of PDGF-D in adult and embryonic tissues.

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Acknowledgements

We thank B. Åkerblom, C. Raynoschek, T. Tainola and G. Bäckström for technical assistance, U. Engström for synthesizing peptides, M. Hansson for help with production of recombinant proteins, A. Pontén and K. Aase for discussions, and C. Betsholtz for comments on the manuscript. This work was supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Finnish Academy of Sciences and the Novo Nordisk Foundation.

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  1. Erika Bergsten and Marko Uutela: These authors contributed equally to this work

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Stockholm Branch, PO Box 240, Stockholm, S-171 77, Sweden

    Erika Bergsten, Xuri Li & Ulf Eriksson

  2. Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, PO Box 21, (Haartmaninkatu 3), SF-00014, Helsinki, Finland

    Marko Uutela & Kari Alitalo

  3. Ludwig Institute for Cancer Research, Uppsala Branch, PO Box 595, Uppsala, S-751 24, Sweden

    Kristian Pietras, Arne Östman & Carl-Henrik Heldin

Authors
  1. Erika Bergsten
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  2. Marko Uutela
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  8. Ulf Eriksson
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Correspondence to Ulf Eriksson.

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Bergsten, E., Uutela, M., Li, X. et al. PDGF-D is a specific, protease-activated ligand for the PDGF β-receptor. Nat Cell Biol 3, 512–516 (2001). https://doi.org/10.1038/35074588

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