Article

  • The EMBO Journal (2004) 23, 3793 - 3802
  • doi:10.1038/sj.emboj.7600397

Published online: 16 September 2004

Tissue plasminogen activator is a potent activator of PDGF-CC

Linda Fredriksson, Hong Li, Christina Fieber, Xuri Li and Ulf Eriksson

  1. Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden

Correspondence to:

Ulf Eriksson, Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, 171 77 Stockholm, Sweden. Tel.: +46 8 728 7109; Fax: +46 8 332812; E-mail: ueri@licr.ki.se

Received 8 April 2004; Accepted 12 August 2004


Tissue plasminogen activator (tPA) is a serine protease involved in the degradation of blood clots through the activation of plasminogen to plasmin. Here we report on the identification of tPA as a specific protease able to activate platelet-derived growth factor C (PDGF-C). The newly identified PDGF-C is secreted as a latent dimeric factor (PDGF-CC) that upon proteolytic removal of the N-terminal CUB domains becomes a PDGF receptor alpha agonist. The CUB domains in PDGF-CC directly interact with tPA, and fibroblasts from tPA-deficient mice fail to activate latent PDGF-CC. We further demonstrate that growth of primary fibroblasts in culture is dependent on a tPA-mediated cleavage of latent PDGF-CC, generating a growth stimulatory loop. Immunohistochemical analysis showed similar expression patterns of PDGF-C and tPA in developing mouse embryos and in tumors, indicating both autocrine and paracrine modes of activation of PDGF receptor-mediated signaling pathways. The identification of tPA as an activator of PDGF signaling establishes a novel role for the protease in normal and pathological tissue growth and maintenance, distinct from its well-known role in plasminogen activation and fibrinolysis.

  • Keywords:

    • activation,
    • CUB,
    • PDGF,
    • proteolysis,
    • tPA
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