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| Subject Categories: Signal Transduction | Differentiation & Death |
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| The EMBO Journal
(2004) 23, 3793–3802, doi:10.1038/sj.emboj.7600397 Published online 16 September 2004 |
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| Tissue plasminogen activator is a potent activator of PDGF-CC |
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| Linda Fredriksson, Hong Li, Christina Fieber, Xuri Li and Ulf Eriksson |
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Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden To whom correspondence should be addressed 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; Published online 16 September 2004. |
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| Abstract |
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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  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. |
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| Keywords: activation, CUB, PDGF, proteolysis, tPA |
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