Tissue plasminogen activator is a potent activator of PDGF-CC.
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.
Fredriksson
Linda
L
Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden.
Li
Hong
H
Fieber
Christina
C
Li
Xuri
X
Eriksson
Ulf
U
D000818:Animals; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008222:Lymphokines; D051379:Mice / Q000196:embryology; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010958:Plasminogen / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000819:agonists; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous
D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D010958:Plasminogen; D020796:Receptor, Platelet-Derived Growth Factor alpha; D010959:Tissue Plasminogen Activator