Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator

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Abstract

Platelet-derived growth factor C (PDGF-C) is one of four members in the PDGF family of growth factors, which are known mitogens and survival factors for cells of mesenchymal origin. PDGF-C has a unique two-domain structure consisting of an N-terminal CUB and a conserved C-terminal growth factor domain that are separated by a hinge region. PDGF-C is secreted as a latent dimeric factor (PDGF-CC), which undergoes ex-tracellular removal of the CUB domains to become a PDGF receptor ␣ agonist. Recently, the multidomain serine protease tissue plasminogen activator (tPA), a thrombolytic agent used for treatment of acute ischemic stroke, was shown to cleave and activate PDGF-CC. In this study we determine the molecular mechanism of tPA-mediated activation of PDGF-CC. Using various PDGF-CC and tPA mutants, we were able to demon-strate that both the CUB and the growth factor domains of PDGF-C, as well as the kringle-2 domain of tPA, are required for the interaction and cleavage to occur. We also show that Arg 231 in PDGF-C is essential for tPA-mediated proteolysis and that the released " free " CUB domain of PDGF-C can act as a competitive inhibitor of the cleavage reaction. Furthermore, we studied how the PDGF-C/tPA axis is regulated in primary fibro-blasts and found that PDGF-C expression is down-regulated by hypoxia but induced by transforming growth factor (TGF)-␤ 1 treatment. Elucidating the reg-ulation and the mechanism of tPA-mediated activation of PDGF-CC will advance our knowledge of the physio-logical function of PDGF-CC and tPA and may provide new therapeutic opportunities for thrombolytic and cardiovascular therapies.

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Fredriksson, L., Ehnman, M., Fieber, C., & Eriksson, U. (2005). Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator. Journal of Biological Chemistry, 280(29), 26856–26862. https://doi.org/10.1074/jbc.M503388200

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