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The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R

  1. Author:
    Resnati, M.
    Pallavicini, I.
    Wang, J. M.
    Oppenheim, J.
    Serhan, C. N.
    Romano, M.
    Blasi, F.

  2. Author Address

    San Raffaele Sci Inst, DIBIT, Dept Cell Biol & Funct Genom, Mol Genet Unit, Via Olgettina 58, I-20132 Milan, Italy. San Raffaele Sci Inst, DIBIT, Dept Cell Biol & Funct Genom, Mol Genet Unit, I-20132 Milan, Italy. Univ Vita Salute San Raffaele, I-20132 Milan, Italy. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Univ Messina, Dept Human Pathol, I-98125 Messina, Italy. Blasi F San Raffaele Sci Inst, DIBIT, Dept Cell Biol & Funct Genom, Mol Genet Unit, Via Olgettina 58, I-20132 Milan, Italy.
    1. Year: 2002
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 99
    2. 3
    3. Pages: 1359-1364
  4. Type of Article: Article
  1. Abstract:

    The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D3(88-274)) to induce chemotaxis, In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D3(88-274)- induced cell migration. (R) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D388-274 in THP-1 cells and human peripheral blood monocytes. (M) Desensitization of FPRL1/ LXA4R prevents the activation of tyrosine kinase Hck induced by D2D3(88-274). (iv) D2D3(88-274) directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor.

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