Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance

DOI PDF 被引用文献3件
  • Mayya Meriane
    1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2
  • Joseph Tcherkezian
    1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2
  • Christine A. Webber
    2Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada T2N 4N1
  • Eric I. Danek
    1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2
  • Ibtissem Triki
    1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2
  • Sarah McFarlane
    2Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada T2N 4N1
  • Evelyne Bloch-Gallego
    3Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM U 567, CNRS UMR 8104, 75014 Paris Cedex 05, France
  • Nathalie Lamarche-Vane
    1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2

説明

<jats:p>Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1–DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1–dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1–dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1–induced axon outgrowth are impaired in Fyn−/− CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.</jats:p>

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