Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B

Nat Cell Biol. 2008 Jun;10(6):698-706. doi: 10.1038/ncb1732. Epub 2008 May 11.


Netrins, a family of secreted molecules, have critical functions in axon guidance and cell migration during neuronal development. In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor. Both UNC5 (that is, UNC5A, UNC5B, UNC5C or UNC5D) and DCC are transmembrane receptors for netrin-1 (Refs 8, 9). In the absence of netrin-1, DCC and UNC5 act as dependence receptors and trigger apoptosis. However, how netrin-1 suppresses the apoptotic activity of the receptors remains elusive. Here we show that netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L. This interaction triggers the activation of PtdIns-3-OH kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. Moreover, this process relies strongly on Fyn because PIKE-L is tyrosine phosphorylated in response to netrin-1, and the netrin-1-mediated interaction of UNC5B with PIKE-L is inhibited in Fyn-null mice. Thus, PIKE-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Membrane / metabolism
  • GTP Phosphohydrolases / genetics
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Nerve Growth Factors / physiology*
  • Nerve Tissue Proteins / genetics
  • Netrin Receptors
  • Netrin-1
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptors, Cell Surface / physiology*
  • Signal Transduction
  • Tumor Suppressor Proteins / physiology*
  • Tyrosine / chemistry
  • ras Proteins / metabolism*


  • GTPase-Activating Proteins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Unc5A protein, mouse
  • Unc5d protein, mouse
  • Netrin-1
  • Tyrosine
  • Proto-Oncogene Proteins c-fyn
  • AGAP2 protein, human
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • PIKE protein, mouse
  • ras Proteins