Endocytosis-mediated Downregulation of LIN-12/Notch Upon Ras Activation in Caenorhabditis Elegans

Nature. 2002 Dec 12;420(6916):686-90. doi: 10.1038/nature01234.


The coordination of signals from different pathways is important for cell fate specification during animal development. Here, we define a novel mode of crosstalk between the epidermal growth factor receptor/Ras/mitogen-activated protein kinase cascade and the LIN-12/Notch pathway during Caenorhabditis elegans vulval development. Six vulval precursor cells (VPCs) are initially equivalent but adopt different fates as a result of an inductive signal mediated by the Ras pathway and a lateral signal mediated by the LIN-12/Notch pathway. One consequence of activating Ras is a reduction of LIN-12 protein in P6.p (ref. 2), the VPC believed to be the source of the lateral signal. Here we identify a 'downregulation targeting signal' (DTS) in the LIN-12 intracellular domain, which encompasses a di-leucine-containing endocytic sorting motif. The DTS seems to be required for internalization of LIN-12, and on Ras activation it might mediate altered endocytic routing of LIN-12, leading to downregulation. We also show that if LIN-12 is stabilized in P6.p, lateral signalling is compromised, indicating that LIN-12 downregulation is important in the appropriate specification of cell fates in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / cytology*
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins*
  • Cell Lineage
  • Down-Regulation*
  • Endocytosis*
  • Enzyme Activation
  • ErbB Receptors / metabolism
  • Female
  • Helminth Proteins / chemistry
  • Helminth Proteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Receptors, Notch
  • Signal Transduction*
  • Vulva / cytology
  • Vulva / embryology
  • Vulva / enzymology
  • Vulva / metabolism
  • ras Proteins / metabolism*


  • Caenorhabditis elegans Proteins
  • Helminth Proteins
  • Lin-12 protein, C elegans
  • Membrane Proteins
  • Receptors, Notch
  • ErbB Receptors
  • Mitogen-Activated Protein Kinases
  • ras Proteins