A critical role for endocytosis in Wnt signaling

BMC Cell Biol. 2006 Jul 6;7:28. doi: 10.1186/1471-2121-7-28.

Abstract

Background: The Wnt signaling pathway regulates many processes during embryonic development, including axis specification, organogenesis, angiogenesis, and stem cell proliferation. Wnt signaling has also been implicated in a number of cancers, bone density maintenance, and neurological conditions during adulthood. While numerous Wnts, their cognate receptors of the Frizzled and Arrow/LRP5/6 families and downstream pathway components have been identified, little is known about the initial events occurring directly after receptor activation.

Results: We show here that Wnt proteins are rapidly endocytosed by a clathrin- and dynamin-mediated process. While endocytosis has traditionally been considered a principal mechanism for receptor down-regulation and termination of signaling pathways, we demonstrate that interfering with clathrin-mediated endocytosis actually blocks Wnt signaling at the level of beta-catenin accumulation and target gene expression.

Conclusion: A necessary component of Wnt signaling occurs in a subcellular compartment distinct from the plasma membrane. Moreover, as internalized Wnts transit partially through the transferrin recycling pathway, it is possible that a "signaling endosome" serves as a nexus for activated Wnt pathway components.

Publication types

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

MeSH terms

  • Animals
  • Cadaverine / analogs & derivatives
  • Cadaverine / pharmacology
  • Chlorpromazine / pharmacology
  • Clathrin / antagonists & inhibitors
  • Clathrin / genetics
  • Clathrin / physiology
  • Clathrin-Coated Vesicles / physiology
  • Culture Media, Conditioned / pharmacology
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology
  • Dynamins / genetics
  • Dynamins / physiology
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Gene Expression Regulation
  • Genes, Reporter
  • L Cells / metabolism
  • Mice
  • Mutation, Missense
  • Point Mutation
  • Proto-Oncogene Proteins / physiology*
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / physiology*
  • Sucrose / pharmacology
  • Transfection
  • Wnt Proteins / physiology*
  • Wnt1 Protein
  • Wnt3 Protein
  • beta Catenin / metabolism

Substances

  • Clathrin
  • Culture Media, Conditioned
  • Drosophila Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt3 Protein
  • beta Catenin
  • wg protein, Drosophila
  • Sucrose
  • Dynamins
  • monodansylcadaverine
  • Cadaverine
  • Chlorpromazine