A critical role for endocytosis in Wnt signaling.
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.


CONCLUSIONS
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.
Blitzer
Jeremy T
JT
Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. jblitzer@stanford.edu
Nusse
Roel
R
D000818:Animals; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D002966:Clathrin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D022163:Clathrin-Coated Vesicles / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D034281:Dynamins / Q000235:genetics / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007739:L Cells / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013395:Sucrose / Q000494:pharmacology; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology*; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D051176:beta Catenin / Q000378:metabolism
D002966:Clathrin; D017077:Culture Media, Conditioned; D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D051176:beta Catenin; C074622:wg protein, Drosophila; D013395:Sucrose; D034281:Dynamins; C008542:monodansylcadaverine; D002103:Cadaverine; D002746:Chlorpromazine