The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling

EMBO J. 2000 Sep 15;19(18):4944-54. doi: 10.1093/emboj/19.18.4944.

Abstract

Frizzled receptors are components of the Wnt signalling pathway, but how they activate the canonical Wnt/beta-catenin pathway is not clear. Here we use three distinct vertebrate frizzled receptors (Xfz3, Xfz4 and Xfz7) and describe whether and how their C-terminal cytoplasmic regions transduce the Wnt/beta-catenin signal. We show that Xfz3 activates this pathway in the absence of exogenous ligands, while Xfz4 and Xfz7 interact with Xwnt5A to activate this pathway. Analysis using chimeric receptors reveals that their C-terminal cytoplasmic regions are functionally equivalent in Wnt/beta-catenin signalling. Furthermore, a conserved motif (Lys-Thr-X-X-X-Trp) located two amino acids after the seventh transmembrane domain is required for activation of the Wnt/beta-catenin pathway and for membrane relocalization and phosphorylation of Dishevelled. Frizzled receptors with point mutations affecting either of the three conserved residues are defective in Wnt/beta-catenin signalling. These findings provide functional evidence supporting a role of this conserved motif in the modulation of Wnt signalling. They are consistent with the genetic features exhibited by Drosophila Dfz3 and Caenorhabditis elegans mom-5 in which the tryptophan is substituted by a tyrosine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Caenorhabditis elegans
  • Cell Membrane / metabolism
  • Cytoplasm / chemistry*
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism*
  • DNA, Complementary / metabolism
  • Dishevelled Proteins
  • Drosophila
  • Drosophila Proteins
  • Embryo, Nonmammalian / metabolism
  • Frizzled Receptors
  • In Situ Hybridization
  • Ligands
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Plasmids / metabolism
  • Point Mutation
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Time Factors
  • Trans-Activators*
  • Wnt Proteins
  • Xenopus
  • Xenopus Proteins*
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, Xenopus
  • Cytoskeletal Proteins
  • DNA, Complementary
  • Dishevelled Proteins
  • Drosophila Proteins
  • FZD3 protein, Xenopus
  • Frizzled Receptors
  • Fzd4 protein, Xenopus
  • Fzd7 protein, Xenopus
  • Ligands
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • Wnt Proteins
  • Xenopus Proteins
  • Zebrafish Proteins
  • beta Catenin
  • dsh protein, Drosophila