LDL-receptor-related protein 6 is a receptor for Dickkopf proteins

Nature. 2001 May 17;411(6835):321-5. doi: 10.1038/35077108.

Abstract

Wnt glycoproteins have been implicated in diverse processes during embryonic patterning in metazoa. They signal through frizzled-type seven-transmembrane-domain receptors to stabilize beta-catenin. Wnt signalling is antagonized by the extracellular Wnt inhibitor dickkopf1 (dkk1), which is a member of a multigene family. dkk1 was initially identified as a head inducer in Xenopus embryos but the mechanism by which it blocks Wnt signalling is unknown. LDL-receptor-related protein 6 (LRP6) is required during Wnt/beta-catenin signalling in Drosophila, Xenopus and mouse, possibly acting as a co-receptor for Wnt. Here we show that LRP6 (ref. 7) is a specific, high-affinity receptor for Dkk1 and Dkk2. Dkk1 blocks LRP6-mediated Wnt/beta-catenin signalling by interacting with domains that are distinct from those required for Wnt/Frizzled interaction. dkk1 and LRP6 interact antagonistically during embryonic head induction in Xenopus where LRP6 promotes the posteriorizing role of Wnt/beta-catenin signalling. Thus, DKKs inhibit Wnt co-receptor function, exemplifying the modulation of LRP signalling by antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Chemokines
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism
  • Embryonic Induction
  • Head / embryology
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / antagonists & inhibitors
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, LDL / antagonists & inhibitors
  • Receptors, LDL / chemistry
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Sequence Deletion / genetics
  • Signal Transduction
  • Substrate Specificity
  • Trans-Activators*
  • Wnt Proteins
  • Xenopus Proteins*
  • Xenopus laevis / embryology
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • CTNNB1 protein, Xenopus
  • CTNNB1 protein, human
  • Chemokines
  • Cytoskeletal Proteins
  • DKK1 protein, human
  • DKK2 protein, human
  • DKK3 protein, human
  • Dkk1 protein, mouse
  • Dkk2 protein, Xenopus
  • Dkk3 protein, Xenopus
  • FZD8 protein, Xenopus
  • Intercellular Signaling Peptides and Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp6 protein, mouse
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, LDL
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Wnt Proteins
  • Xenopus Proteins
  • Zebrafish Proteins
  • beta Catenin
  • dkk1 protein, Xenopus
  • dkk1b protein, zebrafish
  • wnt8a protein, zebrafish