Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling

Nature. 2002 Jun 6;417(6889):664-7. doi: 10.1038/nature756. Epub 2002 May 26.

Abstract

The Wnt family of secreted glycoproteins mediate cell cell interactions during cell growth and differentiation in both embryos and adults. Canonical Wnt signalling by way of the beta-catenin pathway is transduced by two receptor families. Frizzled proteins and lipoprotein-receptor-related proteins 5 and 6 (LRP5/6) bind Wnts and transmit their signal by stabilizing intracellular beta-catenin. Wnt/beta-catenin signalling is inhibited by the secreted protein Dickkopf1 (Dkk1), a member of a multigene family, which induces head formation in amphibian embryos. Dkk1 has been shown to inhibit Wnt signalling by binding to and antagonizing LRP5/6. Here we show that the transmembrane proteins Kremen1 and Kremen2 are high-affinity Dkk1 receptors that functionally cooperate with Dkk1 to block Wnt/beta-catenin signalling. Kremen2 forms a ternary complex with Dkk1 and LRP6, and induces rapid endocytosis and removal of the Wnt receptor LRP6 from the plasma membrane. The results indicate that Kremen1 and Kremen2 are components of a membrane complex modulating canonical Wnt signalling through LRP6 in vertebrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cell Membrane / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Endocytosis
  • Gene Expression Regulation
  • Intercellular Signaling Peptides and Proteins
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Macromolecular Substances
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Precipitin Tests
  • Protein Binding
  • Protein Transport
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, LDL / metabolism
  • Sequence Deletion / genetics
  • Signal Transduction*
  • Trans-Activators*
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Kremen protein, mouse
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp6 protein, mouse
  • Macromolecular Substances
  • Membrane Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, LDL
  • Trans-Activators
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • dkk1b protein, zebrafish

Associated data

  • GENBANK/AJ457192