title: Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling.
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.
authors.affiliation: Molecular Embryology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Mao
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Gary
authors.initials: G
authors.lastname: Davidson
authors.forename: Joachim
authors.initials: J
authors.lastname: Marhold
authors.forename: Mingfa
authors.initials: M
authors.lastname: Li
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Mechler
authors.forename: Hajo
authors.initials: H
authors.lastname: Delius
authors.forename: Dana
authors.initials: D
authors.lastname: Hoppe
authors.forename: Peter
authors.initials: P
authors.lastname: Stannek
authors.forename: Carmen
authors.initials: C
authors.lastname: Walter
authors.forename: Andrei
authors.initials: A
authors.lastname: Glinka
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D004705:Endocytosis; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046911:Macromolecular Substances; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; C486077:Kremen1 protein, mouse; C555476:Lrp6 protein, mouse; C501128:dkk1b protein, zebrafish