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Letters to Nature
Nature 417, 664-667 (6 June 2002) | doi:10.1038/nature756; Received 15 February 2002; Accepted 11 April 2002; Published online 26 May 2002
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Kremen proteins are Dickkopf receptors that regulate Wnt/
-catenin signalling
Bingyu Mao1, Wei Wu1, Gary Davidson1, Joachim Marhold2, Mingfa Li2, Bernard M. Mechler2, Hajo Delius3, Dana Hoppe1, Peter Stannek1, Carmen Walter1, Andrei Glinka1 & Christof Niehrs1
- Molecular Embryology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
- Developmental Genetics Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
- Applied Tumor Virology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
Correspondence to: Christof Niehrs1 Correspondence and requests for materials should be addressed to C.N. (e-mail: Email: Niehrs@DKFZ-Heidelberg.DE). The sequence of murine kremen2 has been deposited with GenBank (accession number AJ457192).
Abstract
The Wnt family of secreted glycoproteins mediate cell–cell interactions during cell growth and differentiation in both embryos and adults1, 2. Canonical Wnt signalling by way of the
-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
-catenin3, 4, 5, 6. Wnt/
-catenin signalling is inhibited by the secreted protein Dickkopf1 (Dkk1), a member of a multigene family, which induces head formation in amphibian embryos7. Dkk1 has been shown to inhibit Wnt signalling by binding to and antagonizing LRP5/68, 9, 10. Here we show that the transmembrane proteins Kremen1 and Kremen2 are high-affinity Dkk1 receptors that functionally cooperate with Dkk1 to block Wnt/
-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.
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