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

Bingyu Mao, Wei Wu, Gary Davidson, Joachim Marhold, Mingfa Li, Bernard M. Mechler, Hajo Delius, Dana Hoppe, Peter Stannek, Carmen Walter, Andrei Glinka and Christof Niehrs ()
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Bingyu Mao: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Wei Wu: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Gary Davidson: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Joachim Marhold: Deutsches Krebsforschungszentrum
Mingfa Li: Deutsches Krebsforschungszentrum
Bernard M. Mechler: Deutsches Krebsforschungszentrum
Hajo Delius: Deutsches Krebsforschungszentrum
Dana Hoppe: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Peter Stannek: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Carmen Walter: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Andrei Glinka: Molecular Embryology Division, Deutsches Krebsforschungszentrum
Christof Niehrs: Molecular Embryology Division, Deutsches Krebsforschungszentrum

Nature, 2002, vol. 417, issue 6889, 664-667

Abstract: 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 β-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 β-catenin3,4,5,6. Wnt/β-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/β-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.

Date: 2002
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DOI: 10.1038/nature756

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