1. Molecular Embryology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
2. Developmental Genetics Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
3. 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 adults^{1, 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 -catenin^{3, 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 LRP5/6^{8, 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.