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

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 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-catenin. Wnt/β-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/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.

[1]  Christof Niehrs,et al.  Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/β-catenin signalling , 2000, Current Biology.

[2]  S. Angers,et al.  Detection of beta 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[4]  Randall T Moon,et al.  Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways , 1999, Oncogene.

[5]  A. M. Arias,et al.  The wingless signalling pathway and the patterning of the wing margin in Drosophila. , 1994, Development.

[6]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[7]  Michael Kühl,et al.  Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6 , 2001, Current Biology.

[8]  T Nakamura,et al.  Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein. , 2001, Biochimica et biophysica acta.

[9]  H. Weintraub,et al.  Xenopus embryos regulate the nuclear localization of XMyoD. , 1994, Genes & development.

[10]  Andrew Tomlinson,et al.  arrow encodes an LDL-receptor-related protein essential for Wingless signalling , 2000, Nature.

[11]  J. Nathans,et al.  Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[12]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[13]  C. Johnson,et al.  A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[15]  Stuart A. Aaronson,et al.  Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow , 2001, Nature Cell Biology.

[16]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[17]  R. Nusse,et al.  Mechanisms of Wnt signaling in development. , 1998, Annual review of cell and developmental biology.

[18]  Yan Li,et al.  LDL-receptor-related protein 6 is a receptor for Dickkopf proteins , 2001, Nature.

[19]  Jeremy Nathans,et al.  A new member of the frizzled family from Drosophila functions as a Wingless receptor , 1996, Nature.