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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Bingyu Mao & Wei Wu & Gary Davidson & Joachim Marhold & Mingfa Li & Bernard M. Mechler & Hajo Delius & Dana Hoppe & Peter Stannek & Carmen Walter & Andrei Glinka & Christof Niehrs, 2002. "Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling," Nature, Nature, vol. 417(6889), pages 664-667, June.
    • Handle: RePEc:nat:nature:v:417:y:2002:i:6889:d:10.1038_nature756
    DOI: 10.1038/nature756
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    Cited by:

    1. Mariko Sasaki & Daiki Kato & Karin Murakami & Hiroshi Yoshida & Shohei Takase & Tsuguteru Otsubo & Hideaki Ogiwara, 2024. "Targeting dependency on a paralog pair of CBP/p300 against de-repression of KREMEN2 in SMARCB1-deficient cancers," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    2. Naveen Kumar & Pon Ganish Prakash & Christian Wentland & Shilpa Mary Kurian & Gaurav Jethva & Volker Brinkmann & Hans-Joachim Mollenkopf & Tobias Krammer & Christophe Toussaint & Antoine-Emmanuel Sali, 2024. "Decoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development through single cell analysis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Ma’ayan Israeli & Yaara Finkel & Yfat Yahalom-Ronen & Nir Paran & Theodor Chitlaru & Ofir Israeli & Inbar Cohen-Gihon & Moshe Aftalion & Reut Falach & Shahar Rotem & Uri Elia & Ital Nemet & Limor Klik, 2022. "Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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