Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling
Abstract
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 beta-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 beta-catenin. Wnt/beta-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/beta-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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LRP6 turnover is regulated by the Dickkopf1/Kremen pathway.
“The LRP6 turnover is regulated by the Dickkopf1/Kremen pathway [81] and R-spondin/Lgr5/Rnf43 module [82].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [81]
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- Authors
- Mao, B., Wu, W., Davidson, G., Marhold, J., Li, M., Mechler, B. M., Delius, H., Hoppe, D., Stannek, P., Walter, C., Glinka, A., & Niehrs, C.
- Affiliations
- German Cancer Research Center (DE)
- Corresponding author
- Niehrs, Christof
- Venue
- Nature
- Published
- 2002-05-26
- Volume
- 417
- Issue
- 6889
- Pages
- 664-667
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2117156715
- Cited by
- 1,038
- References
- 1
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 20 · 2023: 40 · 2022: 43 · 2021: 38 · 2020: 37 · 2019: 34 · 2018: 41 · 2017: 47 · 2016: 30 · 2015: 44 · 2014: 62 · 2013: 56 · 2012: 54
- FWCI
- 13.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- KREMEN1, DKK1, Wnt/β-catenin signaling, LRP6, LRP5/6, Frizzled receptors, receptor internalization, ternary receptor complex, head induction
- MeSH terms
- Animals, Cell Line, Cell Membrane, Cytoskeletal Proteins, Drosophila melanogaster, Endocytosis, Gene Expression Regulation, Membrane Proteins, Microscopy, Fluorescence, Molecular Sequence Data, Precipitin Tests, Protein Binding, Proteins, Proto-Oncogene Proteins, Receptors, LDL, Signal Transduction, Trans-Activators, Sequence Deletion, Protein Transport, Zebrafish Proteins, Animals, Genetically Modified, Intercellular Signaling Peptides and Proteins, Macromolecular Substances, Wnt Proteins, beta Catenin, Mice, Low Density Lipoprotein Receptor-Related Protein-6
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