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LDL-receptor-related proteins in Wnt signal transduction
1Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.
Insights
Low-density lipoprotein receptor-related protein 6 (LRP6) acts as a co-receptor in Wnt signal transduction. This finding is crucial for understanding Wnt signaling in embryonic development and tumor formation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Signaling
Background:
- Wnt signaling molecules are vital for embryonic development and cancer.
- Frizzled (Fz) receptors mediate Wnt signaling, but the transduction mechanism remains unclear.
- Drosophila 'arrow' gene, homologous to mammalian LRP5/LRP6, is linked to Wnt signaling.
Purpose of the Study:
- To investigate the role of LRP6 in Wnt signal transduction.
- To elucidate the mechanism of Wnt-Fz receptor complex function.
Main Methods:
- Xenopus embryo experiments to assess LRP6 function.
- Analysis of Wnt-responsive gene induction and developmental processes.
- Utilizing LRP6 mutants to dissect signaling pathways.
- Biochemical assays to study protein interactions (Wnt-1 and Fz).
Main Results:
- LRP6 functions as a co-receptor, activating Wnt-Fz signaling in Xenopus.
- LRP6 induced Wnt-responsive genes, dorsal axis duplication, and neural crest formation.
- A mutant LRP6 lacking its intracellular domain blocked Wnt/Wnt-Fz signaling but not downstream effectors like Dishevelled or beta-catenin.
- The extracellular domain of LRP6 binds Wnt-1 and associates with Fz.
Conclusions:
- LRP6 is a critical co-receptor in the Wnt signaling pathway.
- LRP6 is a functional component of the Wnt receptor complex.
- Understanding LRP6's role provides insights into developmental processes and oncogenesis.