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Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling
1Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
Abstract:
Dickkopf1 (Dkk1) is a secreted antagonist of the Wnt/beta-catenin signaling pathway that acts by direct binding to and inhibiting the Wnt co-receptor LRP6. The related Dkk2, however, can function either as LRP6 agonist or antagonist, depending on the cellular context, suggesting that its activity is modulated by unknown co-factors. We have recently identified the transmembrane proteins Kremen1 and -2 as additional Dkk receptors, which bind to both Dkk1 and Dkk2 with high affinity. Here we show that Kremen2 (Krm2) regulates Dkk2 activity during Wnt signaling. In human 293 fibroblasts transfected dkk2 activates LRP6 signaling. However, co-transfection of krm2 blocks the ability of Dkk2 to activate LRP6 and enhances inhibition of Wnt/Frizzled signaling. Krm2 also co-operates with Dkk4 to inhibit Wnt signaling, but not with Dkk3, which has no effect on Wnt signaling. Likewise, in Xenopus embryos, Dkk2 and Krm2 co-operate in Wnt inhibition leading to anteriorized embryos. Finally, we show that interaction with Krm2 is mediated by the second cysteine-rich domain of Dkks. These results suggest that Krm2 can function as a switch that turns Dkk2 from an activator into an inhibitor of Wnt/lRP6 signaling.
Insights
Kremen2 (Krm2) acts as a switch, modulating Dickkopf2 (Dkk2) activity in Wnt signaling. Krm2 transforms Dkk2 from a Wnt pathway activator to an inhibitor, impacting LRP6 signaling and embryonic development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Signaling
Background:
- Dickkopf1 (Dkk1) antagonizes Wnt/beta-catenin signaling by inhibiting LRP6.
- Dickkopf2 (Dkk2) exhibits context-dependent activity as an LRP6 agonist or antagonist.
- Kremen1 and Kremen2 (Krm2) are identified as high-affinity transmembrane receptors for Dkk proteins.
Purpose of the Study:
- To investigate the role of Kremen2 (Krm2) in regulating Dickkopf2 (Dkk2) activity.
- To elucidate the mechanism by which Krm2 modulates Wnt signaling pathways.
Main Methods:
- Transfection of human 293 fibroblasts with Dkk2 and Krm2.
- Analysis of Wnt/LRP6 and Wnt/Frizzled signaling.
- Xenopus embryo experiments to assess Wnt inhibition.
- Co-immunoprecipitation to identify Dkk-Krm2 interaction domains.
Main Results:
- Kremen2 (Krm2) blocks Dkk2-mediated LRP6 activation in fibroblasts.
- Krm2 enhances Dkk2's inhibition of Wnt/Frizzled signaling.
- Dkk2 and Krm2 cooperate to inhibit Wnt signaling in Xenopus embryos, causing anteriorization.
- Krm2 interacts with the second cysteine-rich domain of Dkk proteins.
Conclusions:
- Kremen2 (Krm2) functions as a critical regulator of Dkk2 activity.
- Krm2 switches Dkk2 from a Wnt/LRP6 signaling activator to an inhibitor.
- This interaction has implications for Wnt signaling modulation and embryonic development.
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