A mechanism for Wnt coreceptor activation.

@article{Tamai2004AMF,
  title={A mechanism for Wnt coreceptor activation.},
  author={Keiko Tamai and Xin Zeng and Chunming Liu and Xinjun Zhang and Yuko Harada and Zhijie Chang and Xi He},
  journal={Molecular cell},
  year={2004},
  volume={13 1},
  pages={
          149-56
        }
}
LDL receptor related proteins 5 and 6 (LRP5/6) and their Drosophila homolog Arrow are single-span transmembrane proteins essential for Wnt/beta-catenin signaling, likely via acting as Wnt coreceptors. How Wnt activates LRP5/6/Arrow to initiate signal transduction is not well defined. Here we show that a PPPSP motif, which is reiterated five times in the LRP5/6/Arrow intracellular domain, is necessary and sufficient to trigger Wnt/beta-catenin signaling. A single PPPSP motif, upon transfer to… Expand
Cell cycle control of wnt receptor activation.
TLDR
Using a kinome-wide RNAi screen, it is shown that PPPSP phosphorylation requires the Drosophila Cyclin-dependent kinase (CDK) L63, and in Xenopus embryos, Cyclin Y is required in vivo for LRP6 phosphorylated, maternal Wnt signaling, and Wnt-dependent anteroposterior embryonic patterning. Expand
LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way
TLDR
This review highlights recent progress and unresolved issues in understanding the function and regulation of Arrow/Lrp5/Llrp6 in Wnt signaling, and discusses Arrows interactions with Wnt and the Frizzled family of Wnt receptors, and with the intracellular β-catenin degradation apparatus. Expand
Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP
TLDR
This model takes into account several observations reported here: the identification of intracellular residues of Frizzled required for β-catenin signaling and for recruitment of Dvl to the plasma membrane; evidence that Wnt3A binds to the ectodomains of LRP andFrizzled; and demonstrations that a requirement for Wnt ligand can be abrogated by chimeric receptors that allow formation of Frizzle-LRP hetero-oligomers. Expand
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TLDR
How proline- directed kinases and non-proline-directed kinases act upon Lrp6 is summarized, how the phosphorylation is regulated by ligand binding and mitosis, and how Lr p6osphorylation leads to β-catenin stabilization are summarized. Expand
Transmembrane Protein 198 Promotes LRP6 Phosphorylation and Wnt Signaling Activation
TLDR
TMEM198 is identified as a membrane scaffold protein that promotes LRP6 phosphorylation and Wnt signaling activation and is required for Wnt-mediated neural crest formation, antero-posterior patterning, and particularly engrailed-2 expression in Xenopus embryos. Expand
LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation.
TLDR
It is shown that Wnt ligand stimulation induces conformational change of the Frz-LRP6 complex and leads to hexamer formation containing the core LDLR domain-mediated LRP6 homodimer that is stabilized by two pairs of Wnt3a and Frz8, which suggests a previously unrecognized mode of receptor interaction in Wnt signal initiation. Expand
LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin
TLDR
A mechanism whereby LRP6 stabilizes β-catenin independently of Axin degradation by directly inhibiting GSK3's phosphorylation of β- catenin is identified. Expand
Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins
TLDR
A structure–function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling finds that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/β-catenin signaling pathway, and shows that the PPSP motifs within the intracellular domain of LRP 6 are required for signaling. Expand
Wnt Signal Amplification via Activity, Cooperativity, and Regulation of Multiple Intracellular PPPSP Motifs in the Wnt Co-receptor LRP6*
TLDR
The results establish the critical role and a common phosphorylation/activation mechanism for the PPPSP motifs in LRP6 and suggest that the conserved multiplicity and cooperativity of the PP PSP motifs represents a built-in amplifier for Wnt signaling by the L RP6 family of receptors. Expand
Tyrosine-based Signal Mediates LRP6 Receptor Endocytosis and Desensitization of Wnt/β-Catenin Pathway Signaling*
TLDR
The results reveal molecular mechanisms by which LRP6 endocytosis routes regulate its phosphorylation and the strength of Wnt/β-catenin signaling, and have implications on how this pathway can be modulated in human diseases. Expand
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