Editors' ChoiceReceptor signaling

New Wnt Signal

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Science's STKE  27 Jan 2004:
Vol. 2004, Issue 217, pp. tw31-TW31
DOI: 10.1126/stke.2172004TW31

Suddenly Wnt signaling, which uses a distinctive mechanism to regulate gene regulation, looks much more like the well-characterized processes used by more conventional growth factors and cytokines. Interaction of Wnt with its receptor complex results in stabilization of β-catenin, which leads to activation of signaling through members of the T cell factor or lymphocyte enhancer factor family of transcription factors. The receptor complex contains two transmembrane proteins, the Frizzled serpentine receptor protein and LDL (low-density lipoprotein) receptor-related proteins (LRP) 5 and 6. Both are necessary for signaling, but their precise roles have not been clear. Tamai et al. identified a conserved PPP(S or T)P motif in the LRP proteins and showed, using mRNA injection of mutant proteins into Xenopus embryos, that these repeated domains are critical for Wnt signaling. In fact, transfer of just one copy of the PPPSP motif to a related LDL receptor that normally does not promote Wnt signaling allowed that receptor to mimic Wnt signaling and to promote complete axis duplication in Xenopus embryos. The PPPSP motif appears to be phosphorylated, and axin, a scaffolding protein required for control of β-catenin signals, bound only to LDL receptor constructs that contained the phosphorylation site when the proteins were expressed in mammalian cells. The authors used antibodies to the phosphorylated PPPSP motif to show that treatment of cells transiently expressing LRP6 with Wnt-conditioned medium caused rapid phosphorylation of the receptor. The authors note that such rapid phosphorylation, creating potential docking sites for other signaling proteins, is reminiscent of the mechanisms commonly used by the structurally unrelated growth factor and cytokine receptors. The findings also suggest that at least two key components of Wnt signaling--the kinase and phosphatase that regulate phosphorylation of the PPPSP sites--remain to be identified.

K. Tamai, X. Zeng, C. Liu, X. Zhang, Y. Harada, Z. Chang, X. He, A mechanism for Wnt coreceptor activation. Mol. Cell 13, 149-156 (2004). [Online Journal]

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