A Mechanism for Wnt Coreceptor Activation

Keiko Tamai, Xin Zeng, Chunming Liu, Xinjun Zhang, Yuko Harada, Zhijie Chang, Xi He

Research output: Contribution to journalArticlepeer-review

455 Scopus citations


LDL receptor related proteins 5 and 6 (LRP5/6) and their Drosophila homolog Arrow are single-span transmembrane proteins essential for Wnt/β-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/β-catenin signaling. A single PPPSP motif, upon transfer to the LDL receptor, fully activates the Wnt pathway, inducing complete axis duplication in Xenopus and TCF/β-catenin-responsive transcription in human cells. We further show that Wnt signal-ing stimulates, and requires, phosphorylation of the PPPSP motif, which creates an inducible docking site for Axin, a scaffolding protein controlling β-catenin stability. Our study identifies a critical signaling module and a key phosphorylation-dependent activation step of the Wnt receptor complex and reveals a unifying logic for transmembrane signaling by Wnts, growth factors, and cytokines.

Original languageEnglish
Pages (from-to)149-156
Number of pages8
JournalMolecular Cell
Issue number1
StatePublished - Jan 16 2004

Bibliographical note

Funding Information:
We thank B. Holdener for Mesd cDNA, X. Chen for technical help, and M. Semenov and other lab members for discussion. C.M.L. is supported by a B.H. Campbell & A.F. Hall postdoctoral fellowship from The Medical Foundation. Y.H. is supported in part by a postdoctoral fellowship from Naito Foundation (Japan). Z.C. is supported by a grant (3022807) from NSFC (China). X.H. is supported by a grant from NIH, and is a W.M. Keck Foundation Distinguished Young Scholar.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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