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Cell Rep. 2019 Jan 22;26(4):875-883.e5. doi: 10.1016/j.celrep.2018.12.104.

Non-acylated Wnts Can Promote Signaling.

Author information

1
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA; Department of Medicine (Hematology-Oncology), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-5157, USA.
2
Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA.
4
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA; Department of Medicine (Hematology-Oncology), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-5157, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA. Electronic address: pklein@pennmedicine.upenn.edu.
5
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6059, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: mark.lemmon@yale.edu.

Abstract

Wnts are a family of 19 extracellular ligands that regulate cell fate, proliferation, and migration during metazoan embryogenesis and throughout adulthood. Wnts are acylated post-translationally at a conserved serine and bind the extracellular cysteine-rich domain (CRD) of Frizzled (FZD) seven-pass transmembrane receptors. Although crystal structures suggest that acylation is essential for Wnt binding to FZDs, we show here that several Wnts can promote signaling in Xenopus laevis and Danio rerio embryos, as well as in an in vitro cell culture model, without acylation. The non-acylated Wnts are expressed at levels similar to wild-type counterparts and retain CRD binding. By contrast, we find that certain other Wnts do require acylation for biological activity in Xenopus embryos, although not necessarily for FZD binding. Our data argue that acylation dependence of Wnt activity is context specific. They further suggest that acylation may underlie aspects of ligand-receptor selectivity and/or control other aspects of Wnt function.

KEYWORDS:

Frizzled; Wnt; Xenopus laevis; acylation; lipid modification

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