WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification
Open Access
- 1 October 2010
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 123 (19), 3357-3367
- https://doi.org/10.1242/jcs.072132
Abstract
Wnt proteins are secreted post-translationally modified proteins that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number of dedicated factors in the secreting cell whose coordinated functions are not fully understood. A screen for small molecules identified inhibitors of vacuolar acidification as potent inhibitors of Wnt secretion. Inhibition of the V-ATPase or disruption of vacuolar pH gradients by diverse drugs potently inhibited Wnt/β-catenin signaling both in cultured human cells and in vivo, and impaired Wnt-regulated convergent extension movements in Xenopus embryos. WNT secretion requires its binding to the carrier protein wntless (WLS); we find that WLS is ER-resident in human cells and WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A–WLS complex both in cells and at the plasma membrane. Modeling predictions suggest that WLS has a lipid-binding β-barrel that is similar to the lipocalin-family fold. We propose that WLS binds Wnts in part through a lipid-binding domain, and that vacuolar acidification is required to release palmitoylated WNT3A from WLS in secretory vesicles, possibly to facilitate transfer of WNT3A to a soluble carrier protein.Keywords
This publication has 58 references indexed in Scilit:
- Requirement of Prorenin Receptor and Vacuolar H + -ATPase–Mediated Acidification for Wnt SignalingScience, 2010
- Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formationProceedings of the National Academy of Sciences of the United States of America, 2009
- A Structural Basis for the pH-Dependent Xanthophyll Cycle in Arabidopsis thalianaPlant Cell, 2009
- A Wnt Survival Guide: From Flies to Human DiseaseJournal of Investigative Dermatology, 2009
- Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivativesBioorganic & Medicinal Chemistry, 2009
- Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancerNature Chemical Biology, 2009
- Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum StressMolecular and Cellular Biology, 2008
- Regulation of Wnt protein secretion and its role in gradient formationEMBO Reports, 2008
- Lipid-independent Secretion of a Drosophila Wnt ProteinOnline Journal of Public Health Informatics, 2008
- A Wnt-CKIɛ-Rap1 Pathway Regulates Gastrulation by Modulating SIPA1L1, a Rap GTPase Activating ProteinDevelopmental Cell, 2007