WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Coombs, GS; Yu, J; Canning, CA; Veltri, CA; Covey, TM; Cheong, JK; Utomo, V; Banerjee, N; Zhang, ZH; Jadulco, RC; Concepcion, GP; Bugni, TS; Harper, MK; Mihalek, I; Jones, CM; Ireland, CM; Virshup, DM

Published Date

  • October 1, 2010

Published In

Volume / Issue

  • 123 / Pt 19

Start / End Page

  • 3357 - 3367

PubMed ID

  • 20826466

Pubmed Central ID

  • 20826466

Electronic International Standard Serial Number (EISSN)

  • 1477-9137

Digital Object Identifier (DOI)

  • 10.1242/jcs.072132

Language

  • eng

Conference Location

  • England