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XB-ART-42042
J Cell Sci October 1, 2010; 123 (Pt 19): 3357-67.
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WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.

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 .


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.

PubMed ID: 20826466
PMC ID: PMC2939803
Article link: J Cell Sci
Grant support: [+]

Species referenced: Xenopus
Genes referenced: actl6a ctnnb1 fgf8 nodal3.2 odc1 porcn ptgds sia1 tbx2 wls wnt1 wnt3a wnt8a


Article Images: [+] show captions
References [+] :
Arnoux, A structural basis for the pH-dependent xanthophyll cycle in Arabidopsis thaliana. 2009, Pubmed