Unknown

Dataset Information

0

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


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/?-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 ?-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.

SUBMITTER: Coombs GS 

PROVIDER: S-EPMC2939803 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

altmetric image

Publications


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-  ...[more]

Similar Datasets

| S-EPMC4006742 | biostudies-literature
| S-EPMC5791049 | biostudies-literature
| S-EPMC5766956 | biostudies-literature
| S-EPMC3391015 | biostudies-literature
| S-EPMC5935483 | biostudies-literature
| S-EPMC3694887 | biostudies-literature
| S-EPMC2757982 | biostudies-literature
| S-EPMC1345685 | biostudies-literature
| S-EPMC1635107 | biostudies-literature
| S-EPMC8092583 | biostudies-literature