| First Author | Coombs GS | Year | 2010 |
| Journal | J Cell Sci | Volume | 123 |
| Issue | Pt 19 | Pages | 3357-67 |
| PubMed ID | 20826466 | Mgi Jnum | J:164296 |
| Mgi Id | MGI:4831067 | Doi | 10.1242/jcs.072132 |
| Citation | Coombs GS, et al. (2010) WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification. J Cell Sci 123(Pt 19):3357-67 |
| abstractText | 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/beta-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 beta-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. |
