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

Autori
Coombs, G. S. ; Yu, J. ; Canning, C. A. ; Veltri, C. A. ; Covey, T. M. ; Cheong, J. K. ; Utomo, V. ; Banerjee, N. ; Zhang, Z. H. ; Jadulco, R. C. ; Concepcion, G. P. ; Bugni, T. S. ; Harper, M. K. ; Mihalek, I. ; Jones, C. M. ; Ireland, C. M. ; Virshup, D. M.

Izvornik
Journal of Cell Science (0021-9533) 123 (2010), 19; 3357-3367

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Wnt, Acidification, Palmitate, Secretion, WLS

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Računarstvo, Biotehnologija, Interdisciplinarne biotehničke znanosti, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA