79971

WLS

wntless Wnt ligand secretion mediator;WLS;wntless Wnt ligand secretion mediator

G protein-coupled receptor 177|integral membrane protein GPR177|protein evenness interrupted homolog|protein wntless homolog|putative NF-kappa-B-activating protein 373|putative NFkB activating protein 373

1p31.3

protein-coding

Elevated levels of nuclear beta-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ss-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ss-catenin may be regulated in melanoma and thus contributes to differences in ss-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating beta-catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/beta-catenin signalling.