Protein Depalmitoylation Is Induced by Wnt5a and Promotes Polarized Cell Behavior

Background: Wnt5a signaling induces asymmetric localization of the melanoma cell adhesion molecules (MCAM). Results: Wnt5a promotes MCAM depalmitoylation and point mutations in MCAM that block palmitoylation are sufficient to cause asymmetric MCAM localization. Conclusion: Wnt5a induces polarized MCAM localization by promoting MCAM depalmitoylation. Significance: These results reveal a mechanism for Wnt5a-induced polarized cell behavior. Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization, similar to what is observed with Wnt5a stimulation. Inhibition of the depalmitoylating enzyme APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion. Directly altering expression of the basal protein palmitoylation machinery is sufficient to promote cell invasion. Additionally, cancer mutations in palmitoyltransferases decrease MCAM palmitoylation and have impaired ability to suppress cell invasion. Our results provide evidence that Wnt5a induces protein depalmitoylation, which promotes polarized protein localization and cell invasion.