Wang Wei, Runkle Kristin B, Terkowski Samantha M, Ekaireb Rachel I, Witze Eric S
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
J Biol Chem. 2015 Jun 19;290(25):15707-15716. doi: 10.1074/jbc.M115.639609. Epub 2015 May 5.
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.
Wnt5a信号传导调节极化细胞行为，但促进细胞极性的下游信号事件尚未完全了解。我们的结果表明，Wnt5a促进黑色素瘤细胞粘附分子（MCAM）在半胱氨酸590处的去棕榈酰化。将半胱氨酸590突变为甘氨酸足以使MCAM定位极化，类似于Wnt5a刺激时观察到的情况。去棕榈酰化酶APT1的抑制会阻断Wnt5a诱导的去棕榈酰化、不对称MCAM定位和细胞侵袭。直接改变基础蛋白棕榈酰化机制的表达足以促进细胞侵袭。此外，棕榈酰转移酶中的癌症突变会降低MCAM棕榈酰化，并削弱抑制细胞侵袭的能力。我们的结果提供了证据，表明Wnt5a诱导蛋白质去棕榈酰化，从而促进极化蛋白质定位和细胞侵袭。
