Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Elife. 2018 Apr 12;7:e34362. doi: 10.7554/eLife.34362.
Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization. We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis. Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior. Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.
Wnt5a 已被牵涉到黑色素瘤的进展和转移中，尽管导致黑色素瘤转移的确切下游信号事件仍不清楚。Wnt5a 信号导致酰基蛋白硫酯酶 1（APT1）介导的促转移细胞黏附分子 CD44 和 MCAM 的棕榈酰化脱除，导致黑色素瘤侵袭性增加。Wnt5a 介导的 APT1 活性和细胞功能调节的机制细节尚不清楚。在这里，我们显示 Wnt5a 信号通过诱导 APT1 磷酸化来调节 APT1 活性，我们进一步研究了 APT1 磷酸化对其脱棕榈酰化活性的功能作用。我们发现磷酸化增加了 APT1 的脱棕榈酰化活性，减少了 APT1 的二聚化。我们进一步确定 APT1 磷酸化增加了黑色素瘤的体外侵袭，并且与肿瘤分级和转移增加相关。我们的结果进一步确立了 APT1 作为黑色素瘤侵袭和转移行为的重要调节剂。APT1 的抑制可能代表一种治疗 Wnt5a 驱动型癌症的新方法。
