Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior.
Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior.
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DOI：
10.7554/elife.34362
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发表时间：
2018-04-12
期刊：
影响因子：
7.7
通讯作者：
Witze ES
中科院分区：
文献类型：
--
作者：
Sadeghi RS;Kulej K;Kathayat RS;Garcia BA;Dickinson BC;Brady DC;Witze ES
Wnt5a与黑色素瘤的进展和转移有关，尽管对促进黑色素瘤转移的确切下游信号事件知之甚少。Wnt5a信号导致酰基蛋白硫酯酶1 （APT1）介导的前转移细胞粘附分子CD44和MCAM的去棕榈酰化，导致黑色素瘤侵袭增加。wnt5a介导的APT1活性和细胞功能调控的机制细节尚不清楚。本研究表明Wnt5a信号通过诱导APT1磷酸化调节APT1活性，并进一步研究了APT1磷酸化对其去棕榈酰化活性的功能作用。我们发现磷酸化增加了APT1去棕榈酰化活性，降低了APT1二聚化。我们进一步确定APT1磷酸化会增加体外黑色素瘤的侵袭，并与肿瘤分级和转移增加相关。我们的研究结果进一步证实APT1是黑色素瘤侵袭和转移行为的重要调节因子。抑制APT1可能是治疗Wnt5a驱动的癌症的一种新方法。
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.