PDF(Pubmed)
Abstract：
Defects in planar cell polarity (PCP) have been implicated in diverse human pathologies. Vangl2 is one of the core PCP components crucial for PCP signaling. Dysregulation of Vangl2 has been associated with severe neural tube defects and cancers. However, how Vangl2 protein is regulated at the posttranslational level has not been well understood. Using chemical reporters of fatty acylation and biochemical validation, here we present that Vangl2 subcellular localization is regulated by a reversible S-stearoylation cycle. The dynamic process is mainly regulated by acyltransferase ZDHHC9 and deacylase acyl-protein thioesterase 1 (APT1). The stearoylation-deficient mutant of Vangl2 shows decreased plasma membrane localization, resulting in disruption of PCP establishment during cell migration. Genetically or pharmacologically inhibiting ZDHHC9 phenocopies the effects of the stearoylation loss of Vangl2. In addition, loss of Vangl2 stearoylation enhances the activation of oncogenic Yes-associated protein 1 (YAP), serine-threonine kinase AKT, and extracellular signal-regulated protein kinase (ERK) signaling and promotes breast cancer cell growth and HRas G12V mutant (HRasV12)-induced oncogenic transformation. Our results reveal a regulation mechanism of Vangl2, and provide mechanistic insight into how fatty acid metabolism and protein fatty acylation regulate PCP signaling and tumorigenesis by core PCP protein lipidation.
摘要：
平面细胞极性（PCP）的缺陷与多种人类病理有关。Vangl2是对PCP信令至关重要的核心PCP组件之一。Vangl2的失调与严重的神经管缺陷和癌症有关。然而,Vangl2蛋白是如何在翻译后水平上被调节的还没有被很好地理解。使用脂肪酰化和生化验证的化学报告基因，在这里,我们提出Vangl2亚细胞定位受可逆的S-硬脂酰化循环调节.其动态过程主要受ZDHHC9酰基转移酶和脱酰基酶酰蛋白硫酯酶1(APT1)调控。Vangl2的硬脂酰化缺陷型突变体显示出降低的质膜定位,导致细胞迁移过程中PCP建立的破坏。遗传或药理学抑制ZDHHC9表型对Vangl2的硬脂酰化损失的影响。此外,Vangl2硬脂酰化的缺失增强了致癌Yes相关蛋白1（YAP）的激活，丝氨酸-苏氨酸激酶AKT,和细胞外信号调节蛋白激酶（ERK）信号并促进乳腺癌细胞生长和HRasG12V突变体（HRasV12）诱导的致癌转化。我们的结果揭示了Vangl2的调节机制，并提供了有关脂肪酸代谢和蛋白质脂肪酰化如何通过核心PCP蛋白质脂化调节PCP信号传导和肿瘤发生的机制见解。
