Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2

• 成果类型: Article
• 署名作者: Ying, Jiafu; Yang, Yinghong; Zhang, Xuanpu; Dong, Ze; Chen, Baoen
• 署名单位: Zhejiang University; Zhejiang University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Zhejiang University; Zhejiang University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9091
• DOI: 10.1073/pnas.2400569121
• 发表日期: 2024-07-16
• 关键词: planar polarity; PATHWAY; palmitoylation; localization; roles; ras; differentiation; identification; inhibition; migration

摘要

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 ofVangl2 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.