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. 2024 Jul 16;121(29):e2400569121.
doi: 10.1073/pnas.2400569121. Epub 2024 Jul 10.

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

Jiafu Ying  1   2 , Yinghong Yang  1   2 , Xuanpu Zhang  1   2 , Ze Dong  3   4 , Baoen Chen  1   2   5   6
Affiliations

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

Jiafu Ying et al. Proc Natl Acad Sci U S A. .

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.

Keywords: Vangl2; click chemistry; planar cell polarity; protein lipidation; stearoylation.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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References

    1. Zallen J. A., Planar polarity and tissue morphogenesis. Cell 129, 1051–1063 (2007). - PubMed
    1. Butler M. T., Wallingford J. B., Planar cell polarity in development and disease. Nat. Rev. Mol. Cell Biol. 18, 375–388 (2017). - PMC - PubMed
    1. Torban E., Sokol S. Y., Planar cell polarity pathway in kidney development, function and disease. Nat. Rev. Nephrol. 17, 369–385 (2021). - PMC - PubMed
    1. Luga V., et al. , Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151, 1542–1556 (2012). - PubMed
    1. Montcouquiol M., et al. , Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003). - PubMed

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