Scribble (SCRIB) is a tumor-suppressor protein, playing critical roles in establishing and maintaining epithelial cell polarity. SCRIB is frequently amplified in human cancers but does not localize properly to cell-cell junctions, suggesting that mislocalization of SCRIB disrupts its tumor-suppressive activities. Using chemical reporters, here we showed that SCRIB localization was regulated by S-palmitoylation at conserved cysteine residues. Palmitoylation-deficient mutants of SCRIB were mislocalized, leading to disruption of cell polarity and loss of their tumor-suppressive activities to oncogenic YAP, MAPK and PI3K/AKT pathways. We further found that ZDHHC7 was the major palmitoyl acyltransferase regulating SCRIB. Knockout of ZDHHC7 led to SCRIB mislocalization and YAP activation, and disruption of SCRIB's suppressive activities in HRasV12-induced cell invasion. In summary, we demonstrated that ZDHHC7-mediated SCRIB palmitoylation is critical for SCRIB membrane targeting, cell polarity and tumor suppression, providing new mechanistic insights of how dynamic protein palmitoylation regulates cell polarity and tumorigenesis.
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This work was supported by Stewart Rahr–MRA (Melanoma Research Alliance) Young Investigator Award, Research Scholar Award from American Cancer Society (124929-RSG-13-291-01-TBE), and grants from National Institutes of Health (R01CA181537 and R01DK107651-01) to X.W. We appreciate W.-L. Yan for his generous philanthropic donation to Massachusetts General Hospital to support Y.S.B.'s training and research. We thank M. Fukata (National Institute for Physiological Sciences, Japan) for the expression vectors of DHHC proteins, the Confocal Imaging Core at Cutaneous Biology Research Center of Massachusetts General Hospital, and the Shared Instrumentation Grant that covered the purchase of the microscope (1S10RR027673-01), and the Taplin Mass Spec Core at Harvard Medical School for proteomic studies.
The authors declare no competing financial interests.
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Chen, B., Zheng, B., DeRan, M. et al. ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity. Nat Chem Biol 12, 686–693 (2016). https://doi.org/10.1038/nchembio.2119
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