ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity


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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Figure 1: SCRIB is S-palmitoylated at evolutionarily conserved N-terminal cysteine residues.
Figure 2: Palmitoylation of SCRIB regulates its membrane localization and epithelial cell polarity.
Figure 3: Palmitoylation of SCRIB is required to suppress YAP, MAPK and PI3K/AKT pathways.
Figure 4: ZDHHC7 is a major palmitoyl acyltransferase regulating SCRIB palmitoylation.
Figure 5: ZDHHC7-mediated palmitoylation regulates SCRIB localization and YAP translocation.
Figure 6: Palmitoylation of SCRIB is required to suppress HRasV12-induced cell invasion.


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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.

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X.W. conceived the concept and supervised the project. B.C. and X.W. designed the experiments. B.Z. and G.K.J. synthesized the probes, and B.Z. identified Scribble from proteomic studies. B.C. performed biochemistry and cell biology experiments with the help from M.D., G.K.J., J.F., and Y.S.B. B.C. and X.W. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Xu Wu.

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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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