biostudies-literatureChen BNCRR NIH HHSNIDDK NIH HHSNCI NIH HHS686-93https://www.ebi.ac.uk/biostudies/studies/S-EPMC4990496biostudies-literatureUnknown12(9)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 diNature chemical biologyZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity.PMC4990496R01 CA181537R01 DK107651S10 RR027673Brooks YSFu JZheng BDeRan MChen BJarugumilli GKWu XfalseZDHHC7-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 di2016-01-01T00:00:00Z2016 Sep2025-04-21T18:41:10.32Z2019-03-27T02:21:00ZS-EPMC49904962738032110.1038/nchembio.2119