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      APT2 inhibition restores Scribble localization and S-palmitoylation in Snail-transformed cells

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          Summary

          The multi-domain scaffolding protein Scribble (Scrib) organizes key signaling complexes to specify basolateral cell polarity and suppress aberrant growth. In many human cancers, genetically normal Scrib mislocalizes from cell–cell junctions to the cytosol, correlating with enhanced growth signaling and malignancy. Here we confirm that expression of the epithelial-to-mesenchymal transcription factor (EMT-TF) Snail in benign epithelial cells leads to Scrib displacement from the plasma membrane, mimicking the mislocalization observed in aggressive cancers. Upon further examination, Snail promotes a transcriptional program that targets genes in the palmitoylation cycle, repressing many protein acyl transferases and elevating expression and activity of protein acyl thioesterase 2 (APT2). APT2 isoform-selective inhibition or knockdown rescued Scrib membrane localization and palmitoylation while attenuating MEK activation. Overall, inhibiting APT2 restores balance to the Scrib palmitoylation cycle, promoting membrane re-localization and growth attenuation. These findings emphasize the importance of S-palmitoylation as a post-translational gatekeeper of cell polarity-mediated tumor suppression.

          In Brief

          The cell polarity tumor suppressor Scribble re-localizes from lateral membranes to the cytosol in epithelial cancers. Hernandez, et.al. demonstrate that inhibitors of the protein de-palmitoylase APT2 rescue Scribble membrane localization and restore tumor suppressor properties in Snail-expressing cells.

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          Author and article information

          Journal
          101676030
          44856
          Cell Chem Biol
          Cell Chem Biol
          Cell chemical biology
          2451-9456
          23 December 2016
          05 January 2017
          19 January 2017
          19 January 2018
          : 24
          : 1
          : 87-97
          Affiliations
          [1 ]Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109, USA
          [2 ]Program in Chemical Biology, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109, USA
          Author notes
          [* ]Correspondence: brentrm@ 123456umich.edu
          [3]

          Co-first author

          [4]

          Lead Contact

          Article
          PMC5362123 PMC5362123 5362123 nihpa838363
          10.1016/j.chembiol.2016.12.007
          5362123
          28065656
          08f1cc84-df14-49ad-917f-d8508222fc00
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