APT2 Inhibition Restores Scribble Localization and S-Palmitoylation in Snail-Transformed Cells. Issue 1 (19th January 2017)

• Record Type: Journal Article
• Authors: Hernandez, Jeannie L.; Davda, Dahvid; Cheung See Kit, Melanie; Majmudar, Jaimeen D.; Won, Sang Joon; Gang, Margery; Pasupuleti, Sirisha C.; Choi, Alexandria I.; Bartkowiak, Callie M.; Martin, Brent R.
• Is Part Of: Cell chemical biology. Volume 24:Issue 1(2017)
• Page Start: 87
• Page End: 97
• Publication Date: 2017-01-19
• Subjects: protein palmitoylation -- cell polarity -- hydrolase -- inhibitor -- fluorescence imaging -- epithelial-mesenchymal transition -- activity-based profiling; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.12.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The multidomain 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. Graphical Abstract: Highlights: Scribble S -palmitoylation is reduced after overexpression of Snail Snail overexpression reduces levels of select zDHHC protein acyl transferases After Snail overexpression, APT2 inhibition rescues Scribble localization MEK activation is attenuated following APT2 inhibition in Snail-expressing cells Abstract : 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 depalmitoylase APT2 rescue Scribble membrane localization and restore tumor suppressor properties in Snail-expressing cells.