APT2 Inhibition Restores Scribble Localization and S-Palmitoylation in Snail-Transformed Cells

作者：Hernandez Jeannie L; Davda Dahvid; Kit Melanie Cheung See; Majmudar Jaimeen D; Won Sang Joon; Gang Margery; Pasupuleti Sirisha C; Choi Alexandria I; Bartkowiak Callie M; Martin Brent R^*

来源：Cell Chemical Biology, 2017, 24(1): 87-97.

DOI：10.1016/j.chembiol.2016.12.007

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.

• 出版日期2017-1-19