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Cell Chem Biol. 2017 Jan 19;24(1):87-97. doi: 10.1016/j.chembiol.2016.12.007. Epub 2017 Jan 5.

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

Author information

1
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
2
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA; Program in Chemical Biology, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
3
Program in Chemical Biology, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
4
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA; Program in Chemical Biology, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA. Electronic address: brentrm@umich.edu.

Abstract

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.

KEYWORDS:

activity-based profiling; cell polarity; epithelial-mesenchymal transition; fluorescence imaging; hydrolase; inhibitor; protein palmitoylation

PMID:
28065656
PMCID:
PMC5362123
DOI:
10.1016/j.chembiol.2016.12.007
[Indexed for MEDLINE]
Free PMC Article

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