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

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


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.

MeSH terms

  • Cell Membrane / metabolism
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Epithelial-Mesenchymal Transition / genetics*
  • Humans
  • Lipoylation
  • Membrane Proteins / metabolism*
  • Snail Family Transcription Factors / genetics*
  • Thiolester Hydrolases / antagonists & inhibitors*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism
  • Tumor Suppressor Proteins / metabolism*


  • Membrane Proteins
  • SCRIB protein, human
  • Snail Family Transcription Factors
  • Tumor Suppressor Proteins
  • LYPLA2 protein, human
  • Thiolester Hydrolases