title: APT2 Inhibition Restores Scribble Localization and S-Palmitoylation in Snail-Transformed Cells.
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.
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Jeannie L
authors.initials: JL
authors.lastname: Hernandez
authors.affiliation: 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.
authors.forename: Dahvid
authors.initials: D
authors.lastname: Davda
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Cheung See Kit
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Jaimeen D
authors.initials: JD
authors.lastname: Majmudar
authors.affiliation: Program in Chemical Biology, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Won
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Margery
authors.initials: M
authors.lastname: Gang
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Sirisha C
authors.initials: SC
authors.lastname: Pasupuleti
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Alexandria I
authors.initials: AI
authors.lastname: Choi
authors.affiliation: Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Callie M
authors.initials: CM
authors.lastname: Bartkowiak
authors.affiliation: 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.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006801:Humans; D054878:Lipoylation; D008565:Membrane Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C480591:SCRIB protein, human; D000071250:Snail Family Transcription Factors; D025521:Tumor Suppressor Proteins; C581317:LYPLA2 protein, human; D013869:Thiolester Hydrolases
keywords: activity-based profiling; cell polarity; epithelial-mesenchymal transition; fluorescence imaging; hydrolase; inhibitor; protein palmitoylation