ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity
Open accessAbstract
Scribble (SCRIB) is a tumor-suppressor protein, playing critical roles in establishing and maintaining epithelial cell polarity. SCRIB is frequently amplified in human cancers but does not localize properly to cell-cell junctions, suggesting that mislocalization of SCRIB disrupts its tumor-suppressive activities. Using chemical reporters, here we showed that SCRIB localization was regulated by S-palmitoylation at conserved cysteine residues. Palmitoylation-deficient mutants of SCRIB were mislocalized, leading to disruption of cell polarity and loss of their tumor-suppressive activities to oncogenic YAP, MAPK and PI3K/AKT pathways. We further found that ZDHHC7 was the major palmitoyl acyltransferase regulating SCRIB. Knockout of ZDHHC7 led to SCRIB mislocalization and YAP activation, and disruption of SCRIB's suppressive activities in HRas(V12)-induced cell invasion. In summary, we demonstrated that ZDHHC7-mediated SCRIB palmitoylation is critical for SCRIB membrane targeting, cell polarity and tumor suppression, providing new mechanistic insights of how dynamic protein palmitoylation regulates cell polarity and tumorigenesis.
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Junctional localization of Scribble can be mediated by either the LRRs or the PDZ plus C terminus and requires N-terminal palmitoylation.
“Junctional localization can be mediated by either the LRRs or the PDZ plus C terminus (Fig. 2; Navarro et al., 2005) and requires N-terminal palmitoylation (Chen et al., 2016).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Chen et al., 2016
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References 46 · Cited by 119
- Authors
- Chen, B., Zheng, B., DeRan, M., Jarugumilli, G. K., Fu, J., Brooks, Y. S., & Wu, X.
- Affiliations
- Harvard University (US)
- Corresponding author
- Wu, Xu
- Venue
- Nature Chemical Biology
- Published
- 2016-07-04
- Volume
- 12
- Issue
- 9
- Pages
- 686-693
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4990496
- OpenAlex
- W2471723770
- Cited by
- 119
- References
- 46
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 15 · 2020: 5 · 2019: 6 · 2018: 17 · 2017: 13 · 2016: 1
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA181537)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107651)
- National Center for Research Resources (S10RR027673)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- Scribble, S-palmitoylation, palmitoyltransferase, cell polarity, tumor suppression, palmitoylation, protein mislocalization, YAP activation, MAPK signaling, PI3K/Akt signaling, cell invasion, epithelial polarity, cell-cell contact
- MeSH terms
- Acetyltransferases, Humans, Membrane Proteins, Cell Polarity, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Lipoylation, HEK293 Cells
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