AI Article Synopsis
- SCRIB is a tumor-suppressor protein that helps maintain the polarity of epithelial cells but is often mislocalized in cancers, which impairs its function.
- The localization of SCRIB is regulated by a process called S-palmitoylation, and mutations that hinder this process result in loss of cell polarity and tumor suppressive abilities.
- ZDHHC7 is identified as the key enzyme responsible for palmitoylating SCRIB, and its absence leads to SCRIB mislocalization and increased cancer cell invasion via pathways such as YAP activation.
Article Abstract
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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990496 | PMC |
| http://dx.doi.org/10.1038/nchembio.2119 | DOI Listing |
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