The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia

Porter, Andrew P.; White, Gavin R. M.; Mack, Natalie A.; Malliri, Angeliki

Abstract

Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for mitotic spindle orientation in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. We show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions and normal lumen formation. We demonstrate that the MAGUK protein CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, thereby identifying a new cellular function for CASK. Depletion of CASK leads to misoriented divisions in 3D, and to the formation of multilumen structures in cultured kidney and breast epithelial cells. Blocking the CASK–Dlg1 interaction with an interfering peptide, or by deletion of the CASK-interaction domain of Dlg1, disrupts spindle orientation and causes multilumen formation. We show that the CASK–Dlg1 interaction is important for localisation of the canonical LGN–NuMA complex known to be required for spindle orientation. These results establish the importance of the CASK–Dlg1 interaction in oriented cell division and epithelial integrity.

Citation

Porter, A. P., White, G. R. M., Mack, N. A., & Malliri, A. (2019). The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia. Journal of Cell Science, 132(14), Article jcs230086. https://doi.org/10.1242/jcs.230086

• Journal Article Type: Article
• Acceptance Date: Jun 14, 2019
• Online Publication Date: Jul 15, 2019
• Publication Date: Jul 15, 2019
• Deposit Date: Sep 5, 2019
• Publicly Available Date: Sep 6, 2019
• Journal: Journal of Cell Science
• Print ISSN: 0021-9533
• Electronic ISSN: 1477-9137
• Publisher: Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 132
• Issue: 14
• Article Number: jcs230086
• DOI: https://doi.org/10.1242/jcs.230086
• Keywords: CASK, Dlg1, Mitosis, Mitotic spindle orientation, Oriented cell division, Lumen formation
• Public URL: https://nottingham-repository.worktribe.com/output/2301881
• Publisher URL: https://jcs.biologists.org/content/132/14/jcs230086