The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia
AffiliationCell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK
MetadataShow full item record
AbstractOriented 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.This article has an associated First Person interview with the first author of the paper.
CitationPorter AP, White GRM, Mack NA, Malliri A. The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia. J Cell Sci. 2019 Jul 15;132(14).
JournalJournal of Cell Science
- Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN.
- Authors: Saadaoui M, Machicoane M, di Pietro F, Etoc F, Echard A, Morin X
- Issue date: 2014 Sep 15
- CASK deletion in intestinal epithelia causes mislocalization of LIN7C and the DLG1/Scrib polarity complex without affecting cell polarity.
- Authors: Lozovatsky L, Abayasekara N, Piawah S, Walther Z
- Issue date: 2009 Nov
- Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development.
- Authors: Ahn SY, Kim Y, Kim ST, Swat W, Miner JH
- Issue date: 2013 Jun
- Epigenetic Regulation of <i>Dlg1</i>, via <i>Kaiso</i>, Alters Mitotic Spindle Polarity and Promotes Intestinal Tumorigenesis.
- Authors: Young MA, May S, Damo A, Yoon YS, Hur MW, Swat W, Parry L
- Issue date: 2019 Mar
- Intramolecular interaction in LGN, an adaptor protein that regulates mitotic spindle orientation.
- Authors: Takayanagi H, Hayase J, Kamakura S, Miyano K, Chishiki K, Yuzawa S, Sumimoto H
- Issue date: 2019 Dec 20