The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for oriented cell division in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. Here we show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions, and for normal lumen formation in 3D culture. We demonstrate that CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, and thereby identify a new cellular function for CASK. We show that 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 direct interaction between CASK and Dlg1 with an interfering peptide disrupts spindle orientation and causes multilumen formation. We further show that the Dlg1-CASK interaction is important for the membrane localisation of the canonical LGN-NuMA complex, required for attachment of the mitotic spindle to the membrane and its correct positioning, as well as for astral microtubule stability. Together these results establish the importance of the CASK-Dlg1 interaction in oriented cell division and epithelial integrity.