title: The tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell-cell adhesion.
abstract: Dividing epithelial cells need to coordinate spindle positioning with shape changes to maintain cell-cell adhesion. Microtubule interactions with the cell cortex regulate mitotic spindle positioning within the plane of division. How the spindle crosstalks with the actin cytoskeleton to ensure faithful mitosis and spindle positioning is unclear. Here we demonstrate that the tumour suppressor DLC2, a negative regulator of Cdc42, and the interacting kinesin Kif1B coordinate cell junction maintenance and planar spindle positioning by regulating microtubule growth and crosstalk with the actin cytoskeleton. Loss of DLC2 induces the mislocalization of Kif1B, increased Cdc42 activity and cortical recruitment of the Cdc42 effector mDia3, a microtubule stabilizer and promoter of actin dynamics. Accordingly, DLC2 or Kif1B depletion promotes microtubule stabilization, defective spindle positioning, chromosome misalignment and aneuploidy. The tumour suppressor DLC2 and Kif1B are thus central components of a signalling network that guides spindle positioning, cell-cell adhesion and mitotic fidelity.
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vitiello
authors.affiliation: 1] Chromosome Instability &Dynamics Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal [2] Cell Division Unit, Department of Experimental Biology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Ferreira
authors.affiliation: 1] Chromosome Instability &Dynamics Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal [2] Cell Division Unit, Department of Experimental Biology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
authors.forename: Helder
authors.initials: H
authors.lastname: Maiato
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Balda
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Matter
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000782:Aneuploidy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000080865:Formins; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008938:Mitosis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; C491462:DIAPH2 protein, human; D000080865:Formins; D020690:GTPase-Activating Proteins; C091053:KIF1B protein, human; D034741:RNA, Small Interfering; C473607:STARD13 protein, human; D025521:Tumor Suppressor Proteins; D016547:Kinesins; D020764:cdc42 GTP-Binding Protein