title: p120-catenin prevents multinucleation through control of MKLP1-dependent RhoA activity during cytokinesis.
abstract: Spatiotemporal activation of RhoA and actomyosin contraction underpins cellular adhesion and division. Loss of cell-cell adhesion and chromosomal instability are cardinal events that drive tumour progression. Here, we show that p120-catenin (p120) not only controls cell-cell adhesion, but also acts as a critical regulator of cytokinesis. We find that p120 regulates actomyosin contractility through concomitant binding to RhoA and the centralspindlin component MKLP1, independent of cadherin association. In anaphase, p120 is enriched at the cleavage furrow where it binds MKLP1 to spatially control RhoA GTPase cycling. Binding of p120 to MKLP1 during cytokinesis depends on the N-terminal coiled-coil domain of p120 isoform 1A. Importantly, clinical data show that loss of p120 expression is a common event in breast cancer that strongly correlates with multinucleation and adverse patient survival. In summary, our study identifies p120 loss as a driver event of chromosomal instability in cancer.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Robert A H
authors.initials: RA
authors.lastname: van de Ven
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Jolien S
authors.initials: JS
authors.lastname: de Groot
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: van Domselaar
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands.
authors.forename: Karoly
authors.identifier: 0000-0002-1228-4245
authors.initials: K
authors.lastname: Szuhai
authors.affiliation: Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.|Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.|Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: H Raza
authors.initials: HR
authors.lastname: Ali
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.|Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.|Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Hetzer
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D048749:Cytokinesis; D005260:Female; D006367:HeLa Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D011485:Protein Binding; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; C092935:KIF23 protein, human; D008869:Microtubule-Associated Proteins; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin