PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis
María Sanz-Flores,
Miguel Ruiz-Torres,
Cristina Aguirre-Portolés,
Aicha El Bakkali,
Beatriz Salvador-Barberó,
Carolina Villarroya-Beltri,
Sagrario Ortega,
Diego Megías,
Daniel W. Gerlich,
Mónica Álvarez-Fernández,
Marcos Malumbres
Affiliations
María Sanz-Flores
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Miguel Ruiz-Torres
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Cristina Aguirre-Portolés
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Aicha El Bakkali
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Beatriz Salvador-Barberó
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Carolina Villarroya-Beltri
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Sagrario Ortega
Mouse Genome Editing Unit, CNIO, Madrid, Spain
Diego Megías
Confocal Microscopy Unit, CNIO, Madrid, Spain
Daniel W. Gerlich
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria
Mónica Álvarez-Fernández
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Health Research Institute of Asturias (ISPA), University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Corresponding author
Marcos Malumbres
Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; ICREA, Barcelona, Spain; Corresponding author
Summary: Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.
