title: Shugoshin-1 balances Aurora B kinase activity via PP2A to promote chromosome bi-orientation.
abstract: Correction of faulty kinetochore-microtubule attachments is essential for faithful chromosome segregation and dictated by the opposing activities of Aurora B kinase and PP1 and PP2A phosphatases. How kinase and phosphatase activities are appropriately balanced is less clear. Here, we show that a centromeric pool of PP2A-B56 counteracts Aurora B T-loop phosphorylation and is recruited to centromeres through Shugoshin-1 (Sgo1). In non-transformed RPE-1 cells, Aurora B, Sgo1, and PP2A-B56 are enriched on centromeres and levels diminish as chromosomes establish bi-oriented attachments. Elevating Sgo1 levels at centromeres recruits excess PP2A-B56, and this counteracts Aurora B kinase activity, undermining efficient correction of kinetochore-microtubule attachment errors. Conversely, Sgo1-depleted cells display reduced centromeric localization of Aurora B, whereas the remaining kinase is hyperactive due to concomitant reduction of centromeric PP2A-B56. Our data suggest that Sgo1 can tune the stability of kinetochore-microtubule attachments through recruitment of PP2A-B56 that balances Aurora B activity at the centromere.
authors.affiliation: Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Amanda
authors.initials: A
authors.lastname: Meppelink
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kabeche
authors.affiliation: Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Martijn J M
authors.initials: MJ
authors.lastname: Vromans
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
authors.affiliation: Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address: s.m.a.lens@umcutrecht.nl.
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: Lens
mesh_terms: D064107:Aurora Kinase B / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002503:Centromere / Q000378:metabolism*; D023902:Chromosome Pairing; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C496644:SGO1 protein, human; D064107:Aurora Kinase B; D054648:Protein Phosphatase 2