title: Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.
abstract: Error-free chromosome segregation depends on the precise regulation of phosphorylation to stabilize kinetochore-microtubule attachments (K-fibres) on sister chromatids that have attached to opposite spindle poles (bi-oriented). In many instances, phosphorylation correlates with K-fibre destabilization. Consistent with this, multiple kinases, including Aurora B and Plk1, are enriched at kinetochores of mal-oriented chromosomes when compared with bi-oriented chromosomes, which have stable attachments. Paradoxically, however, these kinases also target to prometaphase chromosomes that have not yet established spindle attachments and it is therefore unclear how kinetochore-microtubule interactions can be stabilized when kinase levels are high. Here we show that the generation of stable K-fibres depends on the B56-PP2A phosphatase, which is enriched at centromeres/kinetochores of unattached chromosomes. When B56-PP2A is depleted, K-fibres are destabilized and chromosomes fail to align at the spindle equator. Strikingly, B56-PP2A depletion increases the level of phosphorylation of Aurora B and Plk1 kinetochore substrates as well as Plk1 recruitment to kinetochores. Consistent with increased substrate phosphorylation, we find that chemical inhibition of Aurora or Plk1 restores K-fibres in B56-PP2A-depleted cells. Our findings reveal that PP2A, an essential tumour suppressor, tunes the balance of phosphorylation to promote chromosome-spindle interactions during cell division.
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Foley
authors.forename: Maria
authors.initials: M
authors.lastname: Maldonado
authors.forename: Tarun M
authors.initials: TM
authors.lastname: Kapoor
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018386:Kinetochores / Q000187:drug effects / Q000201:enzymology*; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides; D018797:Cell Cycle Proteins; D007211:Indoles; D007976:Leupeptins; D015739:Nocodazole; D047428:Protein Kinase Inhibitors; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; C518477:BI 2536; C525690:PPP2R5A protein, human; C576921:AURKB protein, human; C474723:hesperadin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde