title: Interactions between the kinetochore complex and the protein kinase A pathway in Saccharomyces cerevisiae.
abstract: The kinetochore is a large structure composed of multiple protein subcomplexes that connect chromosomes to spindle microtubules to enable accurate chromosome segregation. Significant advances have been made in the identification of kinetochore proteins and elucidation of kinetochore structure; however, comparatively little is known about how cellular signals integrate with kinetochore function. In the budding yeast Saccharomyces cerevisiae, the cyclic AMP protein kinase A signaling pathway promotes cellular growth in response to glucose. In this study, we find that decreasing protein kinase A activity, either by overexpressing negative regulators of the pathway or deleting the upstream effector Ras2, improves the viability of ipl1 and spc24 kinetochore mutants. Ipl1/Aurora B is a highly conserved kinase that corrects attachment of sister kinetochores that have attached to the same spindle pole, whereas Spc24 is a component of the conserved Ndc80 kinetochore complex that attaches directly to microtubules. Unexpectedly, we find that kinetochore mutants have increased phosphorylation levels of protein kinase A substrates, suggesting that the cyclic AMP protein kinase A signaling pathway is stimulated. The increase in protein kinase A activity in kinetochore mutants is not induced by activation of the spindle checkpoint or a metaphase delay because protein kinase A activity remains constant during an unperturbed cell cycle. Finally, we show that lowering protein kinase A activity can rescue the chromosome loss defect of the inner kinetochore ndc10 mutant. Overall, our data suggest that the increased protein kinase A activity in kinetochore mutants is detrimental to cellular growth and chromosome transmission fidelity.
authors.affiliation: Wine Research Centre, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Lina
authors.initials: L
authors.lastname: Ma
authors.forename: Krystina
authors.initials: K
authors.lastname: Ho
authors.forename: Nina
authors.initials: N
authors.lastname: Piggott
authors.forename: Zongli
authors.initials: Z
authors.lastname: Luo
authors.forename: Vivien
authors.initials: V
authors.lastname: Measday
mesh_terms: D064127:Aurora Kinases; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; C500717:Spc24 protein, S cerevisiae; D000242:Cyclic AMP; D064127:Aurora Kinases; C576961:IPL1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C489015:RAS2 protein, S cerevisiae; D018631:ras Proteins