title: Removal of centrosomal PP1 by NIMA kinase unlocks the MPF feedback loop to promote mitotic commitment in S. pombe.
abstract: BACKGROUND
  Activation of the Cdk1/cyclin B complex, also known as mitosis-promoting factor (MPF), drives commitment to mitosis. Interphase MPF is inhibited through phosphorylation of Cdk1 by Wee1-related kinases. Because Cdc25 phosphatases remove this phosphate, Cdc25 activity is an essential part of the switch that drives cells into mitosis. The generation of a critical "trigger" of active MPF promotes a positive feedback loop that employs Polo kinase to boost Cdc25 activity and inhibit Wee1, thereby ensuring that mitotic commitment is a bistable switch. Mutations in the spindle pole body (SPB) component Cut12 suppress otherwise lethal deficiencies in Cdc25.
  
  
  RESULTS
  Cut12 harbors a bipartite protein phosphatase 1 (PP1) docking domain. Mutation of either element alone suppressed the temperature-dependent lethality of cdc25.22, whereas simultaneous ablation of both allowed cells to divide in the complete absence of Cdc25. Late G2 phase phosphorylation between the two elements by MPF and the NIMA kinase Fin1 blocked PP1(Dis2) recruitment, thereby promoting recruitment of Polo to Cut12 and the SPB and elevating global Polo kinase activity throughout the cell.
  
  
  CONCLUSIONS
  PP1 recruitment to Cut12 sets a threshold for Polo's feedback-loop activity that locks the cell in interphase until Cdc25 pushes MPF activity through this barrier to initiate mitosis. We propose that events on the SPB (and, by inference, the centrosome) integrate inputs from diverse signaling networks to generate a coherent decision to divide that is appropriate for the particular environmental context of each cell. PP1 recruitment sets one or more critical thresholds for single or multiple local events within this switch.
authors: CRUK Cell Division Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Agnes
authors: A
authors: Grallert
authors: Kuan Yoow
authors: KY
authors: Chan
authors: Maria-Luisa
authors: ML
authors: Alonso-Nuñez
authors: Marisa
authors: M
authors: Madrid
authors: Ashapurna
authors: A
authors: Biswas
authors: Isabel
authors: I
authors: Alvarez-Tabarés
authors: Yvonne
authors: Y
authors: Connolly
authors: Kayoko
authors: K
authors: Tanaka
authors: Alasdair
authors: A
authors: Robertson
authors: José-Miguel
authors: JM
authors: Ortiz
authors: Duncan L
authors: DL
authors: Smith
authors: Iain M
authors: IM
authors: Hagan
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D018385:Centrosome / Q000201:enzymology; D016200:Maturation-Promoting Factor / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D008969:Molecular Sequence Data; D000072380:NIMA-Related Kinase 1; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C111708:Cut12 protein, S pombe; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D029702:Schizosaccharomyces pombe Proteins; D011494:Protein Kinases; C113816:Sid2 protein, S pombe; D000072380:NIMA-Related Kinase 1; C501407:Plo1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; C000606921:fin1 protein, S pombe; D016200:Maturation-Promoting Factor; C570820:Cdc25 protein, S pombe; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1