A novel protein phosphatase 1-dependent spindle checkpoint silencing mechanism.
The spindle checkpoint is a surveillance system acting in mitosis to delay anaphase onset until all chromosomes are properly attached to the mitotic spindle. When the checkpoint is activated, the Mad2 and Mad3 proteins directly bind and inhibit Cdc20, which is an essential activator of an E3 ubiquitin ligase known as the anaphase-promoting complex (APC). When the checkpoint is satisfied, Cdc20-APC is activated and polyubiquitinates securin and cyclin, leading to the dissolution of sister chromatid cohesion and mitotic progression. Several protein kinases play critical roles in spindle checkpoint signaling, but the mechanism (or mechanisms) by which they inhibit mitotic progression remains unclear. Furthermore, it is not known whether their activity needs to be reversed by protein phosphatases before anaphase onset can occur. Here we employ fission yeast to show that Aurora (Ark1) kinase activity is directly required to maintain spindle checkpoint arrest, even in the presence of many unattached kinetochores. Upon Ark1 inhibition, checkpoint complexes are disassembled and cyclin B is rapidly degraded. Importantly, checkpoint silencing and cyclin B degradation require the kinetochore-localized isoform of protein phosphatase 1 (PP1(Dis2)). We propose that PP1(Dis2)-mediated dephosphorylation of checkpoint components forms a novel spindle checkpoint silencing mechanism.
Vanoosthuyse
Vincent
V
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK. vvanoost@staffmail.ed.ac.uk
Hardwick
Kevin G
KG
D064173:Anaphase-Promoting Complex-Cyclosome; D064127:Aurora Kinases; D019926:Cyclin B / Q000378:metabolism; D018816:Genes, cdc / Q000502:physiology*; D018386:Kinetochores / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012568:Schizosaccharomyces; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D008941:Spindle Apparatus / Q000502:physiology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D019926:Cyclin B; D029702:Schizosaccharomyces pombe Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C576962:ark1 protein, S pombe; D054645:Protein Phosphatase 1