The Bub1-Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation.

The spindle checkpoint senses unattached kinetochores and inhibits the Cdc20-bound anaphase-promoting complex or cyclosome (APC/C), to delay anaphase, thereby preventing aneuploidy. A critical checkpoint inhibitor of APC/C(Cdc20) is the mitotic checkpoint complex (MCC). It is unclear whether MCC suffices to inhibit all cellular APC/C. Here we show that human checkpoint ...
kinase Bub1 not only directly phosphorylates Cdc20, but also scaffolds Plk1-mediated phosphorylation of Cdc20. Phosphorylation of Cdc20 by Bub1-Plk1 inhibits APC/C(Cdc20) in vitro and is required for checkpoint signalling in human cells. Bub1-Plk1-dependent Cdc20 phosphorylation is regulated by upstream checkpoint signals and is dispensable for MCC assembly. A phospho-mimicking Cdc20 mutant restores nocodazole-induced mitotic arrest in cells depleted of Mad2 or BubR1. Thus, Bub1-Plk1-mediated phosphorylation of Cdc20 constitutes an APC/C-inhibitory mechanism that is parallel, but not redundant, to MCC formation. Both mechanisms are required to sustain mitotic arrest in response to spindle defects.
Mesh Terms:
Anaphase-Promoting Complex-Cyclosome, Cdc20 Proteins, Cell Cycle Proteins, Cell Line, Tumor, Flow Cytometry, Fluorescent Antibody Technique, HeLa Cells, Humans, Immunoblotting, Immunoprecipitation, In Vitro Techniques, Kinetochores, M Phase Cell Cycle Checkpoints, Mad2 Proteins, Mutation, Nocodazole, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Signal Transduction, Tubulin Modulators, Ubiquitination
Nat Commun
Date: Feb. 25, 2016
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