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Elife 2017 Jan 10;6. doi: 10.7554/eLife.22513.
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A sequential multi-target Mps1 phosphorylation cascade promotes spindle checkpoint signaling.

Ji Z , Gao H , Jia L , Li B , Yu H .

The master spindle checkpoint kinase Mps1 senses kinetochore-microtubule attachment and promotes checkpoint signaling to ensure accurate chromosome segregation. The kinetochore scaffold Knl1, when phosphorylated by Mps1, recruits checkpoint complexes Bub1-Bub3 and BubR1-Bub3 to unattached kinetochores. Active checkpoint signaling ultimately enhances the assembly of the mitotic checkpoint complex (MCC) consisting of BubR1-Bub3, Mad2, and Cdc20, which inhibits the anaphase-promoting complex or cyclosome bound to Cdc20 (APC/CCdc20) to delay anaphase onset. Using in vitro reconstitution, we show that Mps1 promotes APC/C inhibition by MCC components through phosphorylating Bub1 and Mad1. Phosphorylated Bub1 binds to Mad1-Mad2. Phosphorylated Mad1 directly interacts with Cdc20. Mutations of Mps1 phosphorylation sites in Bub1 or Mad1 abrogate the spindle checkpoint in human cells. Therefore, Mps1 promotes checkpoint activation through sequentially phosphorylating Knl1, Bub1, and Mad1. This sequential multi-target phosphorylation cascade makes the checkpoint highly responsive to Mps1 and to kinetochore-microtubule attachment.

PubMed ID: 28072388
PMC ID: PMC5268738
Article link: Elife
Grant support: [+]

Species referenced: Xenopus
Genes referenced: bub1 bub1b bub3 cdc20 igf2bp3 knl1 mad2l1 mcc mxd1 myc pigy rps27

Article Images: [+] show captions
References [+] :
Alfieri, Molecular basis of APC/C regulation by the spindle assembly checkpoint. 2016, Pubmed