MPS1 localizes to end-on microtubule-attached kinetochores to promote microtubule release

In eukaryotes, the spindle assembly checkpoint protects genome stability in mitosis by preventing chromosome segregation until incorrect microtubule-kinetochore attachment geometries have been eliminated and chromosome biorientation has been completed. These error correction and checkpoint processes are linked by the conserved Aurora B and MPS1 Ser/Thr kinases.(1,2) MPS1-dependent checkpoint signaling is believed to be initiatedby kinetochoreswithout end-on microtubule attachments,(3,4) including those generatedby Aurora B-mediated error correction. The current model posits thatMPS1 competeswithmicrotubules for binding sites at the kinetochore.(3,4) MPS1 is thought to first recognize kinetochores not blocked by microtubules and then initiate checkpoint signaling. However, MPS1 is also required for chromosome biorientation and correction of microtubule-kinetochore attachment errors.(5-9) This latter function, which must require direct interaction with microtubule-attached kinetochores, is not readily explained within the constraints of the current model. Here, we show that MPS1 transiently localizes to end-on attached kinetochores and that this recruitment depends on the relative activities of Aurora B and its counteracting phosphatase PP2A-B56 rather than microtubule-attachment state per se. MPS1 autophosphorylation also regulates MPS1 kinetochore levels but does notdetermine the response to microtubule attachment. At end-on attached kinetochores, MPS1 actively promotes microtubule release together with Aurora B. Furthermore, in live cells, MPS1 is detected at attached kinetochores before the removal of microtubules. During chromosome alignment, MPS1, therefore, coordinates both the resolution of incorrect microtubule-kinetochore attachments and the initiation of spindle checkpoint signaling.

Automated summary

In eukaryotes, the spindle assembly checkpoint is important for maintaining genome stability during mitosis. MPS1, together with Aurora B and PP2A-B56, plays a critical role in error correction and checkpoint signaling. MPS1 localizes to end-on attached kinetochores and promotes microtubule release, contributing to the resolution of incorrect microtubule-kinetochore attachments and the initiation of spindle checkpoint signaling.