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Updated: Jan 19, 2026
Rare Event Detection Using Error-corrected DNA and RNA Sequencing
Published on: August 3, 2018
Checkpoint signaling and error correction require regulation of the MPS1 T-loop by PP2A-B56
Daniel Hayward1, James Bancroft1, Davinderpreet Mangat1
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Abstract:
During mitosis, the formation of microtubule-kinetochore attachments is monitored by the serine/threonine kinase monopolar spindle 1 (MPS1). MPS1 is recruited to unattached kinetochores where it phosphorylates KNL1, BUB1, and MAD1 to initiate the spindle assembly checkpoint. This arrests the cell cycle until all kinetochores have been stably captured by microtubules. MPS1 also contributes to the error correction process rectifying incorrect kinetochore attachments. MPS1 activity at kinetochores requires autophosphorylation at multiple sites including threonine 676 in the activation segment or "T-loop." We now demonstrate that the BUBR1-bound pool of PP2A-B56 regulates MPS1 T-loop autophosphorylation and hence activation status in mammalian cells. Overriding this regulation using phosphomimetic mutations in the MPS1 T-loop to generate a constitutively active kinase results in a prolonged mitotic arrest with continuous turnover of microtubule-kinetochore attachments. Dynamic regulation of MPS1 catalytic activity by kinetochore-localized PP2A-B56 is thus critical for controlled MPS1 activity and timely cell cycle progression.
Insights
The protein kinase MPS1 (monopolar spindle 1) controls cell division. PP2A-B56 regulates MPS1 activity, ensuring correct chromosome attachment and timely cell cycle progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Monopolar spindle 1 (MPS1) is a kinase essential for monitoring microtubule-kinetochore attachments during mitosis.
- MPS1 initiates the spindle assembly checkpoint by phosphorylating key proteins at unattached kinetochores, arresting the cell cycle until proper attachment occurs.
- MPS1 also plays a role in correcting erroneous kinetochore attachments.
Purpose of the Study:
- To investigate the regulation of MPS1 activity at kinetochores.
- To identify the specific mechanisms controlling MPS1 autophosphorylation at threonine 676 (T-loop).
- To determine the role of PP2A-B56 in regulating MPS1 activation and its impact on mitotic progression.
Main Methods:
- Utilized phosphomimetic mutations in the MPS1 T-loop to create a constitutively active kinase.
- Investigated the interaction between MPS1 and PP2A-B56 in mammalian cells.
- Observed the effects of altered MPS1 activity on mitotic arrest and microtubule-kinetochore attachment dynamics.
Main Results:
- Demonstrated that the BUBR1-bound PP2A-B56 complex regulates MPS1 T-loop autophosphorylation in mammalian cells.
- Showed that constitutively active MPS1, due to phosphomimetic mutations, leads to prolonged mitotic arrest.
- Observed continuous turnover of microtubule-kinetochore attachments in cells with constitutively active MPS1.
Conclusions:
- Dynamic regulation of MPS1 catalytic activity by kinetochore-localized PP2A-B56 is crucial for controlled MPS1 function.
- This regulation is essential for accurate kinetochore-microtubule attachment and timely cell cycle progression through mitosis.
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