A Biosensor for the Mitotic Kinase MPS1 Reveals Spatiotemporal Activity Dynamics and Regulation
| Autor: | Sonja Weterings, Ana C.F. Bolhaqueiro, Bas Ponsioen, Geert J. P. L. Kops, Maaike L.A. Lambers, Debbie H.M. Staijen, Timo E. F. Kuijt |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aurora B kinase Mitosis Cell Cycle Proteins Spindle Apparatus Biology Protein Serine-Threonine Kinases Microtubules General Biochemistry Genetics and Molecular Biology Chromosome segregation 03 medical and health sciences 0302 clinical medicine Spatio-Temporal Analysis Cell Line Tumor Chromosome Segregation Fluorescence Resonance Energy Transfer Aurora Kinase B Humans Prometaphase Phosphorylation Kinetochores Metaphase Anaphase Cell Nucleus Kinetochore Cell Cycle Protein-Tyrosine Kinases Cell biology Organoids Spindle checkpoint 030104 developmental biology M Phase Cell Cycle Checkpoints General Agricultural and Biological Sciences 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | Current Biology, 30(19), 3862-3870.e6. Cell Press |
| ISSN: | 1879-0445 0960-9822 |
| Popis: | Accurate chromosome segregation during cell division critically depends on error correction of chromosome-spindle interactions and the spindle assembly checkpoint (SAC) [1-3]. The kinase MPS1 is an essential regulator of both processes, ensuring full chromosome biorientation before anaphase onset [3, 4]. To understand when and where MPS1 activation occurs and how MPS1 signaling is modulated during mitosis, we developed MPS1sen, a sensitive and specific FRET-based biosensor for MPS1 activity. By placing MPS1sen at different subcellular locations, we show that MPS1 activity initiates in the nucleus ∼9-12 min prior to nuclear envelope breakdown (NEB) in a kinetochore-dependent manner and reaches the cytoplasm at the start of NEB. Soon after initiation, MPS1 activity increases with switch-like kinetics, peaking at completion of NEB. We further show that timing and extent of pre-NEB MPS1 activity is regulated by Aurora B and PP2A-B56. MPS1sen phosphorylation declines in prometaphase as a result of formation of kinetochore-microtubule attachments, reaching low but still detectable levels at metaphase. Finally, leveraging the sensitivity and dynamic range of MPS1sen, we show deregulated MPS1 signaling dynamics in colorectal cancer cell lines and tumor organoids with diverse genomic instability phenotypes. |
| Databáze: | OpenAIRE |
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