PP6 regulation of Aurora A-TPX2 limits NDC80 phosphorylation and mitotic spindle size
© 2023 Sobajima et al..
Amplification of the mitotic kinase Aurora A or loss of its regulator protein phosphatase 6 (PP6) have emerged as drivers of genome instability. Cells lacking PPP6C, the catalytic subunit of PP6, have amplified Aurora A activity, and as we show here, enlarged mitotic spindles which fail to hold chromosomes tightly together in anaphase, causing defective nuclear structure. Using functional genomics to shed light on the processes underpinning these changes, we discover synthetic lethality between PPP6C and the kinetochore protein NDC80. We find that NDC80 is phosphorylated on multiple N-terminal sites during spindle formation by Aurora A-TPX2, exclusively at checkpoint-silenced, microtubule-attached kinetochores. NDC80 phosphorylation persists until spindle disassembly in telophase, is increased in PPP6C knockout cells, and is Aurora B-independent. An Aurora-phosphorylation-deficient NDC80-9A mutant reduces spindle size and suppresses defective nuclear structure in PPP6C knockout cells. In regulating NDC80 phosphorylation by Aurora A-TPX2, PP6 plays an important role in mitotic spindle formation and size control and thus the fidelity of cell division.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:222 |
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| Enthalten in: |
The Journal of cell biology - 222(2023), 5 vom: 01. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sobajima, Tomoaki [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.03.2023 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1083/jcb.202205117 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM354029606 |
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| 100 | 1 | |a Sobajima, Tomoaki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PP6 regulation of Aurora A-TPX2 limits NDC80 phosphorylation and mitotic spindle size |
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| 500 | |a Date Revised 10.02.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 Sobajima et al. | ||
| 520 | |a Amplification of the mitotic kinase Aurora A or loss of its regulator protein phosphatase 6 (PP6) have emerged as drivers of genome instability. Cells lacking PPP6C, the catalytic subunit of PP6, have amplified Aurora A activity, and as we show here, enlarged mitotic spindles which fail to hold chromosomes tightly together in anaphase, causing defective nuclear structure. Using functional genomics to shed light on the processes underpinning these changes, we discover synthetic lethality between PPP6C and the kinetochore protein NDC80. We find that NDC80 is phosphorylated on multiple N-terminal sites during spindle formation by Aurora A-TPX2, exclusively at checkpoint-silenced, microtubule-attached kinetochores. NDC80 phosphorylation persists until spindle disassembly in telophase, is increased in PPP6C knockout cells, and is Aurora B-independent. An Aurora-phosphorylation-deficient NDC80-9A mutant reduces spindle size and suppresses defective nuclear structure in PPP6C knockout cells. In regulating NDC80 phosphorylation by Aurora A-TPX2, PP6 plays an important role in mitotic spindle formation and size control and thus the fidelity of cell division | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Phosphoprotein Phosphatases |2 NLM | |
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| 650 | 7 | |a protein phosphatase 6 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.16 |2 NLM | |
| 650 | 7 | |a Cytoskeletal Proteins |2 NLM | |
| 650 | 7 | |a Aurora Kinase A |2 NLM | |
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| 650 | 7 | |a Microtubule-Associated Proteins |2 NLM | |
| 700 | 1 | |a Kowalczyk, Katarzyna M |e verfasserin |4 aut | |
| 700 | 1 | |a Skylakakis, Stefanos |e verfasserin |4 aut | |
| 700 | 1 | |a Hayward, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Fulcher, Luke J |e verfasserin |4 aut | |
| 700 | 1 | |a Neary, Colette |e verfasserin |4 aut | |
| 700 | 1 | |a Batley, Caleb |e verfasserin |4 aut | |
| 700 | 1 | |a Kurlekar, Samvid |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Emile |e verfasserin |4 aut | |
| 700 | 1 | |a Gruneberg, Ulrike |e verfasserin |4 aut | |
| 700 | 1 | |a Barr, Francis A |e verfasserin |4 aut | |
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