1. The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis.
- Author
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Ban KH, Torres JZ, Miller JJ, Mikhailov A, Nachury MV, Tung JJ, Rieder CL, and Jackson PK
- Subjects
- Anaphase-Promoting Complex-Cyclosome, CDC2 Protein Kinase metabolism, Chromosomes, Human metabolism, Cyclin B metabolism, Dynactin Complex, Dyneins metabolism, Feedback, Physiological physiology, HCT116 Cells, HeLa Cells, Humans, Microtubule-Associated Proteins metabolism, Protein Binding physiology, Anaphase physiology, Antigens, Nuclear metabolism, Cell Cycle Proteins metabolism, F-Box Proteins metabolism, Nuclear Matrix-Associated Proteins metabolism, Spindle Apparatus enzymology, Ubiquitin-Protein Ligase Complexes metabolism
- Abstract
Cyclin-dependent kinase 1 (Cdk1) initiates mitosis and later activates the anaphase-promoting complex/cyclosome (APC/C) to destroy cyclins. Kinetochore-derived checkpoint signaling delays APC/C-dependent cyclin B destruction, and checkpoint-independent mechanisms cooperate to limit APC/C activity when kinetochores lack checkpoint components in early mitosis. The APC/C and cyclin B localize to the spindle and poles, but the significance and regulation of these populations remain unclear. Here we describe a critical spindle pole-associated mechanism, called the END (Emi1/NuMA/dynein-dynactin) network, that spatially restricts APC/C activity in early mitosis. The APC/C inhibitor Emi1 binds the spindle-organizing NuMA/dynein-dynactin complex to anchor and inhibit the APC/C at spindle poles, and thereby limits destruction of spindle-associated cyclin B. Cyclin B/Cdk1 activity recruits the END network and establishes a positive feedback loop to stabilize spindle-associated cyclin B critical for spindle assembly. The organization of the APC/C on the spindle also provides a framework for understanding microtubule-dependent organization of protein destruction.
- Published
- 2007
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