| 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 novel spindle pole-associated mechanism, called the END (Emi1/NuMA/Dynein-dynactin) network, which 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 limit 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. |
