A model for mitotic checkpoint regulation by Mps1. Prophase: Mps1 is recruited in an Aurora B–dependent manner to unattached and/or tensionless kinetochores, where its activity is stimulated (red), possibly through dimerization. At kinetochores, Mps1 promotes error correction by enhancing Aurora B activity, ensures kinetochore binding of Mad1, inhibits checkpoint silencing mechanisms, and replenishes an interphasic pool of cytoplasmic Mps1 that stabilizes APC/C^Cdc20 inhibitory complexes. Prometaphase: After establishing Mad1 localization, Mps1 promotes kinetochore-dependent catalysis of APC/C^Cdc20 inhibitory complexes via conformational activation of Mad2, and contributes to its own removal from kinetochores. Dotted arrow indicates possibility that Mps1 contributes to maintenance of Mad1 at unattached kinetochores. The unknown details of what pools of Mps1 are dimers is represented by the question mark. Metaphase: The fast turnover of Mps1 at kinetochores allows its removal from kinetochores after stable, bioriented attachment, causing checkpoint silencing and ultimately APC/C^Cdc20 activity toward Cyclin B and Securin. Mis12-Mps1–induced prolonged metaphase: When Mps1 is not removed from kinetochores after biorientation, checkpoint silencing cannot occur. Question mark indicates the likely contribution of a cycling, and thus also cytoplasmic, pool of Mis12-Mps1 (∼60%) with the uncertainty of whether this fusion protein functions as a dimer.