Figure 4. Proposed model for the function of KNL1 in kinetochore-MT attachment regulation and the SAC.

In early mitosis, KNL1 promotes the kinetochore recruitment of SAC proteins Bub1, BubR1, Bub3, Mad1, and Mad2, which leads to generation and amplification of the “wait anaphase” signal that inhibits APC/C^Cdc20 activation. Association of Bub1 with KNL1 promotes Bub1 activity, leading to centromere and kinetochore Aurora B kinase recruitment and activation. Aurora B phosphorylates outer kinetochore substrates, which prevents premature kinetochore-MT stabilization. In late mitosis, KNL1-mediated recruitment of phosphatases antagonizing Aurora B promotes kinetochore-MT attachment stability. PP1 dephosphorylates KNL1, resulting in Bub1 dissociation and subsequent loss of SAC proteins. PP1 binding to KNL1 and KNL1 MT binding additionally promotes SAC silencing. With attached kinetochores no longer amplifying the “wait anaphase” signal, dissembled SAC inhibitory complexes lead to APC/C^Cdc20 activation, Cyclin B and securin degradation, and mitotic exit. *The cartoon shows the Mis12 complex and CENP-T simultaneously binding to the Ndc80 complex for simplicity. However, it has been demonstrated that these two kinetochore components compete for binding to the Ndc80 complex (Bock et al. 2012; Nishino et al. 2013; Schleiffer et al. 2012).