‘Feedback’ pathways in the spindle-assembly checkpoint (SAC) network

The spindle-assembly checkpoint (SAC) network is complex.  In the absence of kinetochore microtubules in prometaphase, several activities converge on the creation of the mitotic checkpoint complex (MCC), which is an anaphase-promoting complex/cyclosome (APC/C) inhibitor.  The Aurora-B (AurB), cyclin- dependent kinase-1 (CDK1) and budding uninhibited by benzimidazole (BUB)1 kinases might stimulate directly the formation of the MCC.  Although the mechanistic details for this are still unclear, phosphorylation of CDC20 by BUB1 and CDK1 (and possibly mitogen-activated protein kinase (MAPK); not shown) might contribute to the formation of the MCC.  The closed MAD2 (C-MAD2)–MAD1 complex is recruited to kinetochores thanks to the ROD (rough deal)–ZW10 (zeste white-10)–ZWILCH (RZZ) complex and is regulated by the multipolar spindle-1 (MPS1) kinase.  C-MAD2–MAD1 activates what is probably the rate-limiting step of MCC formation, the binding of open MAD2 (O-MAD2) to CDC20. In a separate branch of the SAC response, centromere protein (CENP)-E binds and activates BUBR1 at unattached kinetochores.  The kinase activity of BUBR1 is directed against unknown substrates. We have depicted BUBR1 kinase activity as having a direct inhibitory effect on anaphase. On microtubule–kinetochore attachment, a mechanism of ‘stripping’ based on the poleward-directed microtubule-motor activity of the dynein–dynactin complex starts removing SAC proteins, including the RZZ complex, MPS1 and C-MAD2–MAD1, from kinetochores. p31comet might also be reactivated at this stage to inhibit the interaction of C-MAD2 with O-MAD2.  The ability of CENP-E to activate BUBR1 also subsides on formation of stable microtubule–kinetochore attachments. All this results in the activation of the APC/C-dependent polyubiquitylation of cyclin B and securin (SEC) and their subsequent proteolysis, which then allows execution of anaphase through activation of separase.  The ubiquitylation of MPS1 by the APC/C also seems to be required to irreversibly inactivate the SAC at anaphase. BOR, borealin; CPC, chromosomal passenger complex; INCENP, inner centromere protein; SUR, survivin.