page 551. They show that CENP-E, a mitotic checkpoint-silencing protein, also stimulates the amount of checkpoint inhibitor released from an unattached kinetochore.
The mitotic checkpoint is the major mechanism preventing chromosomal loss during mammalian mitosis. Unattached kinetochores generate an inhibitor that blocks the destruction of proteins whose loss is required for initiating chromosome segregation. The chromosomal kinesin CENP-E helps to silence checkpoint signaling by promoting stable bipolar kinetochore attachments to spindle pole microtubules. The checkpoint can be activated in the absence of CENP-E when most of the chromosomes are misattached (as occurs when microtubules are destabilized). But Weaver et al. show that if only one or two chromosomes are not correctly attached (as probably occurs at least transiently in most normal cells preparing for mitosis), cells lacking CENP-E fail to mount a checkpoint and thus produce aneuploid daughter cells.
The checkpoint fails without CENP-E because the checkpoint-activating protein BubR1 is not recruited to kinetochores and because its kinase activity is not stimulated. The group shows that CENP-E binds to BubR1 and activates its autophosphorylation during mitosis. Thus, by activating its binding partner BubR1, CENP-E amplifies the basal checkpoint signal produced at individual kinetochores. ▪