Role in Chromosome Biorientation
Studies in several organisms indicate that Aurora B oversees chromosome biorientation by ensuring that appropriate connections are made between spindle microtubules and kinetochores.
Inhibition of Aurora B function by RNA interference or microinjection of blocking antibodies impairs the alignment of chromosomes at the equator of the mitotic spindle. This process of alignment is referred to as chromosome congression. The reason for this defect is a subject of ongoing study. Aurora B inhibition may lead to an increase in the number of syntelic attachments (sister chromatid pairs in which both sister kinetochores are attached to microtubules radiating from the same spindle pole). Intriguingly, expression of a dominant-negative and catalytically inactive form of Aurora B disrupted microtuble attachment to the kinetochore and prevented the association of dynein and centromere protein E (CENP-E) with kinetochores.
Numerous kinetochore targets of Aurora kinases have been determined in organisms ranging from yeast to man. Most notably, CENP-A is a target of Aurora B. The phosphorylation of CENP-A by Aurora B reaches a maximum in prometaphase. In fact, Aurora A targets the same CENP-A phosphorylation site as Aurora B, and CENP-A phosphorylation by Aurora A is thought to precede that by Aurora B. Thus, a model has been proposed in which CENP-A phosphorylation by Aurora A recruits Aurora B to the centromere, the latter maintaining the phosphorylation state of CENP-A in a positive feedback loop. Oddly, mutation of this phosphorylation site in CENP-A leads to defects in cytokinesis.
Aurora B also interacts with mitotic centromere-associated kinesin (MCAK). Both Aurora B and MCAK localize to the inner centromere during prometaphase. Aurora B has been shown to recruit MCAK to the centromere and directly phosphorylate MCAK on various residues. Phosphorylation of MCAK by Aurora B limits the ability of MCAK to depolymerize microtubules. Importantly, inhibition of MCAK by a number of approaches leads to improper attachment of kinetochores to spindle microtubules.
It has been hypothesized that tension generated by amphitelic attachment (biorientation; the attachment of sister kinetochores to opposite spindle poles) pulls sister kinetochores apart, thus disrupting the interaction of Aurora B at the innermost portion of the centromere with microtubule binding sites on the fibrous corona of the outermost centromere. Specifically, the tension generated by biorientation pulls MCAK outside of the area of Aurora B localization. Thus, mitosis proceeds upon biorientation and dissociation of Aurora B from its substrates.
Read more about this topic: Aurora B Kinase
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