Dataset Information

ICIS and Aurora B coregulate the microtubule depolymerase Kif2a.

ABSTRACT: Kinesins in the mitotic spindle play major roles in determining spindle shape, size, and bipolarity, although specific regulation of these kinesins at distinct locations on the spindle is poorly understood. So that the forces that are required for spindle bipolarity are balanced, microtubule-depolymerizing kinesins are tightly regulated. Aurora B kinase phosphorylates the neck regions of the kinesin-13 family microtubule depolymerases Kif2a and mitotic centromere-associated kinesin (MCAK) and inhibits their depolymerase activities. How they are reactivated and how this is controlled independently on different kinetochore fibers is unknown. We show that inner centromere Kin-I stimulator (ICIS), which stimulates the related depolymerase MCAK, can reactivate Kif2a after Aurora B inhibition. When antibodies that block the ability of ICIS to activate Kif2a are injected into cells, monopolar spindles are generated. This phenotype is rescued by coinjection of anti-Nuf2 antibodies. We have performed a structure-function analysis of the ICIS protein and find that the N terminus of ICIS binds Aurora B and its regulators INCENP and TD60, whereas a central region binds MCAK, Kif2a, and microtubules, suggesting a scaffold function for ICIS. These data argue that ICIS and the chromosomal passenger complex (CPC) regulate Kif2a depolymerase activity.

SUBMITTER: Knowlton AL

PROVIDER: S-EPMC2775053 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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ICIS and Aurora B coregulate the microtubule depolymerase Kif2a.

Knowlton Anne L AL Vorozhko Valeriya V VV Lan Weijie W Gorbsky Gary J GJ Stukenberg P Todd PT

Current biology : CB 20090326 9

Kinesins in the mitotic spindle play major roles in determining spindle shape, size, and bipolarity, although specific regulation of these kinesins at distinct locations on the spindle is poorly understood. So that the forces that are required for spindle bipolarity are balanced, microtubule-depolymerizing kinesins are tightly regulated. Aurora B kinase phosphorylates the neck regions of the kinesin-13 family microtubule depolymerases Kif2a and mitotic centromere-associated kinesin (MCAK) and in ...[more]

PMID: 19327998

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Project description:Chemotherapeutic drugs often target the microtubule cytoskeleton as a means to disrupt cancer cell mitosis and proliferation. Anti-microtubule drugs inhibit microtubule dynamics, thereby triggering apoptosis when dividing cells activate the mitotic checkpoint. Microtubule dynamics are regulated by microtubule-associated proteins (MAPs); however, we lack a comprehensive understanding about how anti-microtubule agents functionally interact with MAPs. In this report, we test the hypothesis that the cellular levels of microtubule depolymerases, in this case kinesin-13 s, modulate the effectiveness of the microtubule disrupting drug colchicine.We used a combination of RNA interference (RNAi), high-throughput microscopy, and time-lapse video microscopy in Drosophila S2 cells to identify a specific MAP, kinesin-like protein 10A (KLP10A), that contributes to the efficacy of the anti-microtubule drug colchicine. KLP10A is an essential microtubule depolymerase throughout the cell cycle. We find that depletion of KLP10A in S2 cells confers resistance to colchicine-induced microtubule depolymerization to a much greater extent than depletion of several other destabilizing MAPs. Using image-based assays, we determined that control cells retained 58% (+/-2%SEM) of microtubule polymer when after treatment with 2 microM colchicine for 1 hour, while cells depleted of KLP10A by RNAi retained 74% (+/-1%SEM). Likewise, overexpression of KLP10A-GFP results in increased susceptibility to microtubule depolymerization by colchicine.Our results demonstrate that the efficacy of microtubule destabilization by a pharmacological agent is dependent upon the cellular expression of a microtubule depolymerase. These findings suggest that expression levels of Kif2A, the human kinesin-13 family member, may be an attractive biomarker to assess the effectiveness of anti-microtubule chemotherapies. Knowledge of how MAP expression levels affect the action of anti-microtubule drugs may prove useful for evaluating possible modes of cancer treatment.

Dataset Information

ICIS and Aurora B coregulate the microtubule depolymerase Kif2a.

Publications

ICIS and Aurora B coregulate the microtubule depolymerase Kif2a.

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