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Aurora A kinase and its substrate TACC3 are required for central spindle assembly.

ABSTRACT: Cell division entails a marked reorganization of the microtubule network to form the spindle, a molecular machine that ensures accurate chromosome segregation to the daughter cells. Spindle organization is highly dynamic throughout mitosis and requires the activity of several kinases and complex regulatory mechanisms. Aurora A (AurA) kinase is essential for the assembly of the metaphase bipolar spindle and, thus, it has been difficult to address its function during the last phases of mitosis. Here, we examine the consequences of inhibiting AurA in cells undergoing anaphase, and show that AurA kinase activity is necessary for the assembly of a robust central spindle during anaphase. We also identify TACC3 as an AurA substrate essential in central spindle formation.

SUBMITTER: Lioutas A

PROVIDER: S-EPMC3790052 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Aurora A kinase and its substrate TACC3 are required for central spindle assembly.

Lioutas Antonios A Vernos Isabelle I

EMBO reports 20130726 9

Cell division entails a marked reorganization of the microtubule network to form the spindle, a molecular machine that ensures accurate chromosome segregation to the daughter cells. Spindle organization is highly dynamic throughout mitosis and requires the activity of several kinases and complex regulatory mechanisms. Aurora A (AurA) kinase is essential for the assembly of the metaphase bipolar spindle and, thus, it has been difficult to address its function during the last phases of mitosis. He ...[more]

PMID: 23887685

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Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly.

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Kinetochore components are required for central spindle assembly.

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Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix.

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Aurora A is involved in central spindle assembly through phosphorylation of Ser 19 in P150Glued.

Project description:Knowledge of Aurora A kinase functions is limited to premetaphase events, particularly centrosome maturation, G2/M transition, and mitotic spindle assembly. The involvement of Aurora A in events after metaphase has only been suggested because appropriate experiments are technically difficult. We report here the design of the first human Aurora A kinase (as-AurA) engineered by chemical genetics techniques. This kinase is fully functional biochemically and in cells, and is rapidly and specifically inhibited by the ATP analogue 1-Naphthyl-PP1 (1-Na-PP1). By treating cells exclusively expressing the as-AurA with 1-Na-PP1, we discovered that Aurora A is required for central spindle assembly in anaphase through phosphorylation of Ser 19 of P150Glued. This paper thus describes a new Aurora A function that takes place after the metaphase-to-anaphase transition and a new powerful tool to search for and study new Aurora A functions.

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Aurora B and Kif2A control microtubule length for assembly of a functional central spindle during anaphase.

Project description:The central spindle is built during anaphase by coupling antiparallel microtubules (MTs) at a central overlap zone, which provides a signaling scaffold for the regulation of cytokinesis. The mechanisms underlying central spindle morphogenesis are still poorly understood. In this paper, we show that the MT depolymerase Kif2A controls the length and alignment of central spindle MTs through depolymerization at their minus ends. The distribution of Kif2A was limited to the distal ends of the central spindle through Aurora B-dependent phosphorylation and exclusion from the spindle midzone. Overactivation or inhibition of Kif2A affected interchromosomal MT length and disorganized the central spindle, resulting in uncoordinated cell division. Experimental data and model simulations suggest that the steady-state length of the central spindle and its symmetric position between segregating chromosomes are predominantly determined by the Aurora B activity gradient. On the basis of these results, we propose a robust self-organization mechanism for central spindle formation.

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Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B.

Project description:A hallmark of advanced maternal age is a significant increase in meiotic chromosome segregation errors, resulting in early miscarriages and congenital disorders. These errors most frequently occur during meiosis I (MI). The spindle assembly checkpoint (SAC) prevents chromosome segregation errors by arresting the cell cycle until proper chromosome alignment is achieved. Unlike in mitosis, the SAC in oocytes is desensitized, allowing chromosome segregation in the presence of improperly aligned chromosomes. Whether SAC integrity further deteriorates with advancing maternal age, and if this decline contributes to increased segregation errors remains a fundamental question. In somatic cells, activation of the SAC depends upon Aurora kinase B (AURKB), which functions to monitor kinetochore-microtubule attachments and recruit SAC regulator proteins. In mice, oocyte-specific deletion of AURKB (Aurkb cKO) results in an increased production of aneuploid metaphase II-arrested eggs and premature age-related infertility. Here, we aimed to understand the cause of the short reproductive lifespan and hypothesized that SAC integrity was compromised. In comparing oocytes from young and sexually mature Aurkb cKO females, we found that SAC integrity becomes compromised rapidly with maternal age. We show that the increased desensitization of the SAC is driven by reduced expression of MAD2, ZW10 and Securin proteins, key contributors to the SAC response pathway. The reduced expression of these proteins is the result of altered protein homeostasis, likely caused by the accumulation of reactive oxygen species. Taken together, our results demonstrate a novel function for AURKB in preserving the female reproductive lifespan possibly by protecting oocytes from oxidative stress.

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Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase.

Project description:Faithful separation of chromosomes prior to cell division at mitosis is a highly regulated process. One family of serine/threonine kinases that plays a central role in regulation is the Aurora family. Aurora B plays a role in the spindle assembly checkpoint, in part, by destabilizing the localization of BubR1 and Mad2 at centrosomes and responds to changes in tension caused by aberrant microtubule kinetochore attachments. Aurora B is overexpressed in a subset of cancers and is required for mitosis, making it an attractive anticancer target. Here, we use mathematical modeling to extend a current model of the spindle assembly checkpoint to incorporate all signaling kinetochores within a cell rather than just one and the role of Aurora B within the resulting model. We find that the current model of the spindle assembly checkpoint is robust to variation in its key diffusion-limited parameters. Furthermore, when Aurora B inhibition is considered within the model, for a certain range of inhibitor concentrations, a prolonged prometaphase/metaphase is observed. This level of inhibitor concentrations has not yet been studied experimentally, to the authors' best knowledge. Therefore, experimental verification of the results discussed here could provide a deeper understanding of how kinetochores and Aurora B cooperate in the spindle assembly checkpoint.

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P190RhoGAP prevents mitotic spindle fragmentation and is required to activate Aurora A kinase at acentriolar poles.

Project description:Assembly of the mitotic spindle is essential for proper chromosome segregation during mitosis. Maintenance of spindle poles requires precise regulation of kinesin- and dynein-generated forces, and improper regulation of these forces disrupts pole integrity leading to pole fragmentation. The formation and function of the mitotic spindle are regulated by many proteins, including Aurora A kinase and the motor proteins Kif2a and Eg5. Here, we characterize a surprising role for the RhoA GTPase-activating protein, p190RhoGAP, in regulating the mitotic spindle. We show that cells depleted of p190RhoGAP arrest for long periods in mitosis during which cells go through multiple transitions between having bipolar and multipolar spindles. Most of the p190RhoGAP-depleted cells finally achieve a stable bipolar attachment and proceed through anaphase. The multipolar spindle phenotype can be rescued by low doses of an Eg5 inhibitor. Moreover, we show that p190RhoGAP-depleted multipolar cells localize Aurora A to all the poles, but the kinase is only activated at the two centriolar poles. Overall, our data identify an unappreciated connection between p190RhoGAP and the proteins that control spindle poles including Aurora A kinase and Eg5 that is required to prevent or correct spindle pole fragmentation.

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Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.

Project description:Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage-induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin- induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings.

| S-EPMC3760020 | biostudies-literature

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