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Uncovering new substrates for Aurora A kinase.

ABSTRACT: Aurora A is a serine/threonine kinase that is essential for a wide variety of cell-cycle-related events, but only a small number of its substrates are known. We present and validate a strategy by which to identify Aurora A substrates and their phosphorylation sites. We developed a computational approach integrating various types of biological information to generate a list of 90 potential Aurora substrates, with a prediction accuracy of about 80%. We also demonstrated the specific phosphorylation of NUSAP (nucleolar and spindle-associated protein) by Aurora A in vivo. Our results provide a means by which to develop an understanding of Aurora A function and suggest unexpected roles for this kinase.

SUBMITTER: Sardon T

PROVIDER: S-EPMC2999863 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Uncovering new substrates for Aurora A kinase.

Sardon Teresa T Pache Roland A RA Stein Amelie A Molina Henrik H Vernos Isabelle I Aloy Patrick P

EMBO reports 20101112 12

Aurora A is a serine/threonine kinase that is essential for a wide variety of cell-cycle-related events, but only a small number of its substrates are known. We present and validate a strategy by which to identify Aurora A substrates and their phosphorylation sites. We developed a computational approach integrating various types of biological information to generate a list of 90 potential Aurora substrates, with a prediction accuracy of about 80%. We also demonstrated the specific phosphorylatio ...[more]

PMID: 21072059

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Sensing chromosome bi-orientation by spatial separation of aurora B kinase from kinetochore substrates.

Project description:Successful cell division requires that chromosomes attach to opposite poles of the mitotic spindle (bi-orientation). Aurora B kinase regulates chromosome-spindle attachments by phosphorylating kinetochore substrates that bind microtubules. Centromere tension stabilizes bi-oriented attachments, but how physical forces are translated into signaling at individual centromeres is unknown. Using fluorescence resonance energy transfer-based biosensors to measure localized phosphorylation dynamics in living cells, we found that phosphorylation of an Aurora B substrate at the kinetochore depended on its distance from the kinase at the inner centromere. Furthermore, repositioning Aurora B closer to the kinetochore prevented stabilization of bi-oriented attachments and activated the spindle checkpoint. Thus, centromere tension can be sensed by increased spatial separation of Aurora B from kinetochore substrates, which reduces phosphorylation and stabilizes kinetochore microtubules.

| S-EPMC2713345 | biostudies-literature

Quantitative phosphoproteomics identifies substrates and functional modules of Aurora and Polo-like kinase activities in mitotic cells.

Project description:Mitosis is a process involving a complex series of events that require careful coordination. Protein phosphorylation by a small number of kinases, in particular Aurora A, Aurora B, the cyclin-dependent kinase-cyclin complex Cdk1/cyclinB, and Polo-like kinase 1 (Plk1), orchestrates almost every step of cell division, from entry into mitosis to cytokinesis. To discover more about the functions of Aurora A, Aurora B, and kinases of the Plk family, we mapped mitotic phosphorylation sites to these kinases through the combined use of quantitative phosphoproteomics and selective targeting of kinase activities by small-molecule inhibitors. Using this integrated approach, we connected 778 phosphorylation sites on 562 proteins with these enzymes in cells arrested in mitosis. By connecting the kinases to protein complexes, we associated these kinases with functional modules. In addition to predicting previously unknown functions, this work establishes additional substrate-recognition motifs for these kinases and provides an analytical template for further use in dissecting kinase signaling events in other areas of cellular signaling and systems biology.

| S-EPMC3808085 | biostudies-literature

Dictyostelium Aurora kinase has properties of both Aurora A and Aurora B kinases.

Project description:Aurora kinases are highly conserved proteins with important roles in mitosis. Metazoans contain two kinases, Aurora A and B, which contribute distinct functions at the spindle poles and the equatorial region respectively. It is not currently known whether the specialized functions of the two kinases arose after their duplication in animal cells or were already present in their ancestral kinase. We show that Dictyostelium discoideum contains a single Aurora kinase, DdAurora, that displays characteristics of both Aurora A and B. Like Aurora A, DdAurora has an extended N-terminal domain with an A-box sequence and localizes at the spindle poles during early mitosis. Like Aurora B, DdAurora binds to its partner DdINCENP and localizes on centromeres at metaphase, the central spindle during anaphase, and the cleavage furrow at the end of cytokinesis. DdAurora also has several unusual properties. DdAurora remains associated with centromeres in anaphase, and this association does not require an interaction with DdINCENP. DdAurora then localizes at the cleavage furrow, but only at the end of cytokinesis. This localization is dependent on DdINCENP and the motor proteins Kif12 and myosin II. Thus, DdAurora may represent the ancestral kinase that gave rise to the different Aurora kinases in animals and also those in other organisms.

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Cdc7 kinase stimulates Aurora B kinase in M-phase.

Project description:The conserved serine-threonine kinase, Cdc7, plays a crucial role in initiation of DNA replication by facilitating the assembly of an initiation complex. Cdc7 is expressed at a high level and exhibits significant kinase activity not only during S-phase but also during G2/M-phases. A conserved mitotic kinase, Aurora B, is activated during M-phase by association with INCENP, forming the chromosome passenger complex with Borealin and Survivin. We show that Cdc7 phosphorylates and stimulates Aurora B kinase activity in vitro. We identified threonine-236 as a critical phosphorylation site on Aurora B that could be a target of Cdc7 or could be an autophosphorylation site stimulated by Cdc7-mediated phosphorylation elsewhere. We found that threonines at both 232 (that has been identified as an autophosphorylation site) and 236 are essential for the kinase activity of Aurora B. Cdc7 down regulation or inhibition reduced Aurora B activity in vivo and led to retarded M-phase progression. SAC imposed by paclitaxel was dramatically reversed by Cdc7 inhibition, similar to the effect of Aurora B inhibition under the similar situation. Our data show that Cdc7 contributes to M-phase progression and to spindle assembly checkpoint most likely through Aurora B activation.

| S-EPMC6901529 | biostudies-literature

Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.

Project description:Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose- and time-dependent manner. This inhibition resulted in apoptosis induction, G(2)-M arrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation.

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Selective disruption of aurora C kinase reveals distinct functions from aurora B kinase during meiosis in mouse oocytes.

Project description:Aurora B kinase (AURKB) is the catalytic subunit of the chromosomal passenger complex (CPC), an essential regulator of chromosome segregation. In mitosis, the CPC is required to regulate kinetochore microtubule (K-MT) attachments, the spindle assembly checkpoint, and cytokinesis. Germ cells express an AURKB homolog, AURKC, which can also function in the CPC. Separation of AURKB and AURKC function during meiosis in oocytes by conventional approaches has not been successful. Therefore, the meiotic function of AURKC is still not fully understood. Here, we describe an ATP-binding-pocket-AURKC mutant, that when expressed in mouse oocytes specifically perturbs AURKC-CPC and not AURKB-CPC function. Using this mutant we show for the first time that AURKC has functions that do not overlap with AURKB. These functions include regulating localized CPC activity and regulating chromosome alignment and K-MT attachments at metaphase of meiosis I (Met I). We find that AURKC-CPC is not the sole CPC complex that regulates the spindle assembly checkpoint in meiosis, and as a result most AURKC-perturbed oocytes arrest at Met I. A small subset of oocytes do proceed through cytokinesis normally, suggesting that AURKC-CPC is not the sole CPC complex during telophase I. But, the resulting eggs are aneuploid, indicating that AURKC is a critical regulator of meiotic chromosome segregation in female gametes. Taken together, these data suggest that mammalian oocytes contain AURKC to efficiently execute meiosis I and ensure high-quality eggs necessary for sexual reproduction.

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Aurora kinase inhibition triggers senescence in human melanoma cells

Project description:Phenotypically, there is a heterogeneous response of cancer cells to chemotherapy or targeted therapy. While therapeutically much attention is focused on cell death, there is growing evidence suggesting that a subpopulation of cancer cells undergo therapy-induced senescence. Depending on the therapy, dose and timing, senescence may be a dominant phenotype over cell death. An integrated FACS approach identified two types of therapy-induced senescence in human melanoma cells, irreversible senescence induced by Aurora kinase inhibition vs. transient senescence induced by B-RAF kinase inhibition. Autophagy and ER stress response precede and are required for therapy-induced senescence in cancer cells, mirroring their functions in normal cells undergoing oncogene-induced senescence. Importantly, autophagy serves a survival pathway for senescent cancer cells. Antagonizing autophagy converts therapy-induced senescence into cell death but paradoxically promotes cell proliferation or quiescence. Our work calls for a rationale-based design of combination therapy for cancer treatment that should lead to a greater synergy. There are three or four replicates per treatment per time point.

2015-06-05 | E-GEOD-38466 | biostudies-arrayexpress

Aurora kinase inhibition triggers senescence in human melanoma cells

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