scholarly journals Cdc7 kinase stimulates Aurora B kinase in M-phase

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sayuri Ito ◽  
Hidemasa Goto ◽  
Kinue Kuniyasu ◽  
Mayumi Shindo ◽  
Masayuki Yamada ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Mitotic Kinase ◽  
M Phase ◽  
Phase Progression ◽  
Autophosphorylation Site

AbstractThe 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.

scholarly journals CSC-1

2003 ◽  
Vol 161 (2) ◽  
pp. 229-236 ◽  
Author(s):  
Alper Romano ◽  
Annika Guse ◽  
Ivica Krascenicova ◽  
Heinke Schnabel ◽  
Ralf Schnabel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Genetic Analysis ◽  
Chromosome Segregation ◽  
Kinase Activity ◽  
Aurora B ◽  
Aurora B Kinase ◽  
C Elegans ◽  
The Individual

The Aurora B kinase complex is a critical regulator of chromosome segregation and cytokinesis. In Caenorhabditis elegans, AIR-2 (Aurora B) function requires ICP-1 (Incenp) and BIR-1 (Survivin). In various systems, Aurora B binds to orthologues of these proteins. Through genetic analysis, we have identified a new subunit of the Aurora B kinase complex, CSC-1. C. elegans embryos depleted of CSC-1, AIR-2, ICP-1, or BIR-1 have identical phenotypes. CSC-1, BIR-1, and ICP-1 are interdependent for their localization, and all are required for AIR-2 localization. In vitro, CSC-1 binds directly to BIR-1. The CSC-1/BIR-1 complex, but not the individual subunits, associates with ICP-1. CSC-1 associates with ICP-1, BIR-1, and AIR-2 in vivo. ICP-1 dramatically stimulates AIR-2 kinase activity. This activity is not stimulated by CSC-1/BIR-1, suggesting that these two subunits function as targeting subunits for AIR-2 kinase.

scholarly journals Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores

2011 ◽  
Vol 22 (18) ◽  
pp. 3318-3330 ◽  
Author(s):  
James M. Kasuboski ◽  
Jason R. Bader ◽  
Patricia S. Vaughan ◽  
Sinji B. F. Tauhata ◽  
Michael Winding ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Cytoplasmic Dynein ◽  
Mass Spectrometry Analysis ◽  
Aurora B ◽  
Spectrometry Analysis ◽  
Mitotic Kinase ◽  
Kinetochore Assembly ◽  
Associated Proteins ◽  
Induced Defects

Aurora B (AurB) is a mitotic kinase responsible for multiple aspects of mitotic progression, including assembly of the outer kinetochore. Cytoplasmic dynein is an abundant kinetochore protein whose recruitment to kinetochores requires phosphorylation. To assess whether AurB regulates recruitment of dynein to kinetochores, we inhibited AurB using ZM447439 or a kinase-dead AurB construct. Inhibition of AurB reduced accumulation of dynein at kinetochores substantially; however, this reflected a loss of dynein-associated proteins rather than a defect in dynein phosphorylation. We determined that AurB inhibition affected recruitment of the ROD, ZW10, zwilch (RZZ) complex to kinetochores but not zwint-1 or more-proximal kinetochore proteins. AurB phosphorylated zwint-1 but not ZW10 in vitro, and three novel phosphorylation sites were identified by tandem mass spectrometry analysis. Expression of a triple-Ala zwint-1 mutant blocked kinetochore assembly of RZZ-dependent proteins and induced defects in chromosome movement during prometaphase. Expression of a triple-Glu zwint-1 mutant rendered cells resistant to AurB inhibition during prometaphase. However, cells expressing the triple-Glu mutant failed to satisfy the spindle assembly checkpoint (SAC) at metaphase because poleward streaming of dynein/dynactin/RZZ was inhibited. These studies identify zwint-1 as a novel AurB substrate required for kinetochore assembly and for proper SAC silencing at metaphase.

AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2034-2040 ◽  
Author(s):  
Jing Yang ◽  
Takayuki Ikezoe ◽  
Chie Nishioka ◽  
Taizo Tasaka ◽  
Ayuko Taniguchi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Growth Arrest ◽  
Leukemia Cells ◽  
Aurora B ◽  
Thymidine Uptake ◽  
Aurora B Kinase ◽  
Aurora Kinases ◽  
Topoisomerase Ii Inhibitor

Abstract Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.

scholarly journals The right place at the right time: Aurora B kinase localization to centromeres and kinetochores

2020 ◽  
Vol 64 (2) ◽  
pp. 299-311 ◽  
Author(s):  
Amanda J. Broad ◽  
Jennifer G. DeLuca
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Protein Complexes ◽  
Centromeric Heterochromatin ◽  
Aurora B ◽  
Mitotic Chromosomes ◽  
Large Protein ◽  
Aurora B Kinase ◽  
Centromeric Protein ◽  
Spindle Microtubules ◽  
The Right

Abstract The fidelity of chromosome segregation during mitosis is intimately linked to the function of kinetochores, which are large protein complexes assembled at sites of centromeric heterochromatin on mitotic chromosomes. These key “orchestrators” of mitosis physically connect chromosomes to spindle microtubules and transduce forces through these connections to congress chromosomes and silence the spindle assembly checkpoint. Kinetochore-microtubule attachments are highly regulated to ensure that incorrect attachments are not prematurely stabilized, but instead released and corrected. The kinase activity of the centromeric protein Aurora B is required for kinetochore-microtubule destabilization during mitosis, but how the kinase acts on outer kinetochore substrates to selectively destabilize immature and erroneous attachments remains debated. Here, we review recent literature that sheds light on how Aurora B kinase is recruited to both centromeres and kinetochores and discuss possible mechanisms for how kinase interactions with substrates at distinct regions of mitotic chromosomes are regulated.

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site

1990 ◽  
Vol 10 (10) ◽  
pp. 5305-5313
Author(s):  
K X Luo ◽  
B M Sefton
Keyword(s):  
T Cell ◽  
Tyrosine Phosphorylation ◽  
Cell Lines ◽  
Kinase Activity ◽  
Cross Linking ◽  
Cell Surface Molecules ◽  
Surface Molecules ◽  
Tyrosine Protein Kinase ◽  
Autophosphorylation Site

p56lck, a lymphocyte-specific tyrosine protein kinase, binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8. Cross-linking of CD4 expressed on the surface of murine thymocytes, splenocytes, and CD4+ T-cell lines induced tyrosine phosphorylation of p56lck dramatically. Cross-linking of CD8 stimulated tyrosine phosphorylation of p56lck strongly in murine L3 and GA4 cells, slightly in splenocytes, but not detectably in thymocytes. Differing effects of cross-linking on in vitro tyrosine kinase activity of p56lck were observed. An increase in the in vitro kinase activity of p56lck, when assayed with [Val5]-angiotensin II as an exogenous substrate, was found to accompany cross-linking of CD4 in three cell lines. No stimulation of the in vitro kinase activity, however, was observed after cross-linking of CD8 in L3 cells. The phosphorylation of p56lck at Tyr-394, the autophosphorylation site, was stimulated by cross-linking in all cell lines examined. Tyr-394 was the predominant site of increased tyrosine phosphorylation in two leukemic cell lines. In the other two cell lines, the phosphorylation of both Tyr-394 and an inhibitory site, Tyr-505, was found to increase. In contrast to cross-linking with antibodies, no striking increase in the tyrosine phosphorylation of p56lck was stimulated by antigenic stimulation. Therefore, the effect of antibody-induced aggregation of CD4 and CD8 on the tyrosine phosphorylation of p56lck differs, at least quantitatively, from what occurs during antigen-induced T-cell activation.

scholarly journals Aurora B kinase activity is regulated by SET/TAF1 on Sgo2 at the inner centromere

2019 ◽  
Vol 218 (10) ◽  
pp. 3223-3236 ◽  
Author(s):  
Yuichiro Asai ◽  
Koh Fukuchi ◽  
Yuji Tanno ◽  
Saki Koitabashi-Kiyozuka ◽  
Tatsuyuki Kiyozuka ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Chromosomal Instability ◽  
Kinase Activity ◽  
Fine Tuning ◽  
Aurora B ◽  
The Novel ◽  
Aurora B Kinase ◽  
Microtubule Attachment ◽  
Molecular Events

The accurate regulation of phosphorylation at the kinetochore is essential for establishing chromosome bi-orientation. Phosphorylation of kinetochore proteins by the Aurora B kinase destabilizes improper kinetochore–microtubule attachments, whereas the phosphatase PP2A has a counteracting role. Imbalanced phosphoregulation leads to error-prone chromosome segregation and aneuploidy, a hallmark of cancer cells. However, little is known about the molecular events that control the balance of phosphorylation at the kinetochore. Here, we show that localization of SET/TAF1, an oncogene product, to centromeres maintains Aurora B kinase activity by inhibiting PP2A, thereby correcting erroneous kinetochore–microtubule attachment. SET localizes at the inner centromere by interacting directly with shugoshin 2, with SET levels declining at increased distances between kinetochore pairs, leading to establishment of chromosome bi-orientation. Moreover, SET overexpression induces chromosomal instability by disrupting kinetochore–microtubule attachment. Thus, our findings reveal the novel role of SET in fine-tuning the phosphorylation level at the kinetochore by balancing the activities of Aurora B and PP2A.

scholarly journals Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

2019 ◽  
Vol 219 (2) ◽  
Author(s):  
Cai Liang ◽  
Zhenlei Zhang ◽  
Qinfu Chen ◽  
Haiyan Yan ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Essential Role ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Chromosome Missegregation ◽  
Proper Timing ◽  
Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

Interplay between mitotic kinesins and the Aurora kinase–PP1 (protein phosphatase 1) axis

2013 ◽  
Vol 41 (6) ◽  
pp. 1761-1765 ◽  
Author(s):  
John C. Meadows
Keyword(s):  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Aurora Kinase ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Spatial Gradient ◽  
Cell Cycle Regulators ◽  
Aurora B Kinase ◽  
Surveillance Mechanism

Correct transmission of genetic information from mother to daughter cells is necessary for development and survival. Accurate segregation is achieved by bipolar attachment of sister kinetochores in each chromatid pair to spindle microtubules emanating from opposite spindle poles, a process known as chromosome bi-orientation. Achieving this requires dynamic interplay between kinetochore proteins, kinesin motor proteins and cell cycle regulators. Chromosome bi-orientation is monitored by a surveillance mechanism known as the SAC (spindle assembly checkpoint). The Aurora B kinase, which is bound to the inner centromere during early mitosis, plays a central role in both chromosome bi-orientation and the spindle checkpoint. The application of tension across centromeres establishes a spatial gradient of high phosphorylation activity at the inner centromere and low phosphorylation activity at the outer kinetochore. This gradient is further refined by the association of PP1 (protein phosphatase 1) to the outer kinetochore, which stabilizes kinetochore–microtubule interactions and silences the spindle checkpoint by dephosphorylating Aurora B kinase targets when chromosome bi-orientation is achieved. In the present review, I discuss emerging evidence that bidirectional cross-talk between mitotic kinesins and the Aurora kinase–PP1 axis is crucial for co-ordinating chromosome bi-orientation and spindle checkpoint signalling in eukaryotes.

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