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Kyosuke Nagata - One of the best experts on this subject based on the ideXlab platform.
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<B>AuroraB> B Kinase activity is regulated By set taf1 on sgo2 at the inner centromere
Journal of Cell Biology, 2019Co-Authors: Yuichiro Asai, Koh Fukuchi, Yuji Tanno, Tatsuyuki Kiyozuka, Yuko Noda, Rieko Matsumura, Tetsuo Koizumi, Atsushi Watanabe, Saki Koitabashikiyozuka, Kyosuke NagataAbstract:The accurate regulation of phosphorylation at the kinetochore is essential for estaBlishing chromosome Bi-orientation. Phosphorylation of kinetochore proteins By the <B>AuroraB> 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 <B>AuroraB> 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 <B>AuroraB> B and PP2A.
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<B>AuroraB> B Kinase activity is regulated By SET/TAF1 on Sgo2 at the inner centromere.
Journal of Cell Biology, 2019Co-Authors: Yuichiro Asai, Koh Fukuchi, Yuji Tanno, Saki Koitabashi-kiyozuka, Tatsuyuki Kiyozuka, Yuko Noda, Rieko Matsumura, Tetsuo Koizumi, Atsushi Watanabe, Kyosuke NagataAbstract:The accurate regulation of phosphorylation at the kinetochore is essential for estaBlishing chromosome Bi-orientation. Phosphorylation of kinetochore proteins By the <B>AuroraB> 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 <B>AuroraB> 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 <B>AuroraB> B and PP2A.
Jill M. Schumacher - One of the best experts on this subject based on the ideXlab platform.
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LAB-1 antagonizes the <B>AuroraB> B Kinase in C. elegans.
Genes & development, 2008Co-Authors: Carlos Egydio De Carvalho, Jill M. Schumacher, Sophie Zaaijer, Sarit Smolikov, Monica P. ColaiácovoAbstract:The Shugoshin/<B>AuroraB> circuitry that controls the timely release of cohesins from sister chromatids in meiosis and mitosis is widely conserved among eukaryotes, although little is known aBout its function in organisms whose chromosomes lack a localized centromere. Here we show that CaenorhaBditis elegans chromosomes rely on an alternative mechanism to protect meiotic cohesin that is shugoshin-independent and instead involves the activity of a new chromosome-associated protein named LAB-1 (Long Arm of the Bivalent). LAB-1 preserves meiotic sister chromatid cohesion By restricting the localization of the C. elegans <B>AuroraB> B Kinase, AIR-2, to the interface Between homologs via the activity of the PP1/Glc7 phosphatase GSP-2. The localization of LAB-1 to chromosomes of dividing emBryos and the suppression of mitotic-specific defects in air-2 mutant emBryos with reduced LAB-1 activity support a gloBal role of LAB-1 in antagonizing AIR-2 in Both meiosis and mitosis. Although the localization of a GFP fusion and the analysis of mutants and RNAi-mediated knockdowns downplay a role for the C. elegans shugoshin protein in cohesin protection, shugoshin nevertheless helps to ensure the high fidelity of chromosome segregation at metaphase I. We propose that, in C. elegans, a LAB-1-mediated mechanism evolved to offset the challenges of providing protection against separase activity throughout a larger chromosome area.
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Tousled-mediated Activation of <B>AuroraB> B Kinase Does Not Require Tousled Kinase Activity in Vivo
The Journal of biological chemistry, 2008Co-Authors: Gary M. Riefler, Sharon Y.r. Dent, Jill M. SchumacherAbstract:The <B>AuroraB> Kinases comprise an evolutionarily conserved protein family that is required for a variety of cell division events, including spindle assemBly, chromosome segregation, and cytokinesis. Emerging evidence suggests that once phosphorylated, a suBset of <B>AuroraB> suBstrates can enhance <B>AuroraB> Kinase activity. Our previous work revealed that the CaenorhaBditis elegans Tousled-like Kinase TLK-1 is a suBstrate and activator of the AIR-2 <B>AuroraB> B Kinase in vitro and that partial loss of TLK-1 enhances the mitotic defects of an air-2 mutant. However, given that these experiments were performed in vitro and with partial loss of function alleles in vivo, a necessary step forward in our understanding of the relationship Between the <B>AuroraB> B and Tousled Kinases is to prove that TLK-1 expression is sufficient for <B>AuroraB> B activation in vivo. Here, we report that heterologous expression of wild-type and Kinase-inactive forms of TLK-1 suppresses the lethality of temperature-sensitive mutants of the yeast <B>AuroraB> B Kinase Ipl1. Moreover, Kinase-dead TLK-1 associates with and augments the activity of Ipl1 in vivo. Together, these results provide critical and compelling evidence that Tousled has a Bona fide Kinase-independent role in the activation of <B>AuroraB> B Kinases in vivo.
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An Afg2/Spaf-Related Cdc48-like AAA ATPase Regulates the StaBility and Activity of the C. elegans <B>AuroraB> B Kinase AIR-2
Developmental cell, 2008Co-Authors: Todd R. Heallen, Henry P. Adams, Tokiko Furuta, Koen J.c. Verbrugghe, Jill M. SchumacherAbstract:The <B>AuroraB> B Kinase is the enzymatic core of the chromosomal passenger complex, which is a critical regulator of mitosis. To identify novel regulators of <B>AuroraB> B, we performed a genome-wide screen for suppressors of a temperature-sensitive lethal allele of the C. elegans <B>AuroraB> B Kinase AIR-2. This screen uncovered a memBer of the Afg2/Spaf suBfamily of Cdc48-like AAA ATPases as an essential inhiBitor of AIR-2 staBility and activity. Depletion of CDC-48.3 restores viaBility to air-2 mutant emBryos and leads to aBnormally high AIR-2 levels at the late telophase/G1 transition. Furthermore, CDC-48.3 Binds directly to AIR-2 and inhiBits its Kinase activity from metaphase through telophase. While canonical p97/Cdc48 proteins have Been assigned contradictory roles in the regulation of <B>AuroraB> B, our results identify a memBer of the Afg2/Spaf AAA ATPases as a critical in vivo inhiBitor of this Kinase during emBryonic development.
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Phosphorylation of the CarBoxyl Terminus of Inner Centromere Protein (INCENP) By the <B>AuroraB> B Kinase Stimulates <B>AuroraB> B
2007Co-Authors: John D. Bishop, Jill M. SchumacherAbstract:How the events of mitosis are coordinated is not well understood. Intriguing mitotic regulators include the chromosomal passenger proteins. Loss of either of the passengers inner centromere protein (INCENP) or the <B>AuroraB> B Kinase results in chromosome segregation defects and failures in cytokinesis. Furthermore, INCENP and <B>AuroraB> B have identical localization patterns during mitosis and directly Bind each other in vitro. These results led to the hypothesis that INCENP is a direct suBstrate of <B>AuroraB> B. Here we show that the CaenorhaBditis elegans <B>AuroraB> B Kinase AIR-2 specifically phosphorylated the C. elegans INCENP ICP-1 at two adjacent serines within the carBoxyl terminus. Furthermore, the full length and a carBoxyl-terminal fragment of ICP-1 stimulated AIR-2 Kinase activity. This increase in AIR-2 activity required that AIR-2 phosphorylate ICP-1 Because mutation of Both serines in the AIR-2 phosphorylation site of ICP-1 aBolished the potentiation of AIR-2 Kinase activity By ICP-1. Thus, ICP-1 is directly phosphorylated By AIR-2 and functions in a positive feedBack loop that regulates AIR-2 Kinase activity. Since the <B>AuroraB> B phosphorylation site within INCENP and the functions of INCENP and <B>AuroraB> B have Been conserved among eukaryotes, the feedBack loop we have identified is also likely to Be evolutionarily conserved.
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The C. elegans Tousled-like Kinase contriButes to chromosome segregation as a suBstrate and regulator of the <B>AuroraB> B Kinase.
Current biology : CB, 2005Co-Authors: Zhenbo Han, Gary M. Riefler, Jennifer R. Saam, Susan E. Mango, Jill M. SchumacherAbstract:Summary Background: The <B>AuroraB> Kinases control multiple aspects of mitosis, among them centrosome maturation, spindle assemBly, chromosome segregation, and cytokinesis. <B>AuroraB> activity is regulated in part By a suBset of <B>AuroraB> suBstrates that, once phosphorylated, can enhance <B>AuroraB> Kinase activity. <B>AuroraB> A suBstrate activators include TPX2 and AjuBa, whereas the only known <B>AuroraB> B suBstrate activator is the chromosomal passenger INCENP. Results: We report that the C. elegans Tousled Kinase TLK-1 is a second suBstrate activator of the <B>AuroraB> B Kinase AIR-2. Tousled Kinase (Tlk) expression and activity have Been linked to ongoing DNA replication, and Tlk can phosphorylate the chromatin assemBly factor Asf. Here, we show that TLK-1 is phosphorylated By AIR-2 during prophase/prometaphase and that phosphorylation increases TLK-1 Kinase activity in vitro. Phosphorylated TLK-1 increases AIR-2 Kinase activity in a manner that is independent of TLK-1 Kinase activity But depends on the presence of ICP-1/INCENP. In vivo, TLK-1 and AIR-2 cooperate to ensure proper mitotic chromosome segregation. Conclusions: The C. elegans Tousled Kinase TLK-1 is a suBstrate and activator of the <B>AuroraB> B Kinase AIR-2. These results suggest that Tousled Kinases have a previously unrecognized role in mitosis and that <B>AuroraB> B associates with discrete regulatory complexes that may impart distinct suBstrate specificities and functions to the <B>AuroraB> B Kinase.
Yuichiro Asai - One of the best experts on this subject based on the ideXlab platform.
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<B>AuroraB> B Kinase activity is regulated By set taf1 on sgo2 at the inner centromere
Journal of Cell Biology, 2019Co-Authors: Yuichiro Asai, Koh Fukuchi, Yuji Tanno, Tatsuyuki Kiyozuka, Yuko Noda, Rieko Matsumura, Tetsuo Koizumi, Atsushi Watanabe, Saki Koitabashikiyozuka, Kyosuke NagataAbstract:The accurate regulation of phosphorylation at the kinetochore is essential for estaBlishing chromosome Bi-orientation. Phosphorylation of kinetochore proteins By the <B>AuroraB> 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 <B>AuroraB> 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 <B>AuroraB> B and PP2A.
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<B>AuroraB> B Kinase activity is regulated By SET/TAF1 on Sgo2 at the inner centromere.
Journal of Cell Biology, 2019Co-Authors: Yuichiro Asai, Koh Fukuchi, Yuji Tanno, Saki Koitabashi-kiyozuka, Tatsuyuki Kiyozuka, Yuko Noda, Rieko Matsumura, Tetsuo Koizumi, Atsushi Watanabe, Kyosuke NagataAbstract:The accurate regulation of phosphorylation at the kinetochore is essential for estaBlishing chromosome Bi-orientation. Phosphorylation of kinetochore proteins By the <B>AuroraB> 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 <B>AuroraB> 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 <B>AuroraB> B and PP2A.
Takanori Ueda - One of the best experts on this subject based on the ideXlab platform.
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Marked upregulation of Survivin and <B>AuroraB>-B Kinase is associated with disease progression in the myelodysplastic syndromes
Haematologica, 2012Co-Authors: Akira Yoshida, Kouichi Zokumasu, Shin Imamura, Shinji Kishi, Yoshimasa Urasaki, Yuji Wano, Takahiro Yamauchi, Kaoru Tohyama, Kazutaka Takagi, Takanori UedaAbstract:BACKGROUND: Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized By ineffective hematopoiesis. Survivin is a memBer of the inhiBitor of apoptosis family and suppresses apoptosis. Survivin also functions as a suBunit of the chromosomal passenger complex for regulating mitosis with <B>AuroraB>-B. Survivin and <B>AuroraB>-B play an important role in maintaining genome staBility. The aim of this study was to determine the role of Survivin and <B>AuroraB>-B Kinase in disease progression and prognosis of myelodysplastic syndromes.\n\nDESIGN AND METHODS: We evaluated the expression levels of these two genes in CD34(+) cells prepared from 64 patients with myelodysplastic syndrome or leukemic Blasts from 50 patients with de novo acute myeloid leukemia using quantitative real-time PCR.\n\nRESULTS: Survivin and <B>AuroraB>-B expression levels were highly correlated with the type of myelodysplastic syndrome, were much higher in refractory anemia with excess Blasts-1, refractory anemia with excess Blasts-2, and secondary acute myeloid leukemia following myelodysplastic syndrome than in normal control, and increased during disease progression. There was a significant correlation Between these expression levels and the International Prognostic Scoring System. Interestingly, these levels were remarkaBly higher in patients with secondary acute myeloid leukemia following myelodysplastic syndromes than in those with de novo acute myeloid leukemia.\n\nCONCLUSIONS: This is the first report showing that high levels of Survivin and <B>AuroraB>-B Kinase expression in CD34(+) cells are distinctive molecular features of high-risk myelodysplastic syndromes and secondary acute myeloid leukemia following myelodysplastic syndrome. Marked upregulation of Survivin and <B>AuroraB>-B Kinase may contriBute to genetic instaBility and disease progression of myelodysplastic syndromes. Our data may explain why patients with high-risk myelodysplastic syndromes frequently show complex chromosomal aBnormality.
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Marked Upregulations of Survivin and <B>AuroraB>-B Kinase Are Associated with Disease Progression in the Myelodysplastic Syndromes,
Blood, 2011Co-Authors: Akira Yoshida, Kouichi Zokumasu, Shinji Kishi, Yoshimasa Urasaki, Takahiro Yamauchi, Kaoru Tohyama, Kazutaka Takagi, Takanori UedaAbstract:ABstract 3823 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized By ineffctive hematopoiesis. Survivin Belongs to the inhiBitors of apoptosis (IAP) family and inhiBits apoptosis. Besides its role as IAP, Survivin appears to function as a suBunit of the chromosomal passenger complex (CPC) for regulating mitosis with other CPC proteins including <B>AuroraB>-B. As the CPC, Survivin and <B>AuroraB>-B play an important role in the maintenance of a staBle genome. Until now, there has Been no report to examine whether expression of Survivin and <B>AuroraB>-B Kinase may Be increased in CD34(+) cells prepared from the patients with MDS during disease progression. To investigate the contriBution of Survivin and <B>AuroraB>-B to the progression and prognosis of MDS, we evaluated the expression levels of these two genes in CD34(+) cells prepared from 57 patients with MDS and 50 patients with de novo AML using real-time quantitative polymerase chain reaction. The degree of Survivin and <B>AuroraB>-B expression was highly correlated with the type of MDS, was much higher in RAEB-1, RAEB-2 and secondary AML following MDS (s-AML) compared with normal control, and increased during disease progression. Expression levels of Both Survivin and <B>AuroraB>-B were significantly correlated with International Prognostic Scoring System (IPSS). Furthermore, the amount of <B>AuroraB>-B Kinase was significantly correlated with Survivin expression in MDS and s-AML, But not in de novo AML. Interestingly, the levels of Survivin and <B>AuroraB>-B were remarkaBly higher in patients with s-AML when compared with de novo AML. We demonstrated for the first time that high levels of Survivin and <B>AuroraB>-B Kinase expression are distinctive molecular feature of high-risk MDS and s-AML. Marked up-regulations of Survivin and <B>AuroraB>-B Kinase may contriBute to genetic instaBility and disease progression of MDS. Disclosures: No relevant conflicts of interest to declare.
Susanne M. A. Lens - One of the best experts on this subject based on the ideXlab platform.
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Shugoshin-1 Balances <B>AuroraB> B Kinase Activity via PP2A to Promote Chromosome Bi-orientation
Cell reports, 2015Co-Authors: Amanda Meppelink, Martijn J. M. Vromans, Lilian Kabeche, Duane A. Compton, Susanne M. A. LensAbstract:Correction of faulty kinetochore-microtuBule attachments is essential for faithful chromosome segregation and dictated By the opposing activities of <B>AuroraB> B Kinase and PP1 and PP2A phosphatases. How Kinase and phosphatase activities are appropriately Balanced is less clear. Here, we show that a centromeric pool of PP2A-B56 counteracts <B>AuroraB> B T-loop phosphorylation and is recruited to centromeres through Shugoshin-1 (Sgo1). In non-transformed RPE-1 cells, <B>AuroraB> B, Sgo1, and PP2A-B56 are enriched on centromeres and levels diminish as chromosomes estaBlish Bi-oriented attachments. Elevating Sgo1 levels at centromeres recruits excess PP2A-B56, and this counteracts <B>AuroraB> B Kinase activity, undermining efficient correction of kinetochore-microtuBule attachment errors. Conversely, Sgo1-depleted cells display reduced centromeric localization of <B>AuroraB> B, whereas the remaining Kinase is hyperactive due to concomitant reduction of centromeric PP2A-B56. Our data suggest that Sgo1 can tune the staBility of kinetochore-microtuBule attachments through recruitment of PP2A-B56 that Balances <B>AuroraB> B activity at the centromere.
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Development of a chemical genetic approach for human <B>AuroraB> B Kinase identifies novel suBstrates of the chromosomal passenger complex
Molecular & cellular proteomics : MCP, 2012Co-Authors: Rutger C.c. Hengeveld, Martijn J. M. Vromans, Nicholas T. Hertz, Chao Zhang, Alma L. Burlingame, Kevan M. Shokat, Susanne M. A. LensAbstract:To understand how the chromosomal passenger complex ensures chromosomal staBility, it is crucial to identify its suBstrates and to find ways to specifically inhiBit the enzymatic core of the complex, <B>AuroraB> B. We therefore developed a chemical genetic approach to selectively inhiBit human <B>AuroraB> B. By mutating the gatekeeper residue Leu-154 in the Kinase active site, the ATP-Binding pocket was enlarged, But Kinase function was severely disrupted. A unique second site suppressor mutation was identified that rescued Kinase activity in the Leu-154 mutant and allowed the accommodation of Bulky N6-suBstituted adenine analogs. Using this analog-sensitive <B>AuroraB> B Kinase, we found that retention of the chromosomal passenger complex at the centromere depends on <B>AuroraB> B Kinase activity. Furthermore, analog-sensitive <B>AuroraB> B was aBle to use Bulky ATPγS analogs and could thiophosphorylate multiple proteins in cell extracts. Utilizing an unBiased approach for Kinase suBstrate mapping, we identified several novel suBstrates of <B>AuroraB> B, including the nucleosomal-Binding protein HMGN2. We confirmed that HMGN2 is a Bona fide <B>AuroraB> B suBstrate in vivo and show that its dynamic association to chromatin is controlled By <B>AuroraB> B.
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<B>AuroraB> B Kinase cooperates with CENP-E to promote timely anaphase onset
Chromosoma, 2010Co-Authors: André F. Maia, Martijn J. M. Vromans, Tália Feijão, Claudio E Sunkel, Susanne M. A. LensAbstract:Error-free chromosome segregation requires that all chromosomes Biorient on the mitotic spindle. The motor protein Centromere-associated protein E (CENP-E) facilitates chromosome congression By mediating the lateral sliding of sister chromatids along existing K-fiBers, while the mitotic Kinase <B>AuroraB> B detaches kinetochore–microtuBule interactions that are not Bioriented. Whether these activities cooperate to promote efficient chromosome Biorientation and timely anaphase onset is not known. We here show that the chromosomes that fail to congress after CENP-E depletion displayed high centromeric <B>AuroraB> B Kinase activity. This activity destaBilized spindle pole proximal kinetochore–microtuBule interactions resulting in a checkpoint-dependent mitotic delay that allowed CENP-E-independent chromosome congression, thus reducing chromosome segregation errors. This shows that <B>AuroraB> B keeps the mitotic checkpoint active By destaBilizing kinetochore fiBers of polar chromosomes to permit chromosome congression in CENP-E-compromised cells and implies that this Kinase normally prevents pole proximal syntelic attachments to allow CENP-E-mediated congression of mono-oriented chromosomes.
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<B>AuroraB> B Kinase cooperates with CENP-E to promote timely anaphase onset
Chromosoma, 2010Co-Authors: André F. Maia, Martijn J. M. Vromans, Tália Feijão, Claudio E Sunkel, Susanne M. A. LensAbstract:Error-free chromosome segregation requires that all chromosomes Biorient on the mitotic spindle. The motor protein Centromere-associated protein E (CENP-E) facilitates chromosome congression By mediating the lateral sliding of sister chromatids along existing K-fiBers, while the mitotic Kinase <B>AuroraB> B detaches kinetochore–microtuBule interactions that are not Bioriented. Whether these activities cooperate to promote efficient chromosome Biorientation and timely anaphase onset is not known. We here show that the chromosomes that fail to congress after CENP-E depletion displayed high centromeric <B>AuroraB> B Kinase activity. This activity destaBilized spindle pole proximal kinetochore–microtuBule interactions resulting in a checkpoint-dependent mitotic delay that allowed CENP-E-independent chromosome congression, thus reducing chromosome segregation errors. This shows that <B>AuroraB> B keeps the mitotic checkpoint active By destaBilizing kinetochore fiBers of polar chromosomes to permit chromosome congression in CENP-E-compromised cells and implies that this Kinase normally prevents pole proximal syntelic attachments to allow CENP-E-mediated congression of mono-oriented chromosomes.
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Sensing Chromosome Bi-Orientation By Spatial Separation of <B>AuroraB> B Kinase from Kinetochore SuBstrates
Science (New York N.Y.), 2009Co-Authors: Dan Liu, Martijn J. M. Vromans, Michael A Lampson, Gerben Vader, Susanne M. A. LensAbstract:Successful cell division requires that chromosomes attach to opposite poles of the mitotic spindle (Bi-orientation). <B>AuroraB> 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 <B>AuroraB> B suBstrate at the kinetochore depended on its distance from the Kinase at the inner centromere. Furthermore, repositioning <B>AuroraB> 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 <B>AuroraB> B from kinetochore suBstrates, which reduces phosphorylation and staBilizes kinetochore microtuBules.
