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AURORA KINASE B; AURKB

AURORA KINASE B; AURKB

Alternative titles; symbolsSERINE/THREONINE PROTEIN KINASE 12; STK12AURORA-RELATED KINASE 2; ARK2AURORA/IPL1-LIKE KINASE 2; AIK2AIM1, RAT, HOMOLOG OF; AIM1HGNC A...

Alternative titles; symbols

  • SERINE/THREONINE PROTEIN KINASE 12; STK12
  • AURORA-RELATED KINASE 2; ARK2
  • AURORA/IPL1-LIKE KINASE 2; AIK2
  • AIM1, RAT, HOMOLOG OF; AIM1

HGNC Approved Gene Symbol: AURKB

Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:8,204,730-8,210,766 (from NCBI)

▼ Description
Chromosomal segregation during mitosis as well as meiosis is regulated by kinases and phosphatases. The Aurora kinases associate with microtubules during chromosome movement and segregation. Aurora kinase B localizes to microtubules near kinetochores, specifically to the specialized microtubules called K-fibers, and Aurora kinase A (603072) localizes to centrosomes (Lampson et al., 2004).

▼ Cloning and Expression
The Drosophila 'aurora' and S. cerevisiae Ipl1 serine/threonine protein kinases (STKs) are involved in mitotic events such as centrosome separation and chromosome segregation. Using a degenerate primer-based PCR method to screen for novel STKs, Shindo et al. (1998) isolated mouse and human cDNAs encoding STK12, which they termed ARK2 (aurora-related kinase-2). Sequence analysis of human STK12 predicted a 344-amino acid protein containing kinase domains that share high homology with the catalytic domains of other STKs. Cell cycle and Northern blot analyses showed that STK12 is expressed in the S phase and persistently thereafter. Western blot analysis indicated that STK12 is localized in the midbodies during anaphase.

By searching sequence databases for clones homologous to AIK (AURKA; 603072), Kimura et al. (1998) obtained a cDNA encoding STK12, which they designated AIK2 (aurora/Ip11-like kinase-2). Northern blot analysis detected strong expression of a 1.5-kb STK12 transcript in thymus, with weaker expression in small intestine, testis, colon, spleen, and brain. Western blot analysis demonstrated expression of a 39-kD STK12 protein.

By screening a HeLa cell cDNA library with a rat Aim1 (aurora- and Ipl1-like midbody-associated protein) probe, Katayama et al. (1998) isolated a cDNA encoding STK12. A kinase-negative STK12 mutant was shown to induce a failure in cytokinesis during mitosis. The authors found that during differentiation of megakaryocytes, there is no cytokinesis and reduced expression of STK12. Tatsuka et al. (1998) found that STK12 is highly expressed as a 1.2-kb transcript in transformed cell lines but not in normal fibroblasts. They also showed that STK12 is associated with multinuclearity and polyploidy.

▼ Gene Function
By immunoprecipitation of epitope-tagged proteins from transfected HEK293 cells, Kunitoku et al. (2003) demonstrated direct interaction between CENPA (117139) and AURKA. In vitro, AURKA phosphorylated CENPA on ser7, a residue that is also phosphorylated by AURKB. Examination of the role of both kinases in the phosphorylation of CENPA revealed that the reaction is mediated sequentially by AURKA and AURKB in early mitosis. Mitotic cells in which the phosphorylation of CENPA on ser7 was prevented exhibited a substantial proportion of misaligned chromosomes resulting from a defect in the ability of kinetochores to attach to microtubules.

Lampson et al. (2004) examined the role of Aurora kinases during mitosis in rat kangaroo kidney cells with use of small reversible inhibitors of molecular motors and Aurora kinases. Maloriented chromosomes accumulated in the presence of an Aurora kinase inhibitor following spindle bipolarization. The inhibitor was removed to activate the kinase and the orientation of the chromosomes was corrected. In the correction process, the maloriented chromosomes first moved to the pole, then moved to the opposite pole, resulting in alignment at the metaphase plate. The manner of K-fiber shortening suggested that kinetochores remained attached to the microtubule plus ends, and that Aurora B function had been interrupted by the inhibitor. Lampson et al. (2004) concluded that syntelic malorientations (both sister kinetocores attached to the same pole) can be corrected by selective K-fiber disassembly, coupled with movement to the pole.

Andrews et al. (2004) presented evidence that Aurora B inhibits the microtubule depolymerizing activity of mitotic centromere-associated kinesin (MCAK; 604538) by phosphorylating MCAK on ser92. This phosphorylation also regulated MCAK translocalization from kinetochores to the centromere, and disruption of Aurora B function prevented centromeric MCAK targeting. Andrews et al. (2004) concluded that Aurora B regulates MCAK activity and cellular localization.

Hirota et al. (2005) showed that antibodies against mitotic chromosome antigens that are associated with human autoimmune diseases specifically recognize histone H3 (see 602810) molecules that are modified by both trimethylation of lys9 and phosphorylation of ser10 (H3K9me3S10ph). The generation of H3K9me3S10ph depends on Suv39h (see 300254) and Aurora B, and occurs at pericentric heterochromatin during mitosis in different eukaryotes. Most heterochromatin protein-1 (HP1; 604478) typically dissociates from chromosomes during mitosis, but if phosphorylation of H3 ser10 is inhibited, HP1 remains chromosome-bound throughout mitosis. H3 phosphorylation by Aurora B is therefore part of a 'methyl/phos switch' mechanism that displaces HP1 and perhaps other proteins from mitotic heterochromatin.

Ramadan et al. (2007) showed that p97 (601023) stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B. During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. Ramadan et al. (2007) concluded that their data revealed an essential pathway that regulates reformation of the nucleus after mitosis and defined ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation.

Rosasco-Nitcher et al. (2008) investigated the activation of Aurora B and described 2 distinct activation mechanisms. First, Aurora B activation in vitro requires 2 cofactors, telophase disc-60 kD, or TD60 (RCC2; 609587) and microtubules. TD60 is critical to localize both the chromosome passenger complex (CPC) and haspin (609240) kinase activity to centromeres and thus regulates Aurora B at several levels. Second, Aurora B substrates can inhibit kinase activation, and this is relieved by phosphorylation of these substrates by the centromeric kinases Plk1 (602098) and haspin. Rosasco-Nitcher et al. (2008) concluded that these regulatory mechanisms suggested models for phosphorylation by Aurora B of centromeric substrates at unaligned chromosomes and merotelic attachments.

By yeast 2-hybrid analysis of a HeLa cell cDNA library and pull-down assays using recombinant proteins, Sun et al. (2008) showed that the C-terminal tail of EB1 (MAPRE1; 603108) interacted specifically with the catalytic domain of AURKB. The proteins colocalized on the central spindle in anaphase and in the midbody during cytokinesis in simian kidney cells, and endogenous EB1 and AURKB coimmunoprecipitated from HeLa cells. EB1 overexpression enhanced AURKB kinase activity, and knockdown of EB1 with small interfering RNA impaired AURKB activity. EB1 protected AURKB from dephosphorylation/inactivation by protein phosphatase-2A (PP2A; see 176915) by blocking binding of PP2A to AURKB. Sun et al. (2008) concluded that EB1 stimulates AURKB activity by antagonizing its dephosphorylation/inactivation by PP2A.

Using fluorescence resonance energy transfer-based biosensors to measure localized phosphorylation dynamics in living cells, Liu et al. (2009) 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 bioriented attachments and activated the spindle checkpoint. Thus, Liu et al. (2009) concluded that centromere tension can be sensed by increased spatial separation of Aurora B from kinetochore substrates, which reduces phosphorylation and stabilizes kinetochore microtubules.

Wang et al. (2010) showed that phosphorylation of histone H3 threonine-3 (H3T3) by haspin is necessary for CPC accumulation at centromeres and that the CPC subunit survivin (603352) binds directly to phosphorylated H3T3 (H3T3ph). A nonbinding survivin-D70A/D71A mutant did not support CPC complex concentration, and both haspin depletion and survivin-D70A/D71A mutation diminished centromere localization of the kinesin MCAK (604538) and the mitotic checkpoint response to taxol. Survivin-D70A/D71A mutation and microinjection of H3T3ph-specific antibody both compromised centromeric Aurora B functions but did not prevent cytokinesis. Therefore, Wang et al. (2010) concluded that H3T3ph generated by haspin positions the CPC at centromeres to regulate selected targets of Aurora B during mitosis.

Kelly et al. (2010) demonstrated that H3T3ph is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of the CPC subunit survivin. This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B. Consistently, modulation of the kinase activity of haspin, which phosphorylates H3T3, leads to defects in the Aurora B-dependent processes of spindle assembly and inhibition of nuclear reformation. Kelly et al. (2010) concluded that their findings established a direct cellular role for mitotic H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.

Yamagishi et al. (2010) showed that phosphorylation of H3T3 mediated by haspin cooperates with bub1 (602452)-mediated histone 2A-serine-121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. Phosphorylated H3T3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin (609168), the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5 (see 613200), whereas bub1 localizes at kinetochores. Thus, Yamagishi et al. (2010) concluded that the inner centromere is defined by intersection of 2 histone kinases.

Campbell and Desai (2013) showed that an engineered truncation of the Sli15 (INCENP; 604411) subunit of budding yeast CPC that eliminates association with the inner centromere nevertheless supports proper chromosome segregation during both mitosis and meiosis. Truncated Sli15 suppressed the deletion phenotypes of the inner centromere-targeting proteins Bir1 (survivin), Nbl1 (borealin; 609977), Bub1, and Sgo1 (shugoshin). Unlike wildtype Sli15, truncated Sli15 localized to preanaphase spindle microtubules. Premature targeting of full-length Sli15 to microtubules by preventing Cdk1 (116940) phosphorylation also suppressed the inviability of Bir1 deletion. Campbell and Desai (2013) concluded that activation of Aurora B kinase by clustering either on chromatin or on microtubules is sufficient for chromosome biorientation.

MIS18A (618137), a component of the MIS18 complex, localizes at the centromere from late telophase to early G1 phase and plays a priming role in CENPA deposition. Lee et al. (2017) found that MIS18A was phosphorylated at ser36 by Aurora B kinase during mitosis in HeLa cells. MIS18A phosphorylation by Aurora B kinase was necessary for faithful segregation of chromosomes during mitosis, but it was not crucial for MIS18A centromere localization or CENPA centromere loading. Knockdown experiments in HeLa cells showed that MIS18A was required for recruitment of PLK1 to kinetochore at early mitosis, and phosphorylation of MIS18A by Aurora B kinase was required for kinetochore localization of PLK1. Immunoprecipitation assays in 293T cell extracts revealed that PLK1 bound via its polo box domain to phosphorylated MIS18A, and this binding enhanced PLK1 recruitment to kinetochore at prometaphase.

▼ Mapping
By FISH and radiation hybrid analysis, Kimura et al. (1998) mapped the STK12 gene to 17p13.1. Tatsuka et al. (1998) noted that the STK12 gene is localized in a region that is frequently deleted in tumors and that contains tumor-related genes such as p53 (191170), CRK (164762), and ABR (600365). Using interspecific backcross mapping, Shindo et al. (1998) mapped the mouse Stk12 gene to chromosome 11 in a region showing homology of synteny with human 17p.

Tags: 17p13.1