Aurora kinase B is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that functions in the attachment of the

mitotic spindle In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process ...

to the

centromere The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fiber ...

and in

cytokinesis Cytokinesis () is the part of the cell division process and part of mitosis during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division ...

Discovery

In 1998, Aurora kinase B was identified in humans by a

polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA (or a part of it) sufficiently to enable detailed st ...

screen for kinases that are overexpressed in cancers. In the same year, rat Aurora kinase B was identified in a screen designed to find

kinases In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

that altered S. cerevisiae proliferation when overexpressed.

Expression and subcellular localization

The expression and activity of Aurora B are regulated according to the

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

. Expression of Aurora B reaches a maximum at the G2-M transition, whereas Aurora B protein is most active during

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

. Aurora B is a chromosomal passenger protein. Specifically, Aurora B localizes to the

chromosomes A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...

prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin retic ...

, the

prometaphase Prometaphase is the phase of mitosis following prophase and preceding metaphase in eukaryotic somatic cells. In prometaphase, the nuclear membrane breaks apart into numerous "membrane vesicles," and the chromosomes inside form protein structure ...

and

metaphase Metaphase ( and ) is a stage of mitosis in the eukaryotic cell cycle in which chromosomes are at their second-most condensed and coiled stage (they are at their most condensed in anaphase). These chromosomes, carrying genetic information, alig ...

, and the central

anaphase Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...

. This localization has been determined by indirect

immunofluorescence Immunofluorescence (IF) is a light microscopy-based technique that allows detection and localization of a wide variety of target biomolecules within a cell or tissue at a quantitative level. The technique utilizes the binding specificity of anti ...

in mammalian, C. elegans, and

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

cells. A more detailed analysis of Aurora B localization has been carried out in mammalian cells by tagging Aurora B with

green fluorescent protein The green fluorescent protein (GFP) is a protein that exhibits green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the protein first isolated from the jellyfish ''Aequorea victo ...

. This analysis showed that the association of Aurora B with centromeres is dynamic (Aurora B at the centromere is constantly exchanging with a pool of cytoplasmic Aurora B). The analysis of tagged Aurora B also suggested that it associates with spindle microtubules during anaphase of mitosis and this association significantly limits its mobility. Finally, a portion of the tagged Aurora B localized to the equatorial cell cortex, having been transported to this location by

astral microtubules An aster is a cellular structure shaped like a star, consisting of a centrosome and its associated microtubules during the early stages of mitosis in an animal cell. Asters do not form during mitosis in plants. Astral rays, composed of microtu ...

Function

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 (MIM 603072) localizes to

centrosomes In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progre ...

(Lampson et al., 2004). upplied by OMIMref name="entrez"> In

cancerous Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

cells, over-expression of these enzymes causes unequal distribution of genetic information, creating

aneuploid Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cel ...

cells, a hallmark of cancer.

Chromosome biorientation

Studies in several organisms indicate that Aurora B oversees chromosome

biorientation Biorientation is the phenomenon whereby microtubules emanating from different microtubule organizing centres (MTOCs) attach to kinetochores of sister chromatids. This results in the sister chromatids moving to opposite poles of the cell during cell ...

by ensuring that appropriate connections are made between spindle

microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

and kinetochores. Inhibition of Aurora B function by

RNA interference RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...

or microinjection of blocking

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

impairs the alignment of chromosomes at the equator of the mitotic spindle. This process of alignment is referred to as chromosome congression. The reason for this defect is a subject of ongoing study. Aurora B inhibition may lead to an increase in the number of syntelic attachments (sister chromatid pairs in which both sister kinetochores are attached to microtubules radiating from the same spindle pole). Intriguingly, expression of a dominant-negative and catalytically inactive form of Aurora B disrupted microtubule attachment to the kinetochore and prevented the association of

dynein Dyneins are a family of cytoskeletal motor proteins (though they are actually protein complexes) that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargo ...

and

centromere protein E Centromere-associated protein E is a protein that in humans is encoded by the ''CENPE'' gene. Centromere-associated protein E is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centromere-associat ...

(CENP-E) with kinetochores. Numerous kinetochore targets of Aurora kinases have been determined in organisms ranging from yeast to man. Most notably, CENP-A is a target of Aurora B. The phosphorylation of CENP-A by Aurora B reaches a maximum in prometaphase. In fact, Aurora A targets the same CENP-A phosphorylation site as Aurora B, and CENP-A phosphorylation by Aurora A is thought to precede that by Aurora B. Thus, a model has been proposed in which CENP-A phosphorylation by Aurora A recruits Aurora B to the centromere, the latter maintaining the phosphorylation state of CENP-A in a

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...

loop. Mutation of this phosphorylation site in CENP-A also leads to defects in

. Aurora B also interacts with mitotic centromere-associated kinesin ( MCAK). Both Aurora B and MCAK localize to the inner centromere during prometaphase. Aurora B has been shown to recruit MCAK to the centromere and directly phosphorylate MCAK on various residues. Phosphorylation of MCAK by Aurora B limits the ability of MCAK to depolymerize microtubules. Importantly, inhibition of MCAK by a number of approaches leads to improper attachment of kinetochores to spindle microtubules. It has been hypothesized that tension generated by amphitelic attachment (biorientation; the attachment of sister kinetochores to opposite spindle poles) pulls sister kinetochores apart, thus disrupting the interaction of Aurora B at the innermost portion of the centromere with microtubule binding sites on the fibrous corona of the outermost centromere. Specifically, the tension generated by biorientation pulls MCAK outside of the area of Aurora B localization. Thus, mitosis proceeds upon biorientation and dissociation of Aurora B from its substrates.

Chromosome condensation and cohesion

Aurora B is responsible for phosphorylation of histone-H3 on serine 10 during mitosis. This modification is conserved from yeast (where the kinase is known as Ipl1) to human. Notably, histone-H3 phosphorylation by Aurora B seems not to be responsible for

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

condensation. Though Aurora B is enriched at centromeres, it localizes diffusely to all chromatin. In Drosophila cells, Aurora B depletion disrupts chromosome structure and compaction. In these cells, the

condensin Condensins are large protein complexes that play a central role in chromosome condensation and segregation during mitosis and meiosis (Figure 1). Their subunits were originally identified as major components of mitotic chromosomes assembled in ' ...

complex does not localize appropriately to the chromosomes. Similarly, in C. elegans, condensin activity is dependent on Aurora B in metaphase. However, in

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos'' = strange, πους, ''pous'' = foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described with ...

egg cell-free extracts, condensin binding and chromosome condensation occur normally even in the absence of Aurora B. Likewise, after treating cells with an Aurora B enzyme inhibitor (Aurora B localization is not affected), the condensin complex localizes normally. Aurora B localizes to the paired arms of homologous chromosomes in metaphase I of C. elegans

meiosis Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one c ...

, and perturbs microtubule dynamics in mitosis. Release of this cohesion, which is dependent on Aurora B, is required for progression to

anaphase I Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one cop ...

and segregation of

homologous chromosomes Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same locus (genetics), loci, where they provide points along e ...

. In mitotic vertebrate B lymphocytes, the proper centromeric localization of a number of Aurora B binding partners requires

cohesin Cohesin is a protein complex that mediates Establishment of sister chromatid cohesion, sister chromatid cohesion, homologous recombination, and Topologically associating domain, DNA looping. Cohesin is formed of SMC3, SMC1A, SMC1, RAD21, SCC1 an ...

Cytokinesis

The Aurora B complex is necessary for

in vertebrates, C. elegans,

, and

fission yeast ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measu ...

. In various cell types, overexpression of a catalytically inactive Aurora B prevents cytokinesis. Disruption of cytokinesis can also arise from Aurora B mislocalization due to mutation of Aurora B binding partners. Aurora B targets a number of proteins that localize to the

cleavage furrow In cell biology, the cleavage furrow is the indentation of the cell's surface that begins the progression of cleavage, by which animal and some algal cells undergo cytokinesis, the final splitting of the membrane, in the process of cell divisio ...

, including the type-III

intermediate filament Intermediate filaments (IFs) are cytoskeleton, cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma' ...

proteins

vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a Intermediate filament#Type III, type III intermediate filamen ...

desmin Desmin is a protein that in humans is encoded by the ''DES'' gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture. ...

, and glial fibrillary acidic protein ( GFAP). In general, phosphorylation destabilizes intermediate filaments. Therefore, it has been proposed that phosphorylation of intermediate filaments at the cleavage furrow destabilizes the filaments in preparation for cytokinesis. In agreement with this hypothesis, mutation of Aurora B target sites in intermediate filament proteins leads to defects in filament deformation and prevents the final stage of cytokinesis. Aurora B also phosphorylates

myosin II Myosins () are a family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-ba ...

regulatory light chain at the cleavage furrow. Inhibition of Aurora B activity prevents proper myosin II localization to the cleavage furrow and disrupts spindle midzone organization.

Spindle assembly checkpoint

The spindle assembly checkpoint inhibits progression of mitosis from metaphase to anaphase until all sister chromatid pairs are bioriented. Presence of Aurora B halts metaphase-to-anaphase transition until proper biorientation is achieved. This is demonstrated in Aurora B deficient cells, where inhibition of Aurora B by hesperadin causes the cell to progress from metaphase to anaphase even when there are misaligned chromosomes in the cell. Aurora B may be involved in the localization of MAD2 and BubR1, proteins that recognize correct chromosome attachment to spindle microtubules. Loss of Aurora B lowers the concentration of Mad2 and BubR1 at the kinetochores. In particular, Aurora B seems to be responsible for maintaining the localization of Mad2 and BubR1 to the kinetochore following their initial recruitment, which occurs independent of Aurora B. Aurora B may be directly or indirectly involved in the hyper-phosphorylation of BubR1 seen in mitosis in wild-type cells.

Axonal outgrowth and axon regeneration

A novel function for Aurora B kinase has recently been reported in neurons. Following axotomy of cultured neurons, significant upregulation in Aurora B kinase gene expression was observed coinciding with regenerative axonal sprouting. Furthermore, overexpression of Aurora B kinase results in accelerated axonal outgrowth of spinal motor neurons in developing zebrafish.

Regulation

Aurora B complexes with three other proteins,

Survivin Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the ''BIRC5'' gene. Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functi ...

, Borealin and

INCENP Inner centromere protein is a protein that in humans is encoded by the ''INCENP'' gene. It is a regulatory protein in the chromosome passenger Protein complex, complex (CPC) . It is involved in regulation of the catalytic proteins Aurora kinase ...

. Each of the four components of the complex is required for the proper localization and function of the other three. INCENP stimulates Aurora B kinase activity. Survivin might do the same. Localization of Aurora B to the centromere during prometaphase and metaphase requires phosphorylation of the mammalian

kinetochore A kinetochore (, ) is a flared oblique-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers, which can be thought of as the ropes pulling chromosomes apart, attach during cell division to ...

-specific

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

-H3 variant centromere protein A (CENP-A). CENP-A associates with the centromere and is necessary for assembly of the kinetochore. Phosphorylation of CENP-A at

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

7 by

Aurora A kinase Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the ''AURKA'' gene. Aurora A is a member of a family of mitotic serine/threonine kinases. It is implicated with important processes during ...

recruits Aurora B to the centromere. Aurora B, itself, can also phosphorylate CENP-A at the same residue once it is recruited (see below). Additionally,

topoisomerase II Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of Adenosine triphosphate, ATP, unlike Type I topoisomerase. In this process, t ...

has been implicated in the regulation of Aurora B localization and enzymatic activity. This regulatory role may be directly associated with the role of topoisomerase II in disjoining

sister chromatids A sister chromatid refers to the identical copies ( chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the du ...

prior to anaphase. In topoisomerase II-depleted cells, Aurora B and INCENP do not transfer to the central spindle in late mitosis. Instead, they remain tightly associated with the centromeres of non-disjoined sister chromatids. Also, cells deficient in topoisomerase II show significantly reduced Aurora B kinase activity. Inhibition of Aurora B due to loss of topoisomerase II seems to depend on BubR1 activity (see below). Aurora B has been shown to bind to end-binding protein 1 ( EB1), a protein that regulates microtubule dynamics. Indirect immunofluorescence showed that Aurora B and EB1 colocalize during anaphase on the central spindle and in the midbody during

. Intriguingly, EB1 overexpression enhances Aurora B kinase activity, at least in part because EB1 blocks the dephosphorylation/inactivation of Aurora B by

protein phosphatase 2 Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in ...

Interactions

Aurora B kinase has been shown to interact with: *

BARD1 BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the ''BARD1'' gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain (residues 46-90), four ankyrin repeats (residues 420-555), and a ...

* BIRC5, *

CDCA8 Borealin is a protein that in humans is encoded by the ''CDCA8'' gene. Function CDCA8 is a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle. Interactions CDCA8 has been shown to interact w ...

* TACC1. * FBXL2.

Clinical significance

Cancer

Abnormally elevated levels of Aurora B kinase cause unequal chromosomal separation during cell division, resulting in the formation of cells with abnormal numbers of chromosomes, which are both a cause and driver of cancer. Inhibition of Aurora B kinase by BI811283 in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (

polyploid Polyploidy is a condition in which the biological cell, cells of an organism have more than two paired sets of (Homologous chromosome, homologous) chromosomes. Most species whose cells have Cell nucleus, nuclei (eukaryotes) are diploid, meaning ...

). Counterintuitively, inhibition of Aurora B kinase actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...

References

External links

* * * {{Portal bar, Biology, border=no EC 2.7.11