Aurora A kinase
Encyclopedia
Aurora A kinase 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 kinase
s. It is implicated with important processes during mitosis and meiosis whose proper function is integral for healthy cell proliferation. Aurora A is activated by one or more phosphorylation
s and its activity peaks during the G2 phase
to M phase transition in the cell cycle.
eggs. The kinase discovered, Eg2, is now referred to as Aurora A. It was not until 1998, however, that Aurora A's meiotic and mitotic importance was realized.
contains three members the Aurora kinase
family: Aurora A kinase, Aurora B kinase
and Aurora C kinase. The Xenopus, Drosophila
, and Caenorhabditis elegans
genomes, on the other hand, contain orthologues only to Aurora A and Aurora B.
In all studied species, the three Aurora mitotic kinases localize to the centrosome
during different phases of mitosis. The family members have highly conserved C-terminal catalytic domains. Their N-terminal domains, however, exhibit a large degree of variance in the size and sequence.
Aurora A and Aurora B kinases play important roles in mitosis
. The Aurora A kinase is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. The Aurora B kinase
is a chromosome
passenger protein and regulates chromosome segregation and cytokinesis
.
Although there is evidence to suggest that Aurora C might be a chromosomal passenger protein, the cellular function of it is less clear.
and early in the S phase
. As the cell cycle progresses, concentrations of Aurora A increase and the kinase associates with the mitotic poles and the adjacent spindle microtubules. Aurora A remains associated with the spindles through telophase
. Right before mitotic exit, Aurora A relocalizes to the mid-zone of the spindle.
is assembled by using microtubules to tether together the mother centrosome to its daughter. The resulting mitotic spindle is then used to propel apart the sister chromosomes into what will become the two new daughter cells. Aurora A is critical for proper formation of mitotic spindle. It is required for the recruitment of several different proteins important to the spindle formation. Among these target proteins are TACC, a microtubule
-associated protein that stabilizes centrosomal microtubules and Kinesin
5, a motor protein involved in the formation of the bipolar mitotic spindle. γ-tubulins, the base structure from which centrosomal microtubules polymerize, are also recruited by Aurora A. Without Aurora A the centrosome does not accumulate the quantity of γ-tubulin that normal centrosomes recruit prior to entering anaphase
. Though the cell cycle continues even in the absence of deficient γ-tubulin, the centrosome never fully matures; it organizes fewer aster
microtubules than normal.
Furthermore, Aurora A is necessary for the proper separation of the centrosomes after the mitotic spindle has been formed. Without Aurora A, the mitotic spindle, depending on the organism, will either never separate or will begin to separate only to collapse back onto itself. In the case of the former, it has been suggested that Aurora A cooperates with the kinase Nek2 in Xenopus to dissolves the structure tethering the cell's centrosomes together. Therefore, without proper expression of Aurora A, the cell's centrosomes are never able to separate.
Aurora A also assures proper organization and alignment of the chromosomes during prometaphase
. It is directly involved in the interaction of the kinetochore, the part of the chromosome at which the mitotic spindle attaches and pulls, and the mitotic spindle's extended microtubules. It is speculated that Aurora B cooperates with Aurora A to complete this task. In the absence of Aurora A mad2, a protein that normally dissipates once a proper kinetochore-microtubule connection is made, remains present even into metaphase.
Finally, Aurora A helps orchestrate an exit from mitosis by contributing to the completion of cytokinesis
- the process by which the cytoplasm of the parent cell is split into two daughter cells. During citokinesis the mother centriole
returns to the mid-body of the mitotic cell at the end of mitosis and causes the central microtubules to release from the mid-body. The release allows mitosis to run to completion. Though the exact mechanism by which Aurora A aids cytokinesis is unknown, it is well documented that it relocalizes to the mid-body immediately before the completion of mitosis.
Intriguingly, abolishment of Aurora A through RNAi
interference results in different mutant phenotypes in different organisms and cell types. For example, deletion of Aurora A in C. elegans results in an initial separation of the cell's centrosomes followed by an immediate collapse of the asters. In Xenopus, deletion disallows the mitotic spindle from ever even forming. And in Drosophila, flies without Aurora A will effectively form spindles and separate but the asteral microtubules will be dwarfed. These observations suggests that while Aurora-A has orthologues in many different organisms, it may play a similar but slightly different role in each.
translation of mRNA's, like the MAP kinase kinase kinase
protein MOS, that are vital to the completion of meiosis in Xenopus Oocyte
s. Prior to the first meiotic metaphase
, Aurora A induces the synthesis of MOS. The MOS protein accumulates until it exceeds a threshold and then transduces the phosphorylation cascade in the map kinase pathway. This signal subsequently activates the kinase RSK which in turn binds to the protein Myt1. Myt1, in complex with RSK, is now unable to inhibit cdc2. As a consequence, cdc2 permits entry into meiosis. A similar Aurora A dependent process regulates the transition from meiosis I-meiosis II.
Furthermore, Aurora A has been observed to have a biphasic pattern of activation during progression through meiosis. It has been suggested that the fluctuations, or phases, of Aurora A activation are dependent on a positive-feedback mechanism with a p13SUC1-associated protein kinase
. If the cell begins mitosis, duplicates its DNA, but is then not able to divide into two separate cells it becomes an aneuploid- containing more chromosomes than normal. Aneuploidy is a trait of many cancerous tumors.. Ordinarily, Aurora A expression levels are kept in check by the tumor suppressor protein p53
.
Mutations of the chromosome region that contains Aurora A, 20q13, are generally considered to have a poor prognosis.
with:
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the AURKA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Aurora A is a member of a family of mitotic serine/threonine kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s. It is implicated with important processes during mitosis and meiosis whose proper function is integral for healthy cell proliferation. Aurora A is activated by one or more phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
s and its activity peaks during the G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...
to M phase transition in the cell cycle.
Discovery
The aurora kinases were first identified in 1990 during a cDNA screen of XenopusXenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
eggs. The kinase discovered, Eg2, is now referred to as Aurora A. It was not until 1998, however, that Aurora A's meiotic and mitotic importance was realized.
Aurora Kinase Family
The human genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
contains three members the Aurora kinase
Aurora Kinase
Aurora kinases are serine/threonine kinases that are essential for cell proliferation. The enzyme helps the dividing cell dispense its genetic materials to its daughter cells. More specifically, Aurora kinases play a crucial role in cellular division by controlling chromatid segregation...
family: Aurora A kinase, Aurora B kinase
Aurora B kinase
Aurora B kinase is a protein that functions in the attachment of the mitotic spindle to the centromere.In cancerous cells, over-expression of these enzymes causes unequal distribution of genetic information, creating aneuploid cells, a hallmark of cancer....
and Aurora C kinase. The Xenopus, Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, and Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
genomes, on the other hand, contain orthologues only to Aurora A and Aurora B.
In all studied species, the three Aurora mitotic kinases localize to the centrosome
Centrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
during different phases of mitosis. The family members have highly conserved C-terminal catalytic domains. Their N-terminal domains, however, exhibit a large degree of variance in the size and sequence.
Aurora A and Aurora B kinases play important roles in mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. The Aurora A kinase is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. The Aurora B kinase
Aurora B kinase
Aurora B kinase is a protein that functions in the attachment of the mitotic spindle to the centromere.In cancerous cells, over-expression of these enzymes causes unequal distribution of genetic information, creating aneuploid cells, a hallmark of cancer....
is a chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
passenger protein and regulates chromosome segregation and cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
.
Although there is evidence to suggest that Aurora C might be a chromosomal passenger protein, the cellular function of it is less clear.
Localization
Aurora A localizes next to the centrosome late in the G1 phaseG1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
and early in the S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
. As the cell cycle progresses, concentrations of Aurora A increase and the kinase associates with the mitotic poles and the adjacent spindle microtubules. Aurora A remains associated with the spindles through telophase
Telophase
Telophase from the ancient Greek "τελος" and "φασις" , is a stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase events are reversed. Two daughter nuclei form in the cell. The nuclear envelopes of the daughter cells are formed from the...
. Right before mitotic exit, Aurora A relocalizes to the mid-zone of the spindle.
Mitosis
During mitosis, a mitotic spindleMitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
is assembled by using microtubules to tether together the mother centrosome to its daughter. The resulting mitotic spindle is then used to propel apart the sister chromosomes into what will become the two new daughter cells. Aurora A is critical for proper formation of mitotic spindle. It is required for the recruitment of several different proteins important to the spindle formation. Among these target proteins are TACC, a microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
-associated protein that stabilizes centrosomal microtubules and Kinesin
Kinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP . The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular...
5, a motor protein involved in the formation of the bipolar mitotic spindle. γ-tubulins, the base structure from which centrosomal microtubules polymerize, are also recruited by Aurora A. Without Aurora A the centrosome does not accumulate the quantity of γ-tubulin that normal centrosomes recruit prior to entering anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
. Though the cell cycle continues even in the absence of deficient γ-tubulin, the centrosome never fully matures; it organizes fewer aster
Aster (cell biology)
An aster is a cellular structure shaped like a star, formed around each centrosome during mitosis in an animal cell. Astral rays, composed of microtubules, radiate from the centrosphere and look like a cloud....
microtubules than normal.
Furthermore, Aurora A is necessary for the proper separation of the centrosomes after the mitotic spindle has been formed. Without Aurora A, the mitotic spindle, depending on the organism, will either never separate or will begin to separate only to collapse back onto itself. In the case of the former, it has been suggested that Aurora A cooperates with the kinase Nek2 in Xenopus to dissolves the structure tethering the cell's centrosomes together. Therefore, without proper expression of Aurora A, the cell's centrosomes are never able to separate.
Aurora A also assures proper organization and alignment of the chromosomes during prometaphase
Prometaphase
Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryotic somatic cells. In Prometaphase, The nuclear envelope breaks into fragments and disappears. The tiny nucleolus inside the nuclear envolope, also dissolves. Microtubules emerging from the centrosomes at the...
. It is directly involved in the interaction of the kinetochore, the part of the chromosome at which the mitotic spindle attaches and pulls, and the mitotic spindle's extended microtubules. It is speculated that Aurora B cooperates with Aurora A to complete this task. In the absence of Aurora A mad2, a protein that normally dissipates once a proper kinetochore-microtubule connection is made, remains present even into metaphase.
Finally, Aurora A helps orchestrate an exit from mitosis by contributing to the completion of cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
- the process by which the cytoplasm of the parent cell is split into two daughter cells. During citokinesis the mother centriole
Centriole
A Centriole is a barrel-shaped cell structure found in most animal eukaryotic cells, though it is absent in higher plants and most fungi. The walls of each centriole are usually composed of nine triplets of microtubules...
returns to the mid-body of the mitotic cell at the end of mitosis and causes the central microtubules to release from the mid-body. The release allows mitosis to run to completion. Though the exact mechanism by which Aurora A aids cytokinesis is unknown, it is well documented that it relocalizes to the mid-body immediately before the completion of mitosis.
Intriguingly, abolishment of Aurora A through RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...
interference results in different mutant phenotypes in different organisms and cell types. For example, deletion of Aurora A in C. elegans results in an initial separation of the cell's centrosomes followed by an immediate collapse of the asters. In Xenopus, deletion disallows the mitotic spindle from ever even forming. And in Drosophila, flies without Aurora A will effectively form spindles and separate but the asteral microtubules will be dwarfed. These observations suggests that while Aurora-A has orthologues in many different organisms, it may play a similar but slightly different role in each.
Meiosis
Aurora A phosphorylation directs the cytoplasmic polyadenylationPolyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
translation of mRNA's, like the MAP kinase kinase kinase
MAP kinase kinase kinase
MAP kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase.In humans there are at least 19 genes:* MAP3K1 * MAP3K2* MAP3K3 * MAP3K4* MAP3K5...
protein MOS, that are vital to the completion of meiosis in Xenopus Oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...
s. Prior to the first meiotic metaphase
Metaphase
Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...
, Aurora A induces the synthesis of MOS. The MOS protein accumulates until it exceeds a threshold and then transduces the phosphorylation cascade in the map kinase pathway. This signal subsequently activates the kinase RSK which in turn binds to the protein Myt1. Myt1, in complex with RSK, is now unable to inhibit cdc2. As a consequence, cdc2 permits entry into meiosis. A similar Aurora A dependent process regulates the transition from meiosis I-meiosis II.
Furthermore, Aurora A has been observed to have a biphasic pattern of activation during progression through meiosis. It has been suggested that the fluctuations, or phases, of Aurora A activation are dependent on a positive-feedback mechanism with a p13SUC1-associated protein kinase
Protein translation
Aurora A is not only implicated with the translation of MOS during meiosis but also in the polyadenylation and subsequent translation of neural mRNAs whose protein products are associated with synaptic plasticity.Clinical significance
Aurora A dysregulation has been associated with high occurrence of cancer. For example, one study showed over-expression of Aurora A in 94 percent of the invasive tissue growth in breast cancer, while surrounding, healthy tissues had normal levels of Aurora A expression. Dysregulation of Aurora A may lead to cancer because Aurora A is required for the completion of cytokinesisCytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
. If the cell begins mitosis, duplicates its DNA, but is then not able to divide into two separate cells it becomes an aneuploid- containing more chromosomes than normal. Aneuploidy is a trait of many cancerous tumors.. Ordinarily, Aurora A expression levels are kept in check by the tumor suppressor protein p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
.
Mutations of the chromosome region that contains Aurora A, 20q13, are generally considered to have a poor prognosis.
Interactions
Aurora A kinase has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
, - MBD3MBD3Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the MBD3 gene.-Interactions:MBD3 has been shown to interact with Aurora A kinase, HDAC1, Methyl-CpG-binding domain protein 2, MTA2 and GATAD2B.-Further reading:...
, - NME1NME1Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene. It is thought to be a metastasis suppressor.-Interactions:...
, - P53P53p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, - TACC1TACC1Transforming acidic coiled-coil-containing protein 1 is a protein that in humans is encoded by the TACC1 gene.-Interactions:TACC1 has been shown to interact with Aurora A kinase, TDRD7, SNRPG, Aurora B kinase, LSM7, BARD1 and CKAP5.-Further reading:...
, - TPX2TPX2Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene.-Interactions:TPX2 has been shown to interact with Aurora A kinase.-Further reading:...
, and - UBE2NUBE2NUbiquitin-conjugating enzyme E2 N is a protein that in humans is encoded by the UBE2N gene.-Interactions:UBE2N has been shown to interact with Aurora A kinase, TRAF2, TRAF6, HLTF and UBE2V1.-Further reading:...
.