Aurora kinase A also known asserine/threonine-protein kinase 6 is anenzyme that in humans is encoded by theAURKAgene.[5][6]
Aurora A is a member of a family of mitoticserine/threonine kinases. It is implicated with important processes during mitosis and meiosis whose proper function is integral for healthycell proliferation. Aurora A is activated by one or morephosphorylations[7] and its activity peaks during theG2 phase toM phase transition in the cell cycle.[8]
Theaurora kinases were first identified in 1990 during acDNA screen ofXenopus eggs.[7] The kinase discovered, Eg2, is now referred to as Aurora A.[9] However, Aurora A's meiotic and mitotic significance was not recognized until 1998.[7]
In all studied species, the three Aurora mitotic kinases localize to thecentrosome[9] during different phases of mitosis.[7] The family members have highly conservedC-terminal catalytic domains. TheirN-terminal domains, however, exhibit a large degree of variance in the size and sequence.[9]
Aurora A and Aurora B kinases play important roles inmitosis. The Aurora kinase A is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. The Aurora kinase B is achromosome passenger protein and regulates chromosome segregation andcytokinesis.
Although there is evidence to suggest that Aurora C might be a chromosomal passenger protein, the cellular function of it is less clear.
Aurora A localizes next to the centrosome late in theG1 phase and early in theS 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 throughtelophase.[7] Right before mitotic exit, Aurora A relocalizes to the mid-zone of the spindle.[10]
During mitosis, amitotic 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, amicrotubule-associated protein that stabilizes centrosomal microtubules andKinesin 5, a motor protein involved in the formation of the bipolar mitotic spindle.[7]γ-tubulins, the base structure from which centrosomal microtubulespolymerize, 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 enteringanaphase. Though the cell cycle continues even in the absence of sufficient γ-tubulin, the centrosome never fully matures; it organizes feweraster microtubules than normal.[8]
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.[8] In the case of the former, it has been suggested that Aurora A cooperates with the kinase Nek2 inXenopus to dissolve the structure tethering the cell's centrosomes together. Therefore, without proper expression of Aurora A, the cell's centrosomes are never able to separate.[10]
Aurora A also assures proper organization and alignment of the chromosomes duringprometaphase. 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.[10]
Finally, Aurora A helps orchestrate an exit from mitosis by contributing to the completion ofcytokinesis- the process by which the cytoplasm of the parent cell is split into two daughter cells. During cytokinesis the mothercentriole 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.[10]
Intriguingly, abolishment of Aurora A throughRNAi interference results in different mutant phenotypes in different organisms and cell types.[10] For example, deletion of Aurora A inC. elegans results in an initial separation of the cell's centrosomes followed by an immediate collapse of the asters. InXenopus, deletion disallows the mitotic spindle from ever even forming.[8] And inDrosophila, flies without Aurora A will effectively form spindles and separate but the aster 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.[10]
Aurora A phosphorylation directs the cytoplasmicpolyadenylation translation of mRNA's, like theMAP kinase kinase kinase protein MOS, that are vital to the completion of meiosis in XenopusOocytes.[9] Prior to the first meioticmetaphase, 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 inhibitcdc2. As a consequence, cdc2 permits entry into meiosis.[7] 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[10]
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.[10]
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.[7] Aurora A has also been shown to be involved in theEpithelial–mesenchymal transition and Neuroendocrine Transdifferentiation ofProstate Cancer cells in aggressive disease.[11]
Dysregulation of Aurora A may lead to cancer because Aurora A is required for the completion ofcytokinesis. If the cell begins mitosis, duplicates its DNA, but is then not able to divide into two separate cells it becomes ananeuploid- containing more chromosomes than normal. Aneuploidy is a trait of many cancerous tumors.[10] Ordinarily, Aurora A expression levels are kept in check by the tumor suppressor proteinp53.[7]
Mutations of the chromosome region that contains Aurora A, 20q13, are generally considered to have a poor prognosis.[7]
Osimertinib androciletinib, two anti cancer drugs forlung cancer, work by shutting off mutantEGFR, which initially kills cancerous tumors, but the tumors rewire and activate Aurora kinase A, becoming cancerous growths again. According to a 2018 study, targeting both EGFR and Aurora prevents return of drug resistant tumors.[12]
^Ewart-Toland A, Briassouli P, de Koning JP, Mao JH, Yuan J, Chan F, et al. (August 2003). "Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human".Nat. Genet.34 (4):403–412.doi:10.1038/ng1220.PMID12881723.S2CID29442841.
Ferchichi I, Stambouli N, Marrackchi R, Arlot Y, Prigent C, Fadiel A, et al. (January 2010). "Experimental and computational studies indicate specific binding of pVHL protein to Aurora-A kinase".J Phys Chem B.114 (3):1486–1497.doi:10.1021/jp909869g.PMID20047310.
Shindo M, Nakano H, Kuroyanagi H, Shirasawa T, Mihara M, Gilbert DJ, et al. (1998). "cDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora-related kinase (ARK) 1 and 2".Biochem. Biophys. Res. Commun.244 (1):285–292.Bibcode:1998BBRC..244..285S.doi:10.1006/bbrc.1998.8250.PMID9514916.
Kimura M, Matsuda Y, Eki T, Yoshioka T, Okumura K, Hanaoka F, et al. (1997). "Assignment of STK6 to human chromosome 20q13.2-->q13.3 and a pseudogene STK6P to 1q41-->q42".Cytogenet. Cell Genet.79 (3–4):201–203.doi:10.1159/000134721.PMID9605851.
