Aurora is the name given to a family of serine/threonine protein kinases that regulate many processes during cell division.
Aurora kinases are involved in the control of the centrosome and nuclear cycles, and have essential functions in mitotic processes such as chromosome condensation, spindle dynamics, kinetochore–microtubule interactions, chromosome orientation and establishment of the metaphase plate. They are also required for the proper completion of cytokinesis(The cellular geography of Aurora kinases, 2003).
There are three family members:
- Aurora A (AURKA)
- Aurora B (AURKB)
- Aurora C (AURKC)
CHEMICAL STRUCTURE AND IMAGES
The three human Aurora kinases range from 309 to 403 amino acids and share 67-76% amino acid sequence identity in their catalytic domains with little similarity in their N-terminus that provide molecular basis for specific but diversified interactions with different effector proteins. These Aurora-effector protein interactions may account for their distinct subcellular localization on mitotic spindle. The Aurora family members share highly conserved sequence in the catalytic domain of the kinase across different organisms. The overall sequence identities between human and rodent proteins are: Aurora-A (82%), Aurora-B (84%) and Aurora-C (78%), respectively(Function and regulation of Aurora/Ipl1p kinase family in cell division,2003).
The high degree of sequence similarity between human Aurora A and B in this region is highlighted in figure, in which sequence conservation has been mapped on the surface of the Aurora-A catalytic domain. This high degree of conservation must be taken into account when considering the specificity of Aurora kinase substrates and inhibitors(The cellular geography of Aurora kinases,2003).
a.The region of Aurora A and B surrounding the catalytic cleft is remarkably conserved. The figure shows the crystal structure of the kinase domain of Aurora A. A linear colour ramp represents the average conservation of each amino acid, ranging from 0.5 (red, divergent) to 1.0 (blue, conserved).
b.The organization of human Aurora-A, -B and -C kinases. The position of the A-box/D-box-activating domain (DAD) and the D-box is shown, as is the position of the activation loop. These features have been characterized most thoroughly in Aurora A, and the boxes shown for Aurora B and C are approximations only.
Protein Aminoacids Percentage
ENZYMATIC ACTIVITY AND CELLULAR FUNCTION
Aurora-A and Aurora-B exhibit divergent functions in mitotic control, corresponding to different subcellular distribution of the two kinases. Aurora A and B are both activated by phosphorylation.
Aurora A. In G2 phase, Aurora-A first localizes to pericentriolar material and is activated by the LIM protein Ajuba(gene),which is required for centrosome maturation. Aurora-A facilitates centrosome maturation in microtubule nucleation ability by recruiting and/or phosphorylating centrosomal components, sequentially contributing to mitotic spindle assembly. The second role of Aurora-A in spindle assembly is exerted when it localizes to the pole proximal ends of microtubules after nuclear envelope breakdown.
Aurora A interacts with TPX2, a prominent spindle component previously implicated in spindle assembly. TPX2 targets Aurora A to spindle MTs but not centrosomes.TPX2 clearly regulates Aurora A activity in both time and space.
After anaphase onset, Aurora A levels are reduced as a consequence of ubiquitin-dependent proteolysis. This down-regulation depends on the recognition, by the ubiquitin ligase Cdh1–APC/C (anaphase promoting complex/cyclosome), of two motifs within Aurora A, a conventional destruction box (D-box) in the C terminus and a novel motif (called A-box or D-box-activating domain) in the N terminus. Interestingly, the timing of Aurora A degradation may be controlled by phosphorylation on a conserved serine residue (Ser51 in the human kinase).Aurora-A regulates centrosome separation and G2-M Transition(Roles of Aurora kinases in mitosis and tumorigenesis,2007).
Aurora B.Aurora-B regulates chromatid separation and plays an essential role in cytokinesis. It forms a tight complex with two proteins: INCENP (inner centromere protein) and survivin. Depletion or inactivation of Aurora B, INCENP or survivin produces similar defects in chromosome segregation and cell division, and all three proteins are dependent on each other for correct localization(Aurora kinases link chromosome segregation and cell division to cancer susceptibility,2004).
Aurora C.Among three human Aurora kinases, there are few functional studies about Aurora-C.Aurora-C is localized to centrosomes from anaphase to cytokinesis.Aurora-C may play a role in centrosome function during the later stages of mitosis.
Despite these similarities, the three mammalian Aurora family members differ in their expression patterns,subcellular localization, and timing of activity.
Localization of Aurora kinases
a | The relative localization of Aurora A and Aurora B in mitotic cells is shown. The level of both kinases is substantially reduced in G1 cells. By prophase, Aurora A (green boxes) is concentrated around the centrosomes, whereas Aurora B (red circles) is nuclear. In metaphase, Aurora A is on the microtubules near the spindle poles, whereas Aurora B is located in the inner centromere. In anaphase, most Aurora A is on the polar microtubules, but some might also be located in the spindle midzone. Aurora B is concentrated in the spindle midzone and at the cell cortex at the site of cleavage-furrow ingression. In cytokinesis, both kinases are concentrated in the midbody. The inset boxes show the results of fluorescence recovery after photobleaching (FRAP) studies, and indicate that Aurora A and B are dynamic at centrosomes and centromeres, respectively, but that Aurora B becomes immobile when targeted to the spindle midzone. Restoration microscopy of Aurora B (red staining), inner centromere protein (INCENP; green staining), and DNA (blue staining) in mitotic HeLa cells in ( b ) metaphase, ( c ) anaphase and ( d ) cytokinesis. Some background staining of INCENP on the spindle is seen in this experiment.
AURORA KINASES AND CANCER
The mammalian Aurora kinases by virtue of their association with interphase centrosomes, the mitotic spindle poles, the mitotic microtubules and the spindle midbody, lend credence to the possibility that these kinases may play pivotal roles in controlling chromosomal ploidy in cells. The three members of the mammalian family, besides being implicated as mitotic regulators, have generated significant interest in the cancer research field due to their elevated expression profiles detected in many human cancers.
(The Aurora kinases: role in cell transformation and tumorigenesis,2003).
All three Aurora kinases have been linked to cancer progression. The three Aurora genes map to chromosomal loci (A:20q13, B:17p13, C:19q13) that are frequently altered in human tumors. Concomitantly, elevated expression of Aurora A in breast, bladder, colon, ovarian and
pancreatic cancers correlates with chromosomal instability and clinically aggressive disease. At present, the evidence linking Aurora B and C to carcinogenesis is primarily correlative, but recent genetic studies have convincingly identified Aurora A as a cancer-susceptibility
gene in both mouse and humans(Aurora kinases link chromosome segregation and cell division to cancer susceptibility,2004).
Aurora Kinases, Tumor Diagnosis, and Therapy
Could Aurora-A serve as a clinical tumor prognosis marker? Microarray-based screening for molecular markers in medulloblastome revealed positive staining for Aurora-A and identified it as an independent prognostic factor for overall survival. However, experiments comparing the level of Aurora-A expression in human breast tumor specimens with clinical variables revealed no association between Aurora-A staining and tumor size, lymph node status, or hormone receptor status.
Despite the above debate, studies of the polymorphism of Aurora-A have proven that Aurora-A is a candidate low-penetrance tumor-susceptibility gene in mouse and human, raising the possibility that it might be useful as a caution of predisposition to cancer. Two functional coding single nucleotide polymorphisms as 91T>A and 169G>A are associated with occurrence of esophageal squamous cell carcinoma and increase the risk of esophageal cancer and gastric cancer. More clinical evidence is needed to answer if the genotype of Aurora-A would be involved in determining “cancer susceptibility.”
Aurora Kinase Inhibitors in Cancer Therapy
RNA interference targeting Aurora-A suppresses tumor growth and enhances the sensitivity to chemotherapy and UV irradiation–induced apoptosis in human cells, showing its potential as a target for cancer therapy.
Several inhibitors of Aurora kinases : VX-680, was designed against the ATP-binding site of Aurora kinases and was proven a high potent, selective, and reversible inhibitor;other inhibitors of Aurora kinases have been analyzed, such as ZM447439 and Hesperadin(Roles of Aurora Kinases in Mitosis and Tumorigenesis,2007).
* Rosalia Canzoneri
* Francesca Napoli