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Aurora kinase A (Aurka) is a member of the highly evolutionarily conserved silk/threonine protein kinase family. Aurka consists mainly of two domains: the regulatory domain at the N-terminus and the catalytic domain at the C-terminus. There are two functional regions, ABox and B-Box, at the N-terminus, which are closely related to the degradation of the kinase. However, the phosphorylation level of the C-terminal threonine is related to the activation of the kinase.
During the process of cell mitosis, the expression level of Aurka changes differently. Aurka is primarily localized to the central body region and the microtubule region at the end of the centrosome. Aurka plays a key role in cell mitosis. Aurka mainly regulates the functions of centrosomes and microtubules, mainly involving the replication and separation of centrosomes, the assembly of spindles, the condensation of chromatin, the conversion of G2-M phase, and the division of the cytoplasm.
Activation and Degradation of Aurka
Activation of Aurka requires the participation of multiple proteins. Current research confirms that TPX 2 is the most important cofactor of Aurka and it is involved in the activation process of Aurka. It was found in African melon cells that PLX1 phosphorylates and activates the N-terminus of TPX2, and activated TPX2 mediates Aurka activation. The study also found that phosphorylation of Ser 204 at TPX2 also activates Aurka, which has the ability to activate Aurka even at low phosphorylation levels. The TPX 2 combines with the Aurka through the N-terminus to promote the activation of the Aurka into the catalytic pocket at the C-terminus. This configuration change in Aurka prevents the PP 138-dependent dephosphorylation from being inactivated by the Thr 288 phosphorylation site.
Degradation of Aurka is a complex process, and APC/C-dependent ubiquitination degradation pathways play an important role. APC /C, with the help of two E2 ubiquitin ligases (Ube2C and Ube2S), can ubiquitinate and degrade the substrate. As a co-activator of Aurka, Cdc 20 and Cdh 1 not only participate in the substrate recognition process, but also enhance the activity of APC /C by increasing the stability of E2 enzyme binding to APC /C.
David et al. found that Cdh1-mediated APC/C-dependent ubiquitination pathways also play an important role. In Hela cells, the expression of Cdh1 was knocked down by the RNA interference technique, and it was found that Aurka was not degraded during the mitotic exit, and the separation of sister chromatids was found to be accelerated. The same result occurred when non-degraded Aurora-A was expressed in Hela cells. This indicates that Cdh1-mediated APC/C-dependent ubiquitination degradation pathway plays a key role in the regulation of Aurka degradation.
Aurka and Tumor
Aurka is overexpressed in a variety of human tumors, including primary colorectal cancer, glioma, breast, ovarian, and pancreatic cancer. Aurka regulates tumor proliferation through various mechanisms. Yan et al. found that the main pathways include: 1. accelerating tumor cell cycle progression; 2 activating tumor cell survival or anti-apoptotic signaling pathway; 3 inducing tumor cell gene instability; 4. promoting tumor cell epithelial-mesenchymal transition; 5. promoting the formation of tumor stem cells with self-renewal ability. Aurka regulates the proliferation, invasion, and metastasis of tumor cells through these mechanisms.
Figure 1. A summary of signaling networks of AURKA in cancer. Solid lines indicate direct regulation, whereas dashed lines indicate indirect regulation. (Katsha, et al. 2015).
Tang et al. found that down-regulation of Aurka expression can lead to obstacles in spindle assembly and chromosome segregation, ultimately leading to genetic instability and tumor formation. Overexpression of Aurka, such as breast cancer, gastric cancer, ovarian cancer, esophageal cancer, colorectal cancer, etc., is found in various tumors of the body, suggesting that Aurka may play an important role in tumor formation. Overexpression of Aurka may be associated with poor prognosis in cancer patients, therefore, it can be a new therapeutic target.
Zhang et al. showed that Aurora can regulate the proliferation of prostate cancer through the AKT signaling pathway. In prostate cancer PC3 cells, the expression of Aurka was knocked down by RNA interference, and it was found that the decrease in AKT phosphorylation was accompanied by an increase in the level of autophagy. Therefore, Aurka can increase the phosphorylation level of AKT signaling pathway and inhibit the autophagy of tumor cells, thereby promoting the proliferation of tumor cells.
In neuroblastoma cells, high expression of Aurka regulates N-Myc expression through a variety of mechanisms, which in turn affects the survival and proliferation of neuroblastoma. In the neuroblastoma cell line BE2-C, the expression of Aurka was knocked down, and it was found that the expression level of N-Myc protein was decreased, and the N-Myc nuclear translocation process was inhibited. Thus Aurka can promote the proliferation, growth, and angiogenesis of neuroblastoma by regulating the N-Myc nuclear translocation process.
Aurka is widely involved in the regulation of glioma stem cell activity and promotes the development of glioma. β-catenin is an important regulator of the Wnt signaling pathway and plays an important role in maintaining the activity of the Wnt signaling pathway. Aurka promotes the self-power and tumorigenicity of glioma stem cells by directly binding to AXIN to disrupt the AXIN/GSK3b /β-catenin complex and stabilize β-catenin, activating Wnt signaling pathway.