AURKA (aurora kinase A)

Description	403 amino acids, 46kDa protein. At the amino terminal domain, three putative conserved Aurora boxes (A-boxI, A-boxII and A-boxIII) can be identified. The functional significance of these boxes are not yet clearly known and there is suggestive evidence in the literature that these may be involved in subcellular localization or substrate recognition for the proteins. One of the serine residues in the A-boxII of Aurora-A kinase has recently been shown to be involved in the degradation of the protein. One activation motif and a destruction box in C-terminal. AURKA is regulated by phosphorylation in a cell cycle dependent manner. This phosphorylation occurs on a conserved residue, threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. AURKA protein is able to physically associate with multiple important cellular proteins such as p53, BRCA1, and TACC1. The interactions of AURKA with those critical molecules have been shown to disrupt/alter their physiological functions and may play roles in tumorigenesis.
Expression	Widely expressed, AURKA mRNA and protein expression levels are low during G1 and S phase and peak during the G2/M phase of the cell cycle. Kinase activity of the protein is also cell cycle regulated and the highest activity coincides with the most elevated expression level of the protein during mitosis.
Localisation	AURKA localizes next to the centrosome late in the G1 phase and early in the S phase. As the cell cycle progresses, concentration of AURKA increases and the kinase associates with the mitotic poles and the adjacent spindle microtubules. AURKA remains associated with the spindles through telophase.
Function	Serine/threonine kinase identified as key regulator of the mitotic cell division process. Known to be involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation processes. AURKA 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. Two upstream regulators of AURKA, Ajuba and targeting protein for Xklp2 ( TPX2 ) are known. TPX2 is a MT-binding protein involved in spindle pole formation and is the best characterized RanGTP-dependent spindle activator. TPX2 is required for AURKA binding to spindle MTs and its binding to AURKA holds the latter in an active conformation. Ajuba and AURKA interact in mitotic cells and become phosphorylated. In vitro analyses revealed that Ajuba induces the autophosphorylation and consequent activation of AURKA. Depletion of Ajuba prevented activation of AURKA at centrosomes in late G2 phase and inhibited mitotic entry. AURKA induces p53 degradation by phosphorylation of Ser-315. It was demonstrated that DNA binding and transactivation activity of p53 was abrogated by AURKA. AURKA phosphorylates p53 at Ser-215 in vitro and in vivo. The inhibition of p53 DNA binding and transactivation activity by AURKA depends on phosphorylation of Ser-215 but not Ser-315. Further, AURKA phosphorylation of Ser-215 of p53 is associated with AURKA -regulated cell cycle progression, cell survival, and transformation. The p53 is a physiological substrate of AURKA and that AURKA exerts its function through phosphorylation of Ser-215 of p53.
Homology	Aurora related kinases, AURKA and AURKB are present in Drosophila,C.elegans and X. laevis. Among mammals, three members of the family, AURKA, -B and -C have so far been identified. The three members of the mammalian kinases of varying peptide lengths share similar catalytic domains located in the carboxyl terminus but their amino terminal extensions are of variable length and display little or no similarity. By examination of the AURKA cDNA sequence the threonine at residue 288 in the catalytic domain was found to be highly conserved in all Aurora family members as well as in various other serine/threonine kinases.

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