Aurora Proteins

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 Aurora Proteins Background

Aurora kinases are serine threonine kinases that play important roles during the cell cycle. The first family member was discovered in a Xenopus screen in 1990 and homologs were discovered afterwards in Saccharomyces cerevisiae (Ipll), Schizosaccharomyces pombe (Arkl) and Drosophila melanogaster (Aurora). A screen in Drosophila melanogaster identified a mutated form of the aurora kinases that causes mitotic arrest with condensed chromosomes and monopolar spindles. The strong phenotype and the similarity to the polar lights (Auroras) in the night sky lead to the name Aurora. Only one Aurora protein is identified in yeast but three family members, Aurora kinase A (AurA), Aurora kinase B (AurB) and Aurora kinase C (AurC) were identified in mammals. All three proteins share a similar structure with an N-terminal regulatory domain and a C-terminal catalytic domain followed by a short C-terminal extension. The regulatory domain is highly variable and is probably involved in substrate binding and cellular localization. On the other hand the kinase domain is conserved between the three family members and shares more than 70% homology. The three Aurora kinases mediate key processes during mitosis ranging from mitotic entry to cytokinesis.

Therefore a strict control of the Aurora kinases is essential to promote coordinated mitotic progression. The regulation depends on gene expression, protein targeting, local activation as well as degradation. The expression levels of the Aurora kinases are low during G1 and S-phase, increase during G2 and reach a maximum in early mitosis when cofactors are required to promote autophosphorylation of a special threonine residue in the activation loop of the catalytic domain and to target the kinases to their distinct locations.

The domain structure of the human Aurora kinases AurA, AurB and AurC

Fig. 1 The domain structure of the human Aurora kinases AurA, AurB and AurC.

Aurora kinase A

Aurora kinase A (AurA) is a centrosome kinase, important for centrosome maturation and separation, mitotic entry and spindle assembly. The activation of AurA is controlled via different mechanisms in order to allow accurate cell cycle progression. The phosphorylation of Thr288 in the activation loop of the kinase is essential for AurA activity and this phosphorylation is counteracted by the protein phosphatases PP1 and PP2A. By binding to cofactor proteins, the auto-phosphorylation of Thr288 is facilitated and dephosphorylation by PP1 and PP2A is blocked. The AurA cofactors Ajuba, Bora and TPX2 target the active kinase to centrosomes and to the mitotic spindle where AurA can interact with specific substrates. In addition AurA protein levels are controlled by degradation via the APC/Ccdh1. A specific carboxy terminal D-box motif (also present in AurB) in combination with an amino-terminal Aurora-box motif (only present in AurA) targets the protein for degradation at the end of mitosis.

During mitosis, AurA can regulate its substrate by phosphorylation. The specific recognition site of AurA [K/R]X[T/S][l/L/V] (X is any amino acid) was first described in budding yeast but was confirmed to be conserved in higher eukaryotes.

Aurora kinase B

Aurora kinase B (AurB) is the enzymatic subunit of the chromosomal passenger complex (CPC). The complex comprises AurB in association with three non-enzymatic proteins, the inner centromeric protein (INCENP), borealin, and survivin.

AurB regulates various functions throughout the cell cycle. It is involved in chromosome condensation, kinetochore maturation, correction of microtubule-kinetochore attachment errors, the formation of the central spindle and cytokinesis. To mediate all these events, AurB needs to be targeted to distinct cellular locations at the correct time of the cell cycle. During prophase, AurB can be detected on chromosome arms before it concentrates to the inner centromere during prometaphase and metaphase. A drastic localization change occurs when AurB is located to the central spindle in anaphase. Finally it can be detected in the midbody region in telophase.

Aurora kinase C

Aurora kinase C (AurC) is the third but least studied member of the Aurora family. It was identified by a homology search for AurB in the protein sequence database (GeneBank). Unlike AurA and AurB the expression of AurC is mainly restricted to the testis were it plays a unique physiological role in spermatogenesis. Men with a homozygous mutation in the AURKC gene produce "large-headed multiflagellar polyploid spermatozoa" and are infertile. The group of Long Yu investigated AurC expression further and observed that apart from the high expression levels in the testis, lower AurC levels can be detected in 16 other human tissues. But probably more important is that AurC is overexpressed in a variety of human tumor cell lines. The expression of AurC throughout the cell cycle is similar to AurA and AurB, with low levels in Gl/S phase, accumulation during G2/M and degradation after mitosis. Although different groups revealed that AurC can replace AurB in the chromosomal passenger complex by interacting with INCENP, borealin and survivin AurB is the preferred binding partner. Nevertheless, AurC can rescue the multinucleation phenotype caused by AurB silencing, showing that AurC is a true chromosomal passenger protein that shares AurB substrates and can restore AurB activity.

Aurora kinases in cancer

The Aurora kinases are strongly linked to the development and progression of human cancers and therefore their expression in different tumor samples and cell lines has been investigated. The AurA gene is located to the 20ql3 region of the genome which is amplified in many human tumors and elevated protein levels can also be observed in many cancers. The AurB gene is located to the 17pl3.1 region. This region is rarely altered in human tumors but protein levels are frequently increased. Both AURKA and AURKB are not bona fide oncogenes since overexpression of AurA or AurB does not transform cells in vitro or enhance tumor formation in vivo. However both AurA and AurB can enhance the effect of other oncogenic mutations to advance tumor formation. Finally AurC expression could be confirmed for some tumors but by now no function for AURKC in tumorigenesis has been reported.

Aurora kinase inhibitors

The first Aurora kinase inhibitor was described in 2003 by the group of Stephen Taylor. In the following years more than 30 drugs were developed by different companies and researchers alike and more than 10 of the developed compounds are being tested in clinical trials. Aurora kinase inhibitors can be subdivided into three groups. The first group of inhibitors inactivates AurA and AurB simultaneously (e.g. ZM447439) while the second group is specific for AurA inhibition (e.g. Alisertib) and the third group specifically targets AurB (e.g. AZD1152).