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 ex
Fig. 1 The domain structure of the human Aurora kinases AurA, AurB and AurC.
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 (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 (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 ex
The Aurora kinases are strongly linked to the development and progression of human cancers and therefore their ex
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).