The structure and functions of aurora kinases

The chromosomal segregation process during mitosis is regulated by the Aurora kinases, a family of serine/threonine kinases that includes Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC). These kinases are crucial for cell division. Aurora kinases are also thought to control meiosis in addition to mitosis. The elimination of Aurora kinases may prevent cell division and impede the development of the embryo.

A variety of malignancies have been linked to the overexpression or gene amplification of Aurora kinases. Additionally, an increasing number of studies have shown that inhibiting Aurora kinases may enhance the effects of chemotherapy. The development of a number of Aurora kinase inhibitors (AKIs) over the last several decades has successfully slowed the growth and progression of many malignancies both in vivo and in vitro, indicating that Aurora kinases may represent a new therapeutic target.

The structure and physiological functions of Aurora kinases in mitosis will be briefly discussed in this review, followed by an explanation of the oncogenic role of Aurora kinases in carcinogenesis. Finally, the effects of combining AKIs with conventional treatment will be covered.

The structure of aurora kinases

The homologous structure of aurora kinases, which consists of an N-terminal domain, a protein kinase domain, and a C-terminal domain, is highly conserved. The catalytic domain of the C-terminal of Aurora kinases, which contains the catalytic T-loop and degradation box (A-box/D-box/KEN-box), is very consistent. A number of protein cofactors, such as inner centromere protein and target protein for Xenopus kinesin-like protein 2 (TPX2), may target and activate Aurora kinases during physical mitosis (INCENP).

The catalytic T-loop residues for each Aurora family member's kinase, which are Thr288 (AURKA), Thr232 (AURKB), and Thr195 (AURKC), respectively, are also auto-phosphorylated to activate the enzymes. The protein phosphatase 1 (PP1)-mediated dephosphorylation process renders Aurora kinases inactive. Anaphase-promoting complex/cyclosome (APC/C) detects Aurora kinases in late mitosis, and they are subsequently destroyed.

The functions of Aurora kinases

AURKA localizes to the centrosome, is activated by the LIM protein ajuba, and reaches its maximal expression and activity during the G2/M transition, causing duplicate centrosomes to split and starting the mitotic process. In a eukaryotic cell, activated AURKA promotes the recruitment of many pericentriolar proteins, such as -tubulin and TACC/MAP215, to the microtubule organizing center (MTOCs). This promotes centrosome maturation and hastens microtubule nucleation. AURKA is activated when the nuclear membrane disintegrates during prometaphase, and TPX2 directs it to the microtubule, where it is necessary for spindle assembly and the conformation of the bipolar spindle microtubule. AURKA is destroyed by the cadherin-1(Cdh1)/APC/C complex and mitotic cells remain at the conclusion of mitosis.

AURKB is a part of the chromosomal passenger complex (CPC), which also includes INCEP, survivin, and borealin as activation regulators. By phosphorylating CENP-A (variant centrosome protein A) on Ser7 and histone H3 on Ser10, it regulates chromosomal condensation. AURKB is also involved in controlling SAC, repairing the damaged kinetochore-spindle connection, preserving accurate chromosome alignment, and faithfully segregating chromosomes. The most recent research showed that Histone H2AX Ser121 phosphorylation by active AURKB enhanced AURKB auto-phosphorylation, creating a positive feedback loop that sped up AURKB activation.

AURKB phosphorylates a number of downstream substrates during anaphase, facilitating their deposition at mid-body and maintaining the stability of the central spindle. These substrates include mitotic kinesin-like protein 1 (MKLP1) and RacGAP1. Additionally, Kif2A, the microtubule depolymerase, might be phosphorylated by AURKB, which would shorten the central spindle and encourage cytokinesis.