Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

Abstract

AURKA is a serine/threonine kinase overexpressed in several cancers. Originally identified as a protein with multifaceted roles during mitosis, improvements in quantitative microscopy uncovered several non-mitotic roles as well. In physiological conditions, AURKA regulates cilia disassembly, neurite extension, cell motility, DNA replication and senescence programs. In cancer-like contexts, AURKA actively promotes DNA repair, it acts as a transcription factor, promotes cell migration and invasion, and it localises at mitochondria to regulate mitochondrial dynamics and ATP production. Here we review the non-mitotic roles of AURKA, and its partners outside of cell division. In addition, we give an insight into how structural data and quantitative fluorescence microscopy allowed to understand AURKA activation and its interaction with new substrates, highlighting future developments in fluorescence microscopy needed to better understand AURKA functions in vivo. Last, we will recapitulate the most significant AURKA inhibitors currently in clinical trials, and we will explore how the non-mitotic roles of the kinase may provide new insights to ameliorate current pharmacological strategies against AURKA overexpression.

Keywords: AURKA; Cell cycle; FRET; Fluorescence microscopy; Non-mitotic roles; Structural data.

Fig. 1

Schematic overview of the physiological non-mitotic roles of AURKA. To the extent of our knowledge, these roles are confined to G0/G1: the disassembly of primary cilia, neurite outgrowth and the formation of the DNA pre-replication complex. The regulation of mitochondrial dynamics appears to take place throughout the interphase, with AURKA regulating mitochondrial fission when expressed under physiological levels

Fig. 2

Schematic overview of the non-mitotic roles of AURKA with relevance for cancer. Cancer-related roles of AURKA outside mitosis are distributed throughout interphase: the activation of senescence programs and cytoskeletal stability are mostly relevant during G0/G1 phase, while in the early S phase we observe the transcriptional activation of key cancer-related factors. Overexpressed AURKA also regulates mitochondrial dynamics, by promoting mitochondrial fusion throughout interphase and fission at mitosis. This has direct consequences on the energetic capabilities of mitochondria, as overexpressed AURKA boosts ATP production