Aurora A Protein Kinase: To the Centrosome and Beyond

Abstract

Accurate chromosome segregation requires the perfect spatiotemporal rearrangement of the cellular cytoskeleton. Isolated more than two decades ago from Drosophila, Aurora A is a widespread protein kinase that plays key roles during cell division. Numerous studies have described the localisation of Aurora A at centrosomes, the mitotic spindle, and, more recently, at mitotic centromeres. In this review, we will summarise the cytoskeletal rearrangements regulated by Aurora A during cell division. We will also discuss the recent discoveries showing that Aurora A also controls not only the dynamics of the cortical proteins but also regulates the centromeric proteins, revealing new roles for this kinase during cell division.

Keywords: Aurora A protein kinase, centrosome, mitotic spindle, polarity, centromere, kinetochore, cohesion, transcription.

Figure 1

Major substrates of Aurora A protein kinase and their roles during mitosis. The area of influence of Aurora A protein kinase in the cell is indicated in light green. This area includes the cellular cortex, centrosomes and mitotic spindle. Note that a pool of Aurora A is also present at the centromeres. MT: microtubule.

Figure 2

Aurora A activation at the centrosome and the mitotic spindle. (A) Model for Aurora A activation and subsequent centrosome maturation based on the literature in different model systems. During mitotic entry, (1) inactive Aurora A is recruited on the centrosome by the Centrosomal Protein 192 (Cep192 or Spd-2 in Drosophila and Caenorhabditis elegans). (2) This recruitment favours dimerization, trans-autophosphorylation and activation. (3) Polo-like kinase 1 (Plk1) is subsequently phosphorylated by Aurora A and docked on Cep192. (4) Active Plk1 phosphorylates Cyclin-Dependent Kinase 5 Regulatory subunit-Associated Protein 2 (CDK5RAP2) (Cnn in Drosophila) that undergoes multimerization. CDK5RAP2 displays a binding site for γ-tubulin ring complex (γTuRC), consequently strong microtubule (MT) nucleation is induced at the centrosome surface. CDK5RAP2 also display a binding site for the Transforming Acidic Coiled-Coil containing Protein 1/Colonic and hepatic Tumour Overexpressed Gene protein (TACC/Ch-TOG) complex. (5) Phosphorylation of TACC by Aurora A triggers recruitment of the TACC/Ch-TOG complex on the centrosome. Ch-TOG stimulates astral MT growth. (6) Aurora A also phosphorylates Centrosomal P4.1 Associated Protein (CPAP), to maintain centrosome architecture. (B) Activation of Aurora A around chromosomes by Targeting Protein for Xklp2 (TPX2). (1) The RAs-related Nuclear Guanine Exchange Factor (RAN-GEF) RCC1 is anchored on mitotic chromatin and triggers the formation of a RAN^GTP gradient around chromosomes. RAN^GTP triggers the release of TPX2 from importins α and β. (2) TPX2 can protect active auto phosphorylated Aurora A from dephosphorylation. (3) TPX2 can bind to and activates Aurora A kinase, without auto phosphorylation. (C) Activation of Aurora A by incorporation into droplets. Aurora A can be incorporated into Bub3 interacting and GLEBS motif containing ZNF207 (BugZ) coacervates/droplets (that also contain spindle matrix proteins), to trigger Aurora A dimerization and auto phosphorylation. The right part of the picture shows the location of each Aurora A activated pool (light green).

Figure 3

Histone phosphorylation events are controlled by Aurora A during mitosis. (A) Representation of an enlarged centromere showing nucleosomes (coloured circles). A nucleosome containing phosphorylated Threonine 3 of histone H3 (H3T3) is shown in blue, phosphorylated Threonine 118 of histone H3 (H3T118) is shown in orange. A nucleosome containing the centromere-specific phosphorylated Serine 7 of CENP-A (CENP-AS7) is displayed in purple. The light and dark grey circles represent histone H3 and CENP-A containing nucleosomes respectively. (B) Centromeric histone phosphorylations by Aurora A during mitosis and possible functions. During prophase and prometaphase, Aurora A (AurA, green) phosphorylates Haspin, a kinase required for cohesion maintenance and H3T3 phosphorylation at centromeres, necessary for CPC assembly. Aurora A also phosphorylates H3T118 on chromosome arms but mostly at centromeres. This phosphorylation may create a chromatin environment that promotes Cohesin dissociation. CENP-AS7 is phosphorylated at centromeres only. We speculate that the centrosomal pool of Aurora A is responsible for H3T118 phosphorylation because unaligned chromosomes in the vicinity of the centrosomes display more intense H3T118 signal (Middle panel). In metaphase, when chromosomes are aligned at the equator plate, phosphorylated H3T3 and CENP-AS7 are still present at the centromere, while phosphorylation of H3-T118 is lost. When sister chromatids are under tension, phosphorylation of CENPA-S7A by a centromeric pool of Aurora A (surrounded by the dashed line) prevents cohesion fatigue (Right panel).