Cross-Talk between AURKA and Plk1 in Mitotic Entry and Spindle Assembly

Abstract

The Aurora kinase A (AURKA) is involved in different aspects of mitotic control, from mitotic entry to cytokinesis. Consistent with its pleiotropic roles, several AURKA interactors are able to modulate its activity, the best characterized being the microtubule-binding protein TPX2, the centrosomal protein Cep192, and Bora. Bora has been described as an essential cofactor of AURKA for phosphorylation-mediated activation of the mitotic kinase polo-like kinase 1 (Plk1) at the G2/M transition. A complex AURKA/Plk1 signaling axis is emerging, with multiple involved actors; recent data suggest that this control network is not restricted to mitotic entry only, but operates throughout mitosis. Here, we integrate available data from the literature to depict the complex interplay between AURKA and Plk1 in G2 and mitosis and how it contributes to their mitotic functions. We will particularly focus on how the activity of specifically localized AURKA/Plk1 pools is modulated in time and space by their reciprocal regulation to ensure the timely and coordinated unfolding of downstream mitotic events.

Keywords: G2/M transition; centrosomes; kinases; mitosis; spindle.

Figure 1

AURKA and Plk1 in mitotic entry and spindle formation. The best characterized links between AURKA and Plk1 are schematized. In mitotic entry (upper box), the combined action of AURKA and Bora activates Plk1, while antagonistic phosphorylation events by Plk1 and cdk1 control Bora stability. The dashed circle on the right indicates the ongoing feedback loop leading to the activation of Plk1, AURKA, and cdk1. Lowered Bora levels enable the interaction of AURKA with Cep192 (central box) and TPX2 (lower box), at centrosomes (centrioles, green; PCM, orange) and microtubules (red), respectively. The enlargement in the central box depicts the scaffolding function of Cep192, leading to recruitment of AURKA and Plk1, activation of the latter and generation by activated Plk1 of γ-TURC-docking sites, with consequent centrosome maturation. Note that Cep192-bound AURKA is activated in a dimeric form, although not represented here to simplify the scheme. Cep192/Plk1/AURKA also contributes to centrosome separation via Eg5 recruitment, and Plk1 independently participates to this process by triggering centrosome linker (light blue lines) dissolution. Separated centrosomes nucleate spindle microtubules that are organized, among others, by AURKA/TPX2 complexes, possibly bound to astrin (lower box). cdk1 phosphorylation of TPX2, possibly influenced by Plk1 activity, yields decreased binding to microtubules. Centrosomal proteins in the lower panel are schematized as in the upper ones, although for space reasons their names are not indicated. The yellow symbols identify PBD-docking sites. Green arrows indicate positive regulatory events, while red arrows represent negative ones. Phosphorylated residues or domains are indicated on the arrows. The different intensities of colors for Plk1 and AURKA denote a different extent of activity.

Figure 2

The multiple AURKA and Plk1 activating networks. (A) A schematic representation of Plk1 and AURKA kinases is shown with activating phosphorylation sites indicated by red asterisks. Yellow boxes represent nuclear localization sequences (N); orange ones are polo boxes (PB1 and 2); and violet ones are degradation motifs (D, destruction box; K, KEN box; A, A box). Catalytic domains are in green. (B) Networks involving NPM, AIBp, PAK1, HEF1/NEDD9, and calmodulin (CaM) as activators and/or substrates of AURKA and Plk1 are represented. Green arrows indicate direct and clarified activating events; phosphorylated residues are indicated; and (A) denotes induction of an autophosphorylation event. Downstream substrates and proposed regulated processes are included.