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.
Highlights
About 20 years ago, two loci encoding for serine–threonine kinases required for correct spindle pole assembly were described in Drosophila and named “polo” and “aurora” [1,2,3]; these were the forefathers of the corresponding kinase families, well characterized as key regulators of the cell cycle and mitotic division
Protein levels peak at G2 and mitosis, paralleled by the activation of kinase enzymatic function [9, 14], and drop in a highly coordinated manner at mitotic exit by proteasome-dependent degradation [15]. Both kinases localize at centrosomes and spindle poles, they display nonoverlapping localization sites, with Aurora kinase A (AURKA) associated to spindle pole microtubules, and polo-like kinase 1 (Plk1) residing at kinetochores; both are found at the spindle midzone and midbody at ana–telophase [16, 17]
What is the functional significance of Bora degradation before mitotic entry by the same protein (Plk1) that it activates? A possible explanation is that the cdk1/AURKA/Plk1 signaling cascade generating the mitotic entry signal [43] must timely switch toward other pathways to sustain spindle assembly and mitotic progression
Summary
About 20 years ago, two loci encoding for serine–threonine kinases required for correct spindle pole assembly were described in Drosophila and named “polo” and “aurora” [1,2,3]; these were the forefathers of the corresponding kinase families, well characterized as key regulators of the cell cycle and mitotic division. Protein levels peak at G2 and mitosis, paralleled by the activation of kinase enzymatic function [9, 14], and drop in a highly coordinated manner at mitotic exit by proteasome-dependent degradation [15] Both kinases localize at centrosomes and spindle poles, they display nonoverlapping localization sites, with AURKA associated to spindle pole microtubules, and Plk residing at kinetochores; both are found at the spindle midzone and midbody at ana–telophase [16, 17]. Data in the literature indicate multiple binding partners (see the following sections) that are able to stimulate AURKA activity without a direct enzymatic action but rather by inducing specific conformational transitions These observations suggest that cells need to manage distinct pools of AURKA, acting at distinct subcellular sites and displaying different extents of activity. Over time, increased cdk1-generated PBD-docking sites on Plk cytoplasmic substrates could retain Plk in the cytoplasm by competing with importins for Plk binding
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