Plk1 regulates mitotic Aurora A function through βTrCP-dependent degradation of hBora (original) (raw)

Complex formation of Plk1 and INCENP required for metaphase–anaphase transition

Nature Cell Biology, 2006

Mitotic chromosomal dynamics is regulated by the coordinated activities of many mitotic kinases 1 , such as cyclin-dependent kinase 1 (Cdk1) 2,3 , Aurora-B 4 or Polo-like kinase 1 (Plk1) 5 , but the mechanisms of their coordination remain unknown. Here, we report that Cdk1 phosphorylates Thr 59 and Thr 388 on inner centromere protein (INCENP), which regulates the localization 4 and kinase activity 6-8 of Aurora-B from prophase to metaphase. INCENP depletion disrupts Plk1 localization specifically at the kinetochore. This phenotype is rescued by the exogenous expression of INCENP wild type and INCENP mutated at Thr 59 to Ala (T59A), but not at Thr 388 to Ala (T388A). The replacement of endogenous INCENP with T388A resulted in the delay of progression from metaphase to anaphase. We propose that INCENP phosphorylation by Cdk1 is necessary for the recruitment of Plk1 to the kinetochore, and that the complex formation of Plk1 and Aurora-B on INCENP may play crucial roles in the regulation of chromosomal dynamics.

Drosophila Aurora B Kinase Is Required for Histone H3 Phosphorylation and Condensin Recruitment during Chromosome Condensation and to Organize the Central Spindle during Cytokinesis

The Journal of Cell Biology, 2001

Aurora/Ipl1-related kinases are a conserved family of enzymes that have multiple functions during mitotic progression. Although it has been possible to use conventional genetic analysis to dissect the function of aurora , the founding family member in Drosophila (Glover, D.M., M.H. Leibowitz, D.A. McLean, and H. Parry. 1995. Cell . 81:95-105), the lack of mutations in a second aurora-like kinase gene, aurora B , precluded this approach. We now show that depleting Aurora B kinase using double-stranded RNA interference in cultured Drosophila cells results in polyploidy. aurora B encodes a passenger protein that associates first with condensing chromatin, concentrates at centromeres, and then relocates onto the central spindle at anaphase. Cells depleted of the Aurora B kinase show only partial chromosome condensation at mitosis. This is associated with a reduction in levels of the serine 10 phosphorylated form of histone H3 and a failure to recruit the Barren condensin protein onto chromosomes. These defects are associated with abnormal segregation resulting from lagging chromatids and extensive chromatin bridging at anaphase, similar to the phenotype of barren mutants (Bhat, M.A., A.V. . Cell . 87:1103-1114. The majority of treated cells also fail to undertake cytokinesis and show a reduced density of microtubules in the central region of the spindle. This is accompanied by a failure to correctly localize the Pavarotti kinesinlike protein, essential for this process. We discuss these conserved functions of Aurora B kinase in chromosome transmission and cytokinesis.

The GIT-Associated Kinase PAK Targets to the Centrosome and Regulates Aurora-A

Molecular Cell 20 Pp 237 249, 2005

Previously, we showed PAK-PIX-GIT targets and regulates focal adhesions; here, we uncover a different function for the complex at the centrosome. Active PAK1 is particularly evident in mitosis and phosphorylates the centrosomal adaptor GIT1 on serine 517. Interestingly, direct centrosome targeting activates the kinase via a process not requiring Rho GTPases; excision of the centrosome prevents this activation. Once activated, PAK1 dissociates from PIX/GIT but can bind to and phosphorylate the important centrosomal kinase Aurora-A. PAK1 promotes phosphorylation of Aurora-A on Thr288 and Ser342, which are key sites for kinase activation in mitosis. In vivo PAK activation causes an accumulation of activated Aurora-A; conversely, when ␤PIX is depleted or PAK is inhibited, there is a delay in centrosome maturation. These observations may underlie reported effects of active PAK on cells, including histone H3 phosphorylation, alterations in centrosome number, and progression through mitosis.

Aurora B Regulates MCAK at the Mitotic Centromere

Developmental Cell, 2004

that the Aurora B complex plays a critical role in estaband Jason R. Swedlow 1 lishing bipolar chromosome attachment and that this 1 Division of Gene Regulation and Expression function is highly conserved. 2 MRC Protein Phosphorylation Unit Aurora B, INCENP, and survivin all behave as chromo-Wellcome Trust Biocentre some passenger proteins, localizing between sister cen-University of Dundee tromeres in the inner centromere from late G2 through Dow Street to metaphase (Andrews et al., 2003; Carmena and Earn-Dundee DD1 5EH shaw, 2003). As chromosome segregation initiates, the United Kingdom complex leaves the inner centromere and concentrates 3 Department of Physiology and Biophysics on central spindle microtubules where it functions in University of Washington School of Medicine cytokinesis. In yeast, the Aurora B/Ipl1p complex phos-1959 N.E. Pacific Street phorylates a number of inner and outer kinetochore pro-Seattle, Washington 98195 teins (Biggins et al., 1999; Cheeseman et al., 2002; Westermann et al., 2003). Aurora B also phosphorylates the centromere-specific histone H3 variant CENP-A (Zeitlin Summary et al., 2001), as well as histone H3 localized throughout the chromosome (Hsu et al., 2000; Murnion et al., 2001).

Playing polo during mitosis: PLK1 takes the lead

Oncogene, 2017

Polo-like kinase 1 (PLK1), the prototypical member of the polo-like family of serine/threonine kinases, is a pivotal regulator of mitosis and cytokinesis in eukaryotes. Many layers of regulation have evolved to target PLK1 to different subcellular structures and to its various mitotic substrates in line with its numerous functions during mitosis. Collective work is starting to illuminate an important set of substrates for PLK1: the mitotic kinases that together ensure the fidelity of the cell division process. Amongst these, recent developments argue that PLK1 regulates the activity of the histone kinases Aurora B and Haspin to define centromere identity, of MPS1 to initiate spindle checkpoint signaling, and of BUB1 and its pseudokinase paralog BUBR1 to coordinate spindle checkpoint activation and inactivation. Here, we review the recent work describing the regulation of these kinases by PLK1. We highlight common themes throughout and argue that a major mitotic function of PLK1 is as a master regulator of these key kinases.