Sugiyama, K. et al. Aurora-B associated protein phosphatases as negative regulators of kinase activation. Oncogene 21, 3103-3111

Department of Applied Chemistry, Osaka Prefecture University, Sakai, Ōsaka, Japan
Oncogene (Impact Factor: 8.46). 06/2002; 21(20):3103-11. DOI: 10.1038/sj.onc.1205432
Source: PubMed


The human serine/threonine kinase Aurora-B is structurally related to the protein kinase Ipl1p from S cerevisiae and aurora from Drosophila melanogaster, which are key regulators of mitosis. The present study shows that human Aurora-B is activated by okadaic acid and forms complexes with the protein serine/threonine phosphatase type 1 (PP1) or PP2A, but not with PP5. These data identified Aurora-B associated protein phosphatases as negative regulators of kinase activation. We then used a series of substrates based on a histone H3 phosphorylation site (residues 5-15) to determine the substrate specificity of human Aurora-B. We found that this enzyme is an arginine-directed kinase that can phosphorylate histone H3 at serines 10 and 28 in vitro, suggesting that human Aurora-B is a mitotic histone H3 kinase.

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Available from: Hiroshi Shima, May 29, 2014
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    • "Similar to Aurora A, activation of Aurora B requires autophosphorylation of the T-loop, which is, in this case, facilitated by the other members of the CPC, which are in turn also phosphorylated by Aurora B [41–45]. Inactivation of Aurora B is mediated by PP1 and PP2A phosphatases [46,47]. "
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    ABSTRACT: The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules.
    Full-text · Article · Mar 2013 · Open Biology
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    • "Both kinase reactions included GST-YY1, GST-YY1 S180A, GST-YY1 S184A and GST-YY1 S180,184A incubated with Aurora B. The results show that serine 184 is the major site of phosphorylation by Aurora B. Aurora B also appears to phosphorylate serine 180 of YY1, but to a much lower extent in vitro (Fig. 3C). The main antagonist of Aurora B phosphorylation is PP1 [53]–[55]. After YY1 phosphorylation at serine 184 by Aurora B, the addition of purified PP1 can efficiently dephosphorylate serine 184, but not PP2A (Fig. 3E). "
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    ABSTRACT: Yin Yang 1 (YY1) is a ubiquitously expressed and highly conserved multifunctional transcription factor that is involved in a variety of cellular processes. Many YY1-regulated genes have crucial roles in cell proliferation, differentiation, apoptosis, and cell cycle regulation. Numerous mechanisms have been shown to regulate the function of YY1, such as DNA binding affinity, subcellular localization, and posttranslational modification including phosphorylation. Polo-like kinase 1(Plk1) and Casein kinase 2α (CK2 α) were the first two kinases identified to phosphorylate YY1. In this study, we identify a third kinase. We report that YY1 is a novel substrate of the Aurora B kinase both in vitro and in vivo. Serine 184 phosphorylation of YY1 by Aurora B is cell cycle regulated and peaks at G2/M and is rapidly dephosphorylated, likely by protein phosphatase 1 (PP1) as the cells enter G1. Aurora A and Aurora C can also phosphorylate YY1 in vitro, but at serine/threonine residues other than serine 184. We present evidence that phosphorylation of YY1 in the central glycine/alanine (G/A)-rich region is important for DNA binding activity, with a potential phosphorylation/acetylation interplay regulating YY1 function. Given their importance in mitosis and overexpression in human cancers, Aurora kinases have been identified as promising therapeutic targets. Increasing our understanding of Aurora substrates will add to the understanding of their signaling pathways.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "A similar caveat exists for the phosphorylation gradients produced by the CPC. Phosphatase activity, specifically that of PP1 and PP2a, has been shown to oppose Aurora B kinase in genetic and biochemical systems [114,115,127-129]. Experiments to elucidate the spatial regulation of CPC activity by phosphatases are in progress [127]. "
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    ABSTRACT: Gradients are used in a number of biological systems to transmit spatial information over a range of distances. The best studied are morphogen gradients where information is transmitted over many cell lengths. Smaller mitotic gradients reflect the need to organize several distinct events along the length of the mitotic spindle. The intracellular gradients that characterize mitosis are emerging as important regulatory paradigms. Intracellular gradients utilize intrinsic auto-regulatory feedback loops and diffusion to establish stable regions of activity within the mitotic cytosol. We review three recently described intracellular mitotic gradients. The Ran GTP gradient with its elaborate cascade of nuclear transport receptors and cargoes is the best characterized, yet the dynamics underlying the robust gradient of Ran-GTP have received little attention. Gradients of phosphorylation have been observed on Aurora B kinase substrates both before and after anaphase onset. In both instances the phosphorylation gradient appears to result from a soluble gradient of Aurora B kinase activity. Regulatory properties that support gradient formation are highlighted. Intracellular activity gradients that regulate localized mitotic events bare several hallmarks of self-organizing biologic systems that designate spatial information during pattern formation. Intracellular pattern formation represents a new paradigm in mitotic regulation.
    Full-text · Article · Jan 2010 · Cell Division
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