Portal de Periódicos da CAPES

Aurora B Defines Its Own Chromosomal Targeting by Opposing the Recruitment of the Phosphatase Scaffold Repo-Man

2013; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1016/j.cub.2013.05.017

1879-0445

Junbin Qian, Monique Beullens, Bart Lesage, Mathieu Bollen,

Cancer-related Molecular Pathways

Aurora B is the catalytic subunit of the chromosomal passenger complex (CPC), which coordinates mitotic processes through phosphorylation of key regulatory proteins [1Carmena M. Wheelock M. Funabiki H. Earnshaw W.C. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis.Nat. Rev. Mol. Cell Biol. 2012; 13: 789-803Crossref PubMed Scopus (563) Google Scholar]. In prometaphase, the CPC is enriched at the centromeres to regulate the spindle checkpoint and kinetochore-microtubule interactions. Centromeric CPC binds to histone H3 that is phosphorylated at T3 (H3T3ph) by Aurora B-stimulated Haspin [2Kelly A.E. Ghenoiu C. Xue J.Z. Zierhut C. Kimura H. Funabiki H. Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B.Science. 2010; 330: 235-239Crossref PubMed Scopus (352) Google Scholar, 3Wang F. Dai J. Daum J.R. Niedzialkowska E. Banerjee B. Stukenberg P.T. Gorbsky G.J. Higgins J.M. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis.Science. 2010; 330: 231-235Crossref PubMed Scopus (339) Google Scholar, 4Wang F. Ulyanova N.P. van der Waal M.S. Patnaik D. Lens S.M. Higgins J.M. A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis.Curr. Biol. 2011; 21: 1061-1069Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 5Yamagishi Y. Honda T. Tanno Y. Watanabe Y. Two histone marks establish the inner centromere and chromosome bi-orientation.Science. 2010; 330: 239-243Crossref PubMed Scopus (336) Google Scholar]. PP1/Repo-Man acts antagonistically to Haspin and dephosphorylates H3T3ph at the chromosome arms but is somehow prevented from causing a net dephosphorylation of centromeric H3T3ph during prometaphase [6Qian J. Lesage B. Beullens M. Van Eynde A. Bollen M. PP1/Repo-man dephosphorylates mitotic histone H3 at T3 and regulates chromosomal aurora B targeting.Curr. Biol. 2011; 21: 766-773Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 7Vagnarelli P. Ribeiro S. Sennels L. Sanchez-Pulido L. de Lima Alves F. Verheyen T. Kelly D.A. Ponting C.P. Rappsilber J. Earnshaw W.C. Repo-Man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit.Dev. Cell. 2011; 21: 328-342Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar]. Here, we show that Aurora B phosphorylates Repo-Man at S893, preventing its recruitment by histones. We also identify PP2A as a mitotic interactor of Repo-Man that dephosphorylates S893 and thereby promotes the targeting of Repo-Man to chromosomes and the dephosphorylation of H3T3ph by PP1. Thus, Repo-Man-associated PP1 and PP2A collaborate to oppose the chromosomal targeting of Aurora B. We propose that the reciprocal feedback regulation of Haspin and Repo-Man by Aurora B generates a robust bistable response that culminates in the centromeric targeting of the CPC during prometaphase.