title: A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis.
abstract: Haspin phosphorylates histone H3 at Thr3 (H3T3ph) during mitosis [1, 2], providing a chromatin binding site for the chromosomal passenger complex (CPC) at centromeres to regulate chromosome segregation [3-5]. H3T3ph becomes increasingly focused at inner centromeres during prometaphase [1, 2], but little is known about how its level or location and the consequent chromosomal localization of the CPC are regulated. In addition, CPC binding to shugoshin proteins contributes to centromeric Aurora B localization [5, 6]. Recruitment of the shugoshins to centromeres requires the phosphorylation of histone H2A at Thr120 (H2AT120ph) by the kinetochore kinase Bub1 [7], but the molecular basis for the collaboration of this pathway with H3T3ph has been unclear. Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. We propose that Aurora B activity triggers a CPC-Haspin-H3T3ph feedback loop that promotes generation of H3T3ph on chromatin. We also provide evidence that the Bub1-shugoshin-CPC pathway supplies a signal that boosts the CPC-Haspin-H3T3ph feedback loop specifically at centromeres to produce the well-known accumulation of the CPC in these regions.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Fangwei
authors.initials: F
authors.lastname: Wang
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Ulyanova
authors.forename: Maike S
authors.initials: MS
authors.lastname: van der Waal
authors.forename: Debasis
authors.initials: D
authors.lastname: Patnaik
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: Lens
authors.forename: Jonathan M G
authors.initials: JM
authors.lastname: Higgins
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D002503:Centromere; D002877:Chromosomes, Human; D005246:Feedback; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C530656:HASPIN protein, human; D017346:Protein Serine-Threonine Kinases