title: Autoinhibition and Polo-dependent multisite phosphorylation restrict activity of the histone H3 kinase Haspin to mitosis.
abstract: The mitosis-specific phosphorylation of histone H3 at Thr3 (H3T3ph) plays an important role in chromosome segregation by recruiting Aurora B. H3T3 phosphorylation is catalyzed by Haspin, an atypical protein kinase whose kinase domain is intrinsically active without phosphorylation at the activation loop. Here, we report the molecular basis for Haspin inhibition during interphase and its reactivation in M phase. We identify a conserved basic segment that autoinhibits Haspin during interphase. This autoinhibition is neutralized when Cdk1 phosphorylates the N terminus of Haspin in order to recruit Polo-like kinase (Plk1/Plx1), which, in turn, further phosphorylates multiple sites at the Haspin N terminus. Although Plx1, and not Aurora B, is critical for H3T3 phosphorylation in Xenopus egg extracts, Plk1 and Aurora B both promote this modification in human cells. Thus, M phase-specific H3T3 phosphorylation is governed by the combinatorial action of mitotic kinases that neutralizes Haspin autoinhibition through a mechanism dependent on multisite phosphorylation.
authors.affiliation: Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghenoiu
authors.affiliation: Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wheelock
authors.affiliation: Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: funabih@rockefeller.edu.
authors.forename: Hironori
authors.initials: H
authors.lastname: Funabiki
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007399:Interphase / Q000235:genetics; D008938:Mitosis / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000097869:Polo-Like Kinase 1
chemical_list: D064107:Aurora Kinase B; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D029867:Xenopus Proteins; C101085:Plk1 protein, Xenopus; D000097869:Polo-Like Kinase 1; C576938:aurkb protein, Xenopus; C553143:haspin protein, Xenopus laevis