Autoinhibition and Polo-Dependent Multisite Phosphorylation Restrict Activity of the Histone H3 Kinase Haspin to Mitosis

• Published in: Molecular cell Vol. 52; no. 5; pp. 734 - 745
• Main Authors: Ghenoiu, Cristina, Wheelock, Michael S., Funabiki, Hironori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-12-2013
• Subjects: Animals; Aurora Kinase B - genetics; Aurora Kinase B - metabolism; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Division - genetics; Cell Line, Tumor; chromosome segregation; Conserved Sequence; eggs; HeLa Cells; histones; Histones - genetics; Histones - metabolism; Humans; interphase; Interphase - genetics; mitosis; Mitosis - genetics; neutralization; Phosphorylation; phosphotransferases (kinases); Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Xenopus; Xenopus laevis; Xenopus Proteins - genetics; Xenopus Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.10.002

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.
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•The histone H3T3 kinase Haspin is autoinhibited by a basic segment during interphase•Priming phosphorylation of Haspin by Cdk1 during M phase recruits Polo-like kinase•Polo-dependent multisite phosphorylation of Haspin neutralizes the autoinhibition•Polo and Aurora B act together to support H3T3 phosphorylation in human cells