Research ArticleMitosis

Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1-binding RVxF motif in PP1 regulatory proteins

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Science Signaling  15 May 2018:
Vol. 11, Issue 530, eaai8669
DOI: 10.1126/scisignal.aai8669

Yin and yang of mitotic phosphorylation

Mitotic kinases promote cell cycle progression by targeting a large set of proteins that collectively drive mitosis. Phosphatases, such as protein phosphatase 1 (PP1), reverse these phosphorylation events to enable cells to exit mitosis. The subcellular localization and activity of PP1 are controlled by regulatory proteins that bind to PP1 through conserved RVxF motifs. Nasa et al. found that RVxF motifs in a subset of PP1 regulatory proteins in which the “x” residue is a serine or threonine (RV[S/T]F) were phosphorylated during mitosis. Phosphorylation of these motifs, which was mediated primarily by the mitotic kinase Aurora B, prevented proteins that harbored these motifs from interacting with PP1 and was required for maintaining the high amount of overall protein phosphorylation in mitotic cells. These findings identify a mechanism that coordinates the activities of Aurora B and PP1 to control cell cycle progression.


Protein phosphatase 1 (PP1) is a highly conserved protein phosphatase that performs most of the serine- and threonine-dephosphorylation reactions in eukaryotes and opposes the actions of a diverse set of serine and threonine (Ser-Thr) protein kinases. PP1 gains substrate specificity through binding to a large number (>200) of regulatory proteins that control PP1 localization, activity, and interactions with substrates. PP1 recognizes the well-characterized RVxF binding motif that is present in many of these regulatory proteins, thus generating a multitude of distinct PP1 holoenzymes. We showed that a subset of the RVxF binding motifs, in which x is a phosphorylatable amino acid (RV[S/T]F), was phosphorylated specifically during mitosis and that this phosphorylation event abrogated the interaction of PP1 with the regulatory protein. We determined that this phosphorylation was primarily governed by the mitotic protein kinase Aurora B and that high phosphorylation site stoichiometry of these sites maintained the phosphorylation of PP1 substrates during mitosis by disrupting the assembly of PP1 holoenzymes. We generated an antibody that recognizes the phosphorylated form of the RV[S/T]F motif (RVp[S/T]F) and used it to identify known PP1 regulatory proteins (KNL1, CDCA2, and RIF1) and multiple proteins that could potentially act as PP1 binding partners (UBR5, ASPM, SEH1, and ELYS) governed by this mechanism. Together, these data suggest a general regulatory mechanism by which the coordinated activities of Aurora B and PP1 control mitotic progression.

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