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Mitotic function and regulation of the phosphatase scaffold Repo-Man
Reversible protein phosphorylation represents one of the most common posttranslational modifications in eukaryotes. It is tightly controlled inspace and time by protein kinases and protein phosphatases. This also applies to histone H3, one of the most abundant mitotic phosphoproteins. Many protein kinases of histone H3 have already been identified and functionally characterized. In contrast, very little is known on the counteracting phosphatases.
Here, we show that PP1 is the major histone H3 phosphatase acting on the mitotically phosphorylated (ph) residues H3T3ph, H3S10ph, H3T11ph, and H3S28ph. In addition, we identify Repo-Man as a histone H3T3ph targeting subunit of PP1 that acts antagonistically to protein kinase Haspin. Consistent with this notion, the Repo-Man/PP1 complex opposes the spreading of H3T3ph to the chromosome arms until metaphase and catalyzes the net dephosphorylation of H3T3ph at the end of mitosis. During (pro)metaphase PP1/Repo-Man is prevented fromcausing a net dephosphorylation of centromeric H3T3ph. This can be explained by the Aurora B-mediated phosphorylation of Repo-Man at Ser893 (S893), which prevents its association with histones. We also identified 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.
Here, we show that PP1 is the major histone H3 phosphatase acting on the mitotically phosphorylated (ph) residues H3T3ph, H3S10ph, H3T11ph, and H3S28ph. In addition, we identify Repo-Man as a histone H3T3ph targeting subunit of PP1 that acts antagonistically to protein kinase Haspin. Consistent with this notion, the Repo-Man/PP1 complex opposes the spreading of H3T3ph to the chromosome arms until metaphase and catalyzes the net dephosphorylation of H3T3ph at the end of mitosis. During (pro)metaphase PP1/Repo-Man is prevented fromcausing a net dephosphorylation of centromeric H3T3ph. This can be explained by the Aurora B-mediated phosphorylation of Repo-Man at Ser893 (S893), which prevents its association with histones. We also identified 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.
Date:1 Jun 2009 → 28 Mar 2014
Keywords:PP1, histone dephosphorylation
Disciplines:Systems biology
Project type:PhD project