4.6 Article

Suppression of Scant Identifies Endos as a Substrate of Greatwall Kinase and a Negative Regulator of Protein Phosphatase 2A in Mitosis

Journal

PLOS GENETICS
Volume 7, Issue 8, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002225

Keywords

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Funding

  1. MRC [G0501718, G1001696]
  2. National Center on Minority Health and Health Disparities, National Institutes of Health [MHIRT 2T37MD001368]
  3. Research Foundation-Flanders [G.0582.11N]
  4. MRC [G1001696, G0501718] Funding Source: UKRI
  5. Medical Research Council [G1001696, G0501718] Funding Source: researchfish

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Protein phosphatase 2A (PP2A) plays a major role in dephosphorylating the targets of the major mitotic kinase Cdk1 at mitotic exit, yet how it is regulated in mitotic progression is poorly understood. Here we show that mutations in either the catalytic or regulatory twins/B55 subunit of PP2A act as enhancers of gwl(Scant), a gain-of-function allele of the Greatwall kinase gene that leads to embryonic lethality in Drosophila when the maternal dosage of the mitotic kinase Polo is reduced. We also show that heterozygous mutant endos alleles suppress heterozygous gwl(Scant); many more embryos survive. Furthermore, heterozygous PP2A mutations make females heterozygous for the strong mutation polo(11) partially sterile, even in the absence of gwl(Scant). Heterozygosity for an endos mutation suppresses this PP2A/polo(11) sterility. Homozygous mutation or knockdown of endos leads to phenotypes suggestive of defects in maintaining the mitotic state. In accord with the genetic interactions shown by the gwl(Scant) dominant mutant, the mitotic defects of Endos knockdown in cultured cells can be suppressed by knockdown of either the catalytic or the Twins/B55 regulatory subunits of PP2A but not by the other three regulatory B subunits of Drosophila PP2A. Greatwall phosphorylates Endos at a single site, Ser68, and this is essential for Endos function. Together these interactions suggest that Greatwall and Endos act to promote the inactivation of PP2A-Twins/B55 in Drosophila. We discuss the involvement of Polo kinase in such a regulatory loop.

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