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Originally published as Genetics Published Articles Ahead of Print on December 15, 2008.
Genetics, Vol. 181, 933-943, March 2009, Copyright © 2009
doi:10.1534/genetics.108.096016
The Role of Protein Phosphatase 4 in Regulating Microtubule Severing in the Caenorhabditis elegans Embryo
Xue Han*,1,
José-Eduardo Gomes
,
Cheryl L. Birmingham*,2,
Lionel Pintard,
Asako Sugimoto
and
Paul E. Mains*,3
* Genes and Development Research Group, Department of Biochemistry and Molecular Biology and Department of Medical Genetics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, Institut Jacques Monod, CNRS, Université Paris Diderot et UPMC, 75251 Paris Cedex 05, France and Laboratory for Developmental Genomics, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan
3 Corresponding author: Department of Biochemistry and Molecular Biology, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada.
E-mail: mains{at}ucalgary.ca
MEI-1, the catalytic subunit of the Caenorhabditis elegans "katanin" microtubule-severing complex, is required for meiotic spindle formation. However, MEI-1 must be inactivated after the completion of meiosis to allow formation of the first mitotic spindle. Recent work demonstrated that post-meiotic MEI-1 undergoes ubiquitin-dependent degradation mediated by two independent pathways. Here we describe another level of MEI-1 regulation involving the protein phosphatase 4 (PP4) complex. The PP4 R1 regulatory subunit protein phosphatase four regulatory subunit 1 (ppfr-1) was identified in an RNA interference (RNAi) screen for suppressors of a mei-1(gf) allele that is refractory to post-meiotic degradation. RNAi to the PP4 catalytic subunit PPH-4.1 or to the 
4 regulatory PPFR-4 also suppressed lethality of ectopic MEI-1. These results suggest that PP4(+) activates MEI-1, and therefore loss of PP4 decreases ectopic MEI-1(gf) activity. PPH-4.1 and MEI-1 co-immunoprecipitate with one another, indicating that the PP4 complex likely regulates MEI-1 activity directly rather than through an intermediate. The ppfr-1 mutant has subtle meiotic defects indicating that PPFR-1 also regulates MEI-1 during meiosis. MBK-2 is the only kinase known to phosphorylate MEI-1 and triggers post-meiotic MEI-1 degradation. However, genetic interactions between PP4 and mbk-2 were not consistent with an antagonistic relationship between the phosphatase and kinase. Additionally, reducing PP4 in mei-1(gf) did not change the level or localization of post-meiotic MEI-1. Thus, by making use of a genetic background where MEI-1 is ectopically expressed, we have uncovered a third mechanism of MEI-1 regulation, one based on phosphorylation but independent of degradation. The redundant regulatory pathways likely contribute in different ways to the rapid and precise post-meiotic inactivation of MEI-1 microtubule-severing activity.
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Genetics 2009 181: NP.
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