Myosin phosphatase-targeting subunit 1 controls chromatid segregation.
Myosin phosphatase is a heterotrimeric holoenzyme consisting of myosin phosphatase-targeting subunit 1 (MYPT1), a catalytic subunit of PP1Cβ, and a 20-kDa subunit of an unknown function. We have previously reported that myosin phosphatase also controls mitosis, apparently by antagonizing polo-like kinase 1 (PLK1). Here we found that depletion of MYPT1 by siRNA led to precocious chromatid segregation when HeLa cells were arrested at metaphase by a proteasome inhibitor, MG132, or by Cdc20 depletion. Consistently, cyclin B1 and securin were not degraded, indicating that the chromatid segregation is independent of the anaphase-promoting complex/cyclosome. Precocious segregation induced by MYPT1 depletion requires PLK1 activity because a PLK1 inhibitor, BI-2536, blocked precocious segregation. Furthermore, the expression of an unphosphorylatable mutant of SA2 (SCC3 homologue 2), a subunit of the cohesin complex, prevented precocious chromatid segregation induced by MYPT1 depletion. It has been shown that SA2 at centromeres is protected from phosphorylation by PP2A phosphatase recruited by Shugoshin (Sgo1), whereas SA2 along chromosome arms is phosphorylated by PLK1, leading to SA2 dissociation at chromosome arms. Taken together, our results suggest that hyperactivation of PLK1 caused by MYPT1 reduction could override the counteracting PP2A phosphatase, resulting in precocious chromatid segregation. We propose that SA2 at the centromeres is protected by two phosphatases. One is PP2A directly dephosphorylating SA2, and the other is myosin phosphatase counteracting PLK1.
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA.
Fumio
F
Matsumura
Yoshihiko
Y
Yamakita
Shigeko
S
Yamashiro
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002503:Centromere / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D043263:Myosin-Light-Chain Phosphatase; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C496644:SGO1 protein, human; C490372:PPP1R12A protein, human
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