The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals an Arpp19/PP2A-B55 feedback loop

Abstract Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosp...

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Published inNature communications Vol. 12; no. 1; p. 3565
Main Authors Labbé, Jean Claude, Vigneron, Suzanne, Méchali, Francisca, Robert, Perle, Roque, Sylvain, Genoud, Cindy, Goguet-Rubio, Perrine, Barthe, Phillipe, Labesse, Gilles, Cohen-Gonsaud, Martin, Castro, Anna, Lorca, Thierry
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 11.06.2021
Nature Publishing Group UK
Nature Portfolio
Subjects
Affinity
Catalysis
Cell activation
Cell cycle
Cell division
Control theory
Cyclin B
Dephosphorylation
Feedback
Feedback loops
Gametocytes
Kinases
Kinetics
Life Sciences
Meiosis
Oocytes
Phosphatase
Phosphoprotein phosphatase
Phosphorylation
Prophase
Protein kinase A
Protein phosphatase
Substrates
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Summary:Abstract Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as a competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signalling mechanism is elusive. Here, we characterize the molecular determinants conferring high affinity and slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we show that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discover a double feed-back loop between these two phospho-sites essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-23657-0