Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23657-0
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Funding
- Agence National de la Recherche (KiPARPP) [ANR-18-CE13-0013]
- La Ligue Nationale Contre le Cancer (Equipe Labellisee)
- national infrastructure FRISBI [ANR-10-INBS-05]
- LABEX EpiGenMed 'Investisement d'Avenir' programme [ANR-10-LABEX-12-01]
- La Ligue National Contre le cancer
- Fondation de France
- Agence Nationale de la Recherche (ANR) [ANR-18-CE13-0013] Funding Source: Agence Nationale de la Recherche (ANR)
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Arpp19 is a potent inhibitor of PP2A-B55 that plays a regulatory role in stable phosphorylation of mitotic/meiotic substrates. Phosphorylation states of Ser67 and Ser109 of Arpp19 create a double feedback loop that coordinates Arpp19-dependent inhibition of PP2A-B55 and Cyclin B activation during cell cycle progression.
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. Progression of the cell division cycle requires feedback loops including those of phosphorylation and dephosphorylation; however the precise regulation of phosphorylation kinetics of Arpp19, an inhibitor of protein phosphatase 2A, is unclear. Here, the authors report that feedback between phosphorylation states of Ser67 and Ser109 of Arpp19 coordinates Arpp19-dependent inhibition of PP2A-B55 and Cyclin B activation during cell cycle progression.
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