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.
Highlights
Arpp[19] is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates
Substrate phosphorylation is triggered at mitotic entry by the activation of Cyclin B/Cdk[1], it is only fully achieved if PP2A-B55 activity is negatively regulated 8–11
Discussion the essential function of Arpp19-dependent PP2A-B55 inhibition in mitosis and meiosis has been well established, little is known about the molecular mechanisms controlling this inhibition
Summary
Arpp[19] is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. Entry and exit of mitosis and meiosis is induced by oscillations of protein phosphorylation/dephosphorylation These oscillations are the result of the activation and inactivation of the master kinase Cyclin B/Cdk[1] and of its counterbalancing phosphatase PP2A-B551–7. Substrate phosphorylation is triggered at mitotic entry by the activation of Cyclin B/Cdk[1], it is only fully achieved if PP2A-B55 activity is negatively regulated 8–11 This regulation is in charge of Arpp[19] and ENSA, two members of the endosulfine family of proteins recently identified as two potent inhibitors of PP2A-B553,4. The ablation of this protein in mouse embryonic fibroblasts promotes the premature dephosphorylation of mitotic substrates resulting in the disruption of the correct temporal order of cellular events during mitotic progression[6] Both Arpp[19] and ENSA are the unique substrates of the Greatwall (Gwl) kinase. We have discovered a double feedback loop between these two phospho-sites, which would be required to coordinate the proper temporal pattern of Arpp19dependent PP2A-B55 inhibition and Cyclin B/Cdk[1] activation, ensuring a correct progression through meiosis and mitosis
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