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bioRxiv · 10.1101/2020.05.11.087890

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

Labbe, J. C.·Vigneron, S.·Mechali, F.·Robert, P.·Genoud, C.·Goguet-Rubio, P.·Barthe, P.·Labesse, G.·Cohen-Gonsaud, M.·Castro, A.·Lorca, T.
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Abstract

Arpp19 is a potent inhibitor of PP2A-B55 that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by Greatwall on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as an "unfair" 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 signaling mechanism is elusive. Here, we characterized the molecular determinants conferring slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we showed that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discovered a double feed-back loop between these two phospho-sites which is essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.

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Labbe, J. C., Vigneron, S., Mechali, F., Robert, P., Genoud, C., Goguet-Rubio, P., Barthe, P., Labesse, G., Cohen-Gonsaud, M., Castro, A., Lorca, T.. 2020-05-12. The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop. https://doi.org/10.1101/2020.05.11.087890

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