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bioRxiv · 10.1101/2020.10.05.326793

Bistable, biphasic regulation of PP2A-B55 accounts for the dynamics of mitotic substrate phosphorylation

Kamenz, J.·Gelens, L.·Ferrell, J. E.
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Abstract

The phosphorylation of mitotic proteins is bistable, which contributes to the decisiveness of the transitions into and out of M phase. The bistability in substrate phosphorylation has been attributed to bistability in the activation of the cyclin-dependent kinase Cdk1. However, more recently it has been suggested that bistability also arises from positive feedback in the regulation of the Cdk1-counteracting phosphatase, PP2A-B55. Here, we demonstrate biochemically using Xenopus laevis egg extracts that the Cdk1-counteracting phosphatase PP2A-B55 functions as a bistable switch, even when the bistability of Cdk1 activation is suppressed. In addition, Cdk1 regulates PP2A-B55 in a biphasic manner; low concentrations of Cdk1 activate PP2A-B55 and high concentrations inactivate it. As a consequence of this incoherent feedforward regulation, PP2A-B55 activity rises concurrently with Cdk1 activity during interphase and suppresses substrate phosphorylation. PP2A-B55 activity is then sharply downregulated at the onset of mitosis. During mitotic exit Cdk1 activity initially falls with no obvious change in substrate phosphorylation; dephosphorylation then commences once PP2A-B55 spikes in activity. These findings suggest that changes in Cdk1 activity are permissive for mitotic entry and exit, but the changes in PP2A-B55 activity are the ultimate trigger.

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Kamenz, J., Gelens, L., Ferrell, J. E.. 2020-10-06. Bistable, biphasic regulation of PP2A-B55 accounts for the dynamics of mitotic substrate phosphorylation. https://doi.org/10.1101/2020.10.05.326793

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