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XB-ART-57676
Curr Biol February 22, 2021; 31 (4): 794-808.e6.

Bistable, Biphasic Regulation of PP2A-B55 Accounts for the Dynamics of Mitotic Substrate Phosphorylation.

Kamenz J , Gelens L , Ferrell JE .


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 that the changes in PP2A-B55 activity are the ultimate trigger.

PubMed ID: 33357450
PMC ID: PMC7904671
Article link: Curr Biol
Grant support: [+]

Genes referenced: arpp19 cdc20 cdc27 cdk1 cdknx cfp ensa mastl mink1 myt1 npy4r nup35 ptpa rasgrf1 rps3a wee1
GO keywords: mitotic M phase [+]
Antibodies: Ccnb2 Ab2 Cdc27 Ab1 Cdk1 Ab2 Ppp1a Ab2


Article Images: [+] show captions
References [+] :
Akopyan, Assessing kinetics from fixed cells reveals activation of the mitotic entry network at the S/G2 transition. 2014, Pubmed