Cargando…

Two Bistable Switches Govern M Phase Entry

The abrupt and irreversible transition from interphase to M phase is essential to separate DNA replication from chromosome segregation. This transition requires the switch-like phosphorylation of hundreds of proteins by the cyclin-dependent kinase 1 (Cdk1):cyclin B (CycB) complex. Previous studies h...

Descripción completa

Detalles Bibliográficos
Autores principales: Mochida, Satoru, Rata, Scott, Hino, Hirotsugu, Nagai, Takeharu, Novák, Béla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5196020/
https://www.ncbi.nlm.nih.gov/pubmed/27889260
http://dx.doi.org/10.1016/j.cub.2016.10.022
_version_ 1782488441600081920
author Mochida, Satoru
Rata, Scott
Hino, Hirotsugu
Nagai, Takeharu
Novák, Béla
author_facet Mochida, Satoru
Rata, Scott
Hino, Hirotsugu
Nagai, Takeharu
Novák, Béla
author_sort Mochida, Satoru
collection PubMed
description The abrupt and irreversible transition from interphase to M phase is essential to separate DNA replication from chromosome segregation. This transition requires the switch-like phosphorylation of hundreds of proteins by the cyclin-dependent kinase 1 (Cdk1):cyclin B (CycB) complex. Previous studies have ascribed these switch-like phosphorylations to the auto-activation of Cdk1:CycB through the removal of inhibitory phosphorylations on Cdk1-Tyr15 [1, 2]. The positive feedback in Cdk1 activation creates a bistable switch that makes mitotic commitment irreversible [2, 3, 4]. Here, we surprisingly find that Cdk1 auto-activation is dispensable for irreversible, switch-like mitotic entry due to a second mechanism, whereby Cdk1:CycB inhibits its counteracting phosphatase (PP2A:B55). We show that the PP2A:B55-inhibiting Greatwall (Gwl)-endosulfine (ENSA) pathway is both necessary and sufficient for switch-like phosphorylations of mitotic substrates. Using purified components of the Gwl-ENSA pathway in a reconstituted system, we found a sharp Cdk1 threshold for phosphorylation of a luminescent mitotic substrate. The Cdk1 threshold to induce mitotic phosphorylation is distinctly higher than the Cdk1 threshold required to maintain these phosphorylations—evidence for bistability. A combination of mathematical modeling and biochemical reconstitution show that the bistable behavior of the Gwl-ENSA pathway emerges from its mutual antagonism with PP2A:B55. Our results demonstrate that two interlinked bistable mechanisms provide a robust solution for irreversible and switch-like mitotic entry.
format Online
Article
Text
id pubmed-5196020
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Cell Press
record_format MEDLINE/PubMed
spelling pubmed-51960202017-01-04 Two Bistable Switches Govern M Phase Entry Mochida, Satoru Rata, Scott Hino, Hirotsugu Nagai, Takeharu Novák, Béla Curr Biol Report The abrupt and irreversible transition from interphase to M phase is essential to separate DNA replication from chromosome segregation. This transition requires the switch-like phosphorylation of hundreds of proteins by the cyclin-dependent kinase 1 (Cdk1):cyclin B (CycB) complex. Previous studies have ascribed these switch-like phosphorylations to the auto-activation of Cdk1:CycB through the removal of inhibitory phosphorylations on Cdk1-Tyr15 [1, 2]. The positive feedback in Cdk1 activation creates a bistable switch that makes mitotic commitment irreversible [2, 3, 4]. Here, we surprisingly find that Cdk1 auto-activation is dispensable for irreversible, switch-like mitotic entry due to a second mechanism, whereby Cdk1:CycB inhibits its counteracting phosphatase (PP2A:B55). We show that the PP2A:B55-inhibiting Greatwall (Gwl)-endosulfine (ENSA) pathway is both necessary and sufficient for switch-like phosphorylations of mitotic substrates. Using purified components of the Gwl-ENSA pathway in a reconstituted system, we found a sharp Cdk1 threshold for phosphorylation of a luminescent mitotic substrate. The Cdk1 threshold to induce mitotic phosphorylation is distinctly higher than the Cdk1 threshold required to maintain these phosphorylations—evidence for bistability. A combination of mathematical modeling and biochemical reconstitution show that the bistable behavior of the Gwl-ENSA pathway emerges from its mutual antagonism with PP2A:B55. Our results demonstrate that two interlinked bistable mechanisms provide a robust solution for irreversible and switch-like mitotic entry. Cell Press 2016-12-19 /pmc/articles/PMC5196020/ /pubmed/27889260 http://dx.doi.org/10.1016/j.cub.2016.10.022 Text en © 2016 The Authors. Published by Elsevier Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Report
Mochida, Satoru
Rata, Scott
Hino, Hirotsugu
Nagai, Takeharu
Novák, Béla
Two Bistable Switches Govern M Phase Entry
title Two Bistable Switches Govern M Phase Entry
title_full Two Bistable Switches Govern M Phase Entry
title_fullStr Two Bistable Switches Govern M Phase Entry
title_full_unstemmed Two Bistable Switches Govern M Phase Entry
title_short Two Bistable Switches Govern M Phase Entry
title_sort two bistable switches govern m phase entry
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5196020/
https://www.ncbi.nlm.nih.gov/pubmed/27889260
http://dx.doi.org/10.1016/j.cub.2016.10.022
work_keys_str_mv AT mochidasatoru twobistableswitchesgovernmphaseentry
AT ratascott twobistableswitchesgovernmphaseentry
AT hinohirotsugu twobistableswitchesgovernmphaseentry
AT nagaitakeharu twobistableswitchesgovernmphaseentry
AT novakbela twobistableswitchesgovernmphaseentry