A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast.
A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast.
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DOI：
10.1091/mbc.e11-04-0340
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发表时间：
2011-10
影响因子：
3.3
通讯作者：
Kellogg DR
中科院分区：
文献类型：
--
作者：
Harvey SL;Enciso G;Dephoure N;Gygi SP;Gunawardena J;Kellogg DR
The Wee1 kinase inhibits cyclin-dependent kinase 1 (Cdk1) during early mitosis. A low level of Cdk1 activity must escape Wee1 inhibition to initiate early mitotic events, but the underlying mechanisms have remained unknown. In this paper, we show that a specific form of protein phosphatase 2A opposes activation of Wee1, which allows low-level activation of Cdk1 in early mitosis. Entry into mitosis is initiated by synthesis of cyclins, which bind and activate cyclin-dependent kinase 1 (Cdk1). Cyclin synthesis is gradual, yet activation of Cdk1 occurs in a stepwise manner: a low level of Cdk1 activity is initially generated that triggers early mitotic events, which is followed by full activation of Cdk1. Little is known about how stepwise activation of Cdk1 is achieved. A key regulator of Cdk1 is the Wee1 kinase, which phosphorylates and inhibits Cdk1. Wee1 and Cdk1 show mutual regulation: Cdk1 phosphorylates Wee1, which activates Wee1 to inhibit Cdk1. Further phosphorylation events inactivate Wee1. We discovered that a specific form of protein phosphatase 2A (PP2ACdc55) opposes the initial phosphorylation of Wee1 by Cdk1. In vivo analysis, in vitro reconstitution, and mathematical modeling suggest that PP2ACdc55 sets a threshold that limits activation of Wee1, thereby allowing a low constant level of Cdk1 activity to escape Wee1 inhibition in early mitosis. These results define a new role for PP2ACdc55 and reveal a systems-level mechanism by which dynamically opposed kinase and phosphatase activities can modulate signal strength.
