Revisiting phosphoregulation of Cdc25C during M-phase induction
Tan Tan,
Chuanfen Wu,
Ruoning Wang,
Bih-Fang Pan,
David Hawke,
Fumin Yin,
Zehao Su,
Boye Liu,
Sue-Hwa Lin,
Wei Zhang,
Jian Kuang
Affiliations
Tan Tan
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, University of South China, Hengyang, Hunan 421001, China
Chuanfen Wu
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Ruoning Wang
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Bih-Fang Pan
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
David Hawke
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Fumin Yin
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
Zehao Su
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
Boye Liu
Key Laboratory for Biodiversity and Ecological Engineering of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
Sue-Hwa Lin
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Wei Zhang
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China; Corresponding author
Jian Kuang
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
Summary: Cdc25C undergoes a sudden and substantial gel mobility shift at M-phase onset, correlating with abrupt activation of both Cdc25C and Cdk1 activities. A positive feedback loop between Cdk1 and Cdc25C has been used to explain this hallmark phenomenon. Here, we demonstrate that the M-phase supershift and robust activation of Cdc25C are due to the site-comprehensive phosphorylation of its long intrinsically disordered regulatory domain without requiring Cdk1 or other major mitotic kinase activities. The phosphorylation process involves substrate-mediated assembly of phosphorylation machinery that catalyzes multisite phosphorylation continuously without substrate dissociation. In contrast to the site-comprehensive phosphorylation of Cdc25C occurring at M-phase onset, the site-specific phosphorylation of Cdc25C by Cdk1 or other major mitotic kinases generates slight gel mobility shifts and modest activation of Cdc25C prior to M-phase onset. These findings suggest a two-stage framework consisting of site-specific phosphorylation followed by site-comprehensive phosphorylation for Cdc25C regulation during M-phase induction.
