Revisiting phosphoregulation of Cdc25C during M-phase induction

  • iScience. 2024 Dec 15;28(1):111603. doi: 10.1016/j.isci.2024.111603.
Tan Tan  1  2 ,  Chuanfen Wu  1 ,  Ruoning Wang  1 ,  Bih-Fang Pan  3 ,  David Hawke  3 ,  Fumin Yin  4 ,  Zehao Su  4 ,  Boye Liu  5 ,  Sue-Hwa Lin  6 ,  Wei Zhang  4 ,  Jian Kuang  1
Affiliations
  • 1. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2. Department of Biochemistry and Molecular Biology, University of South China, Hengyang, Hunan 421001, China.
  • 3. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4. Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 5. Key Laboratory for Biodiversity and Ecological Engineering of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 6. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
PMID: 39834856 DOI: 10.1016/j.isci.2024.111603
Abstract

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.

Keywords
Biological sciences; Cell; Cell biology.
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