Ultrasensitivity in the Regulation of Cdc25C by Cdk1

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Feb 5

PMID 21292159

Citations 83

Authors

Nicole B Trunnell

Andy C Poon

Sun Young Kim

James E Ferrell Jr

Affiliations

Soon will be listed here.

Abstract

Cdc25C is a critical component of the interlinked positive and double-negative feedback loops that constitute the bistable mitotic trigger. Computational studies have indicated that the trigger's bistability should be more robust if the individual legs of the loops exhibit ultrasensitive responses. Here, we show that in Xenopus extracts two measures of Cdc25C activation (hyperphosphorylation and Ser 287 dephosphorylation) are highly ultrasensitive functions of the Cdk1 activity; estimated Hill coefficients were 11 to 32. Some of Cdc25C's ultrasensitivity can be reconstituted in vitro with purified components, and the reconstituted ultrasensitivity depends upon multisite phosphorylation. The response functions determined here for Cdc25C and previously for Wee1A allow us to formulate a simple mathematical model of the transition between interphase and mitosis. The model shows how the continuously variable regulators of mitosis work collectively to generate a switch-like, hysteretic response.

Citing Articles

Revisiting phosphoregulation of Cdc25C during M-phase induction.

Tan T, Wu C, Wang R, Pan B, Hawke D, Yin F iScience. 2025; 28(1):111603.

PMID: 39834856 PMC: 11743101. DOI: 10.1016/j.isci.2024.111603.

Positively charged specificity site in cyclin B1 is essential for mitotic fidelity.

Heinzle C, Hofler A, Yu J, Heid P, Kremer N, Schunk R Nat Commun. 2025; 16(1):853.

PMID: 39833154 PMC: 11747444. DOI: 10.1038/s41467-024-55669-x.

Mechanistic origins of temperature scaling in the early embryonic cell cycle.

Rombouts J, Tavella F, Vandervelde A, Phong C, Ferrell J, Ferrell Jr J bioRxiv. 2025; .

PMID: 39763717 PMC: 11703202. DOI: 10.1101/2024.12.24.630245.

A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.

Schunk R, Halder M, Schafer M, Johannes E, Heim A, Boland A EMBO Rep. 2025; 26(3):768-790.

PMID: 39747666 PMC: 11811201. DOI: 10.1038/s44319-024-00347-8.

Spatial heterogeneity accelerates phase-to-trigger wave transitions in frog egg extracts.

Puls O, Ruiz-Reynes D, Tavella F, Jin M, Kim Y, Gelens L Nat Commun. 2024; 15(1):10455.

PMID: 39622792 PMC: 11612452. DOI: 10.1038/s41467-024-54752-7.

References

Toyoshima-Morimoto F, Taniguchi E, Nishida E . Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep. 2002; 3(4):341-8. PMC: 1084057. DOI: 10.1093/embo-reports/kvf069. View

Shen M, Stukenberg P, Kirschner M, Lu K . The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 1998; 12(5):706-20. PMC: 316589. DOI: 10.1101/gad.12.5.706. View

Nash P, Tang X, Orlicky S, Chen Q, Gertler F, Mendenhall M . Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature. 2001; 414(6863):514-21. DOI: 10.1038/35107009. View

Furnari B, Rhind N, Russell P . Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Science. 1997; 277(5331):1495-7. DOI: 10.1126/science.277.5331.1495. View

Booher R, Holman P, Fattaey A . Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. J Biol Chem. 1997; 272(35):22300-6. DOI: 10.1074/jbc.272.35.22300. View

Markevich N, Hoek J, Kholodenko B . Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J Cell Biol. 2004; 164(3):353-9. PMC: 2172246. DOI: 10.1083/jcb.200308060. View

Mueller P, Coleman T, Kumagai A, Dunphy W . Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science. 1995; 270(5233):86-90. DOI: 10.1126/science.270.5233.86. View

Strickfaden S, Winters M, Ben-Ari G, Lamson R, Tyers M, Pryciak P . A mechanism for cell-cycle regulation of MAP kinase signaling in a yeast differentiation pathway. Cell. 2007; 128(3):519-31. PMC: 1847584. DOI: 10.1016/j.cell.2006.12.032. View

Lee G, White L, Hurov K, Stappenbeck T, Piwnica-Worms H . Response of small intestinal epithelial cells to acute disruption of cell division through CDC25 deletion. Proc Natl Acad Sci U S A. 2009; 106(12):4701-6. PMC: 2660721. DOI: 10.1073/pnas.0900751106. View

10.

McGowan C, Russell P . Cell cycle regulation of human WEE1. EMBO J. 1995; 14(10):2166-75. PMC: 398322. DOI: 10.1002/j.1460-2075.1995.tb07210.x. View

11.

Fauman E, Cogswell J, Lovejoy B, Rocque W, Holmes W, Montana V . Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Cell. 1998; 93(4):617-25. DOI: 10.1016/s0092-8674(00)81190-3. View

12.

Ferrell J, Xiong W . Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible. Chaos. 2003; 11(1):227-236. DOI: 10.1063/1.1349894. View

13.

Hoffmann I, Clarke P, Marcote M, Karsenti E, Draetta G . Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 1993; 12(1):53-63. PMC: 413175. DOI: 10.1002/j.1460-2075.1993.tb05631.x. View

14.

Wu J, Guo J, Tang W, Yang C, Freel C, Chen C . PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation. Nat Cell Biol. 2009; 11(5):644-51. PMC: 2788612. DOI: 10.1038/ncb1871. View

15.

Peng C, Graves P, Ogg S, Thoma R, Byrnes 3rd M, Wu Z . C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Cell Growth Differ. 1998; 9(3):197-208. View

16.

Heald R, McLoughlin M, McKeon F . Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell. 1993; 74(3):463-74. DOI: 10.1016/0092-8674(93)80048-j. View

17.

Thron C . Theoretical dynamics of the cyclin B-MPF system: a possible role for p13suc1. Biosystems. 1994; 32(2):97-109. DOI: 10.1016/0303-2647(94)90035-3. View

18.

Moses A, Heriche J, Durbin R . Clustering of phosphorylation site recognition motifs can be exploited to predict the targets of cyclin-dependent kinase. Genome Biol. 2007; 8(2):R23. PMC: 1852407. DOI: 10.1186/gb-2007-8-2-r23. View

19.

Sha W, Moore J, Chen K, Lassaletta A, Tyson J, Sible J . Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proc Natl Acad Sci U S A. 2003; 100(3):975-80. PMC: 298711. DOI: 10.1073/pnas.0235349100. View

20.

Kumagai A, Dunphy W . Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science. 1996; 273(5280):1377-80. DOI: 10.1126/science.273.5280.1377. View