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Molecular and Cellular Biology, October 2002, p. 7226-7241, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7226-7241.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Distinct Cell Cycle Timing Requirements for Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase Signaling Pathways in Somatic Cell Mitosis

Elisabeth C. Roberts,1 Paul S. Shapiro,2 Theresa Stines Nahreini,3 Gilles Pages,4 Jacques Pouyssegur,4 and Natalie G. Ahn3,5*

Departments of Molecular Cellular and Developmental Biology,1 Chemistry and Biochemistry,3 Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309,5 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201,2 Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR, Centre Antoine Lacassagne, 06189 Nice, France4

Received 20 March 2002/ Returned for modification 22 April 2002/ Accepted 8 July 2002

Mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K) pathways are necessary for cell cycle progression into S phase; however the importance of these pathways after the restriction point is poorly understood. In this study, we examined the regulation and function of extracellular signal-regulated kinase (ERK) and PI3K during G2/M in synchronized HeLa and NIH 3T3 cells. Phosphorylation and activation of both the MAP kinase kinase/ERK and PI3K/Akt pathways occur in late S and persist until the end of mitosis. Signaling was rapidly reversed by cell-permeable inhibitors, indicating that both pathways are continuously activated and rapidly cycle between active and inactive states during G2/M. The serum-dependent behavior of PI3K/Akt versus ERK pathway activation indicates that their mechanisms of regulation differ during G2/M. Effects of cell-permeable inhibitors and dominant-negative mutants show that both pathways are needed for mitotic progression. However, inhibiting the PI3K pathway interferes with cdc2 activation, cyclin B1 expression, and mitotic entry, whereas inhibiting the ERK pathway interferes with mitotic entry but has little effect on cdc2 activation and cyclin B1 and retards progression from metaphase to anaphase. Thus, our study provides novel evidence that ERK and PI3K pathways both promote cell cycle progression during G2/M but have different regulatory mechanisms and function at distinct times.

* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, University of Colorado, Boulder CO 80309. Phone: (303) 492-4799. Fax: (303) 492-2439. E-mail: natalie.ahn{at}colorado.edu.

Molecular and Cellular Biology, October 2002, p. 7226-7241, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7226-7241.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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