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Molecular and Cellular Biology, July 2002, p. 4984-4996, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.4984-4996.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

14-3-3 Antagonizes Ras-Mediated Raf-1 Recruitment to the Plasma Membrane To Maintain Signaling Fidelity

Yvonne Light, Hugh Paterson, and Richard Marais*

Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, London SW3 6JB, United Kingdom

Received 29 August 2001/ Returned for modification 24 October 2001/ Accepted 19 April 2002

We have investigated the role that S259 phosphorylation, S621 phosphorylation, and 14-3-3 binding play in regulating Raf-1 activity. We show that 14-3-3 binding, rather than Raf-1 phosphorylation, is required for the correct regulation of kinase activity. Phosphorylation of S621 is not required for activity, but 14-3-3 binding is essential. When 14-3-3 binding to conserved region 2 (CR2) was disrupted, Raf-1 basal kinase activity was elevated and it could be further activated by V12,G37Ras, V23TC21, and V38R-Ras. Disruption of 14-3-3 binding at CR2 did not recover binding of Raf-1 to V12,G37Ras but allowed more efficient recruitment of Raf-1 to the plasma membrane and stimulated its phosphorylation on S338. Finally, V12Ras, but not V12,G37Ras, displaced 14-3-3 from full-length Raf-1 and the Raf-1 bound to Ras. GTP was still phosphorylated on S259. Our data suggest that stable association of Raf-1 with the plasma membrane requires Ras-mediated displacement of 14-3-3 from CR2. Small G proteins that cannot displace 14-3-3 fail to recruit Raf-1 to the membrane efficiently and so fail to stimulate kinase activity.

* Corresponding author. Mailing address: Signal Transduction Laboratory, Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, United Kingdom. Phone: 020 7878 3856. Fax: 020 7352 3299. E-mail: rmarais{at}icr.ac.uk.

Molecular and Cellular Biology, July 2002, p. 4984-4996, Vol. 22, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.14.4984-4996.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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