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Molecular and Cellular Biology, September 1998, p. 5229-5238, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

14-3-3 Proteins Are Required for Maintenance of Raf-1 Phosphorylation and Kinase Activity

John A. Thorson,1 Lily W. K. Yu,1 Alice L. Hsu,1 Neng-Yao Shih,1 Paul R. Graves,2 J. William Tanner,1 Paul M. Allen,1 Helen Piwnica-Worms,2,3 and Andrey S. Shaw1,*

Center for Immunology and Department of Pathology,1 Department of Cell Biology and Physiology,2 and Howard Hughes Medical Institute,3 Washington University School of Medicine, St. Louis, Missouri

Received 6 February 1998/Returned for modification 23 March 1998/Accepted 8 June 1998

By binding to serine-phosphorylated proteins, 14-3-3 proteins function as effectors of serine phosphorylation. The exact mechanism of their action is, however, still largely unknown. Here we demonstrate a requirement for 14-3-3 for Raf-1 kinase activity and phosphorylation. Expression of dominant negative forms of 14-3-3 resulted in the loss of a critical Raf-1 phosphorylation, while overexpression of 14-3-3 resulted in enhanced phosphorylation of this site. 14-3-3 levels, therefore, regulate the stoichiometry of Raf-1 phosphorylation and its potential activity in the cell. Phosphorylation of Raf-1, however, was insufficient by itself for kinase activity. Removal of 14-3-3 from phosphorylated Raf abrogated kinase activity, whereas addition of 14-3-3 restored it. This supports a paradigm in which the effects of phosphorylation on serine as well as tyrosine residues are mediated by inducible protein-protein interactions.

* Corresponding author. Mailing address: Center for Immunology and Department of Pathology, Box 8118, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110. Phone: (314) 362-4614. Fax: (314) 362-8888. E-mail: shaw{at}immunology.wustl.edu.

Molecular and Cellular Biology, September 1998, p. 5229-5238, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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