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Molecular and Cellular Biology, July 1999, p. 4819-4824, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Tyrosine Phosphorylation of the Proto-Oncoprotein Raf-1 Is Regulated by Raf-1 Itself and the Phosphatase Cdc25A

Kai Xia,1,2,3 Robert S. Lee,1 Radha P. Narsimhan,1,3 Nishit K. Mukhopadhyay,1 Benjamin G. Neel,4 and Thomas M. Roberts1,3,*

Dana-Farber Cancer Institute,1 Division of HST,2 and Department of Pathology,3 Harvard Medical School, and Cancer Biology Program, Beth Israel Deaconess Medical Center,4 Boston, Massachusetts 02115

Received 14 October 1998/Returned for modification 19 November 1998/Accepted 15 April 1999

There is a growing body of evidence demonstrating that Raf-1 is phosphorylated on tyrosines upon stimulation of a variety of receptors. Although detection of Raf-1 tyrosine phosphorylation has remained elusive, genetic analyses have demonstrated it to be important for Raf-1 activation. Here we report new findings which indicate that Raf-1 tyrosine phosphorylation is regulated in vivo. In both a mammalian and baculovirus expression system, a kinase-inactive allele of Raf-1 was found to be tyrosine phosphorylated at levels much greater than that of wild-type Raf-1. The level of tyrosine phosphate on Raf-1 was markedly increased upon treatment with phosphatase inhibitors either before or after cell lysis. Cdc25A was found to dephosphorylate Raf-1 on tyrosines that resulted in a significant decrease in Raf-1 kinase activity. In NIH 3T3 cells, coexpression of wild-type Raf-1 and phosphatase-inactive Cdc25A led to a marked increase in Raf-1 tyrosine phosphorylation in response to platelet-derived growth factor. These data suggest that the tyrosine phosphorylation of Raf-1 is regulated not only by itself but also by Cdc25A.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Smith 970, Boston, MA 02115. Phone: (617) 632-3049. Fax: (617) 632-4770. E-mail: thomas_roberts{at}dfci.harvard.edu.

Molecular and Cellular Biology, July 1999, p. 4819-4824, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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