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Eukaryotic Cell, April 2004, p. 459-470, Vol. 3, No. 2
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.2.459-470.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tfs1p, a Member of the PEBP Family, Inhibits the Ira2p but Not the Ira1p Ras GTPase-Activating Protein in Saccharomyces cerevisiae

Hélène Chautard,1 Michel Jacquet,2 Françoise Schoentgen,1 Nicole Bureaud,1 and Hélène Bénédetti1*

Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, UPR 4301, University of Orléans and INSERM, 45071 Orléans Cedex 2,1 Laboratoire Information Génétique et Développement, Institut de Génétique et Microbiologie, UMR CNRS-Université 8621, Université Paris-Sud, 91405 Orsay Cedex, France2

Received 2 February 2004/ Accepted 3 February 2004

Ras proteins are guanine nucleotide-binding proteins that are highly conserved among eukaryotes. They are involved in signal transduction pathways and are tightly regulated by two sets of antagonistic proteins: GTPase-activating proteins (GAPs) inhibit Ras proteins, whereas guanine exchange factors activate them. In this work, we describe Tfs1p, the first physiological inhibitor of a Ras GAP, Ira2p, in Saccharomyces cerevisiae. TFS1 is a multicopy suppressor of the cdc25-1 mutation in yeast and corresponds to the so-called Ic CPY cytoplasmic inhibitor. Moreover, Tfs1p belongs to the phosphatidylethanolamine-binding protein (PEBP) family, one member of which is RKIP, a kinase and serine protease inhibitor and a metastasis inhibitor in prostate cancer. In this work, the results of (i) a two-hybrid screen of a yeast genomic library, (ii) glutathione S-transferase pulldown experiments, (iii) multicopy suppressor tests of cdc25-1 mutants, and (iv) stress resistance tests to evaluate the activation level of Ras demonstrate that Tfs1p interacts with and inhibits Ira2p. We further show that the conserved ligand-binding pocket of Tfs1—the hallmark of the PEBP family—is important for its inhibitory activity.

* Corresponding author. Mailing address: Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, UPR 4301, rue Charles Sadron, 45071 Orleans Cedex 2, France. Phone: 00 33 2 38 25 55 84. Fax: 00 33 2 38 63 15 17. E-mail: benedett{at}cnrs-orleans.fr.

Eukaryotic Cell, April 2004, p. 459-470, Vol. 3, No. 2
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.2.459-470.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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