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J Biol Chem, Vol. 274, Issue 31, 21823-21829, July 30, 1999

Pseudomonas aeruginosa Exoenzyme S Disrupts Ras-mediated Signal Transduction by Inhibiting Guanine Nucleotide Exchange Factor-catalyzed Nucleotide Exchange

Anand K. Ganesan, Timothy S. Vincent^§, Joan C. Olson^§, and Joseph T. Barbieri

From the  Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, Wisconsin 53226 and the ^§ Medical University of South Carolina, Department of Pathology and Laboratory Medicine, Charleston, South Carolina 29425

Pseudomonas aeruginosa exoenzyme S double ADP-ribosylates Ras at Arg⁴¹ and Arg¹²⁸. Since Arg⁴¹ is adjacent to the switch 1 region of Ras, ADP-ribosylation could interfere with Ras-mediated signal transduction via several mechanisms, including interaction with Raf, or guanine nucleotide exchange factor-stimulated or intrinsic nucleotide exchange. Initial experiments showed that ADP-ribosylated Ras (ADP-r-Ras) and unmodified Ras (Ras) interacted with Raf with equal efficiencies, indicating that ADP-ribosylation did not interfere with Ras-Raf interactions. While ADP-r-Ras and Ras possessed equivalent intrinsic nucleotide exchange rates, guanine nucleotide exchange factor (Cdc25) stimulated the nucleotide exchange of ADP-r-Ras at a 3-fold slower rate than Ras. ADP-r-Ras did not affect the nucleotide exchange of Ras, indicating that the ADP-ribosylation of Ras was not a dominant negative phenotype. Ras-R41K and ADP-r-Ras R41K possessed similar exchange rates as Ras, indicating that ADP-ribosylation at Arg¹²⁸ did not inhibit Cdc25-stimulated nucleotide exchange. Consistent with the slower nucleotide exchange rate of ADP-r-Ras as compared with Ras, ADP-r-Ras bound its guanine nucleotide exchange factor (Cdc25) less efficiently than Ras in direct binding experiments. Together, these data indicate that ADP-ribosylation of Ras at Arg⁴¹ disrupts Ras-Cdc25 interactions, which inhibits the rate-limiting step in Ras signal transduction, the activation of Ras by its guanine nucleotide exchange factor.

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