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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.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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