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J. Biol. Chem., Vol. 278, Issue 5, 2807-2818, January 31, 2003
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From the Department of Medicine and Cancer Center, University of
California, San Diego, La Jolla, California 92093-0652
Transformation by oncogenic Ras requires
signaling through Rho family proteins including RhoA, but the
mechanism(s) whereby oncogenic Ras regulates the activity of RhoA is
(are) unknown. We examined the effect of Ras on RhoA activity in NIH
3T3 cells either stably transfected with H-Ras(V12) under control of an inducible promoter or transiently expressing the activated H-Ras. Using
a novel method to quantitate enzymatically the GTP bound to Rho, we
found that expression of the oncogenic Ras increased Rho activity
~2-fold. Increased Rho activity was associated with increased plasma
membrane binding of RhoA and decreased activity of the
Rho/Ras-regulated p21WAF1/CIP1 promoter. RhoA
activation by oncogenic Ras could be explained by a decrease in
cytosolic p190 Rho-GAP activity and translocation of p190 Rho-GAP from
the cytosol to a detergent-insoluble cytoskeletal fraction.
Pharmacologic inhibition of the Ras/Raf/MEK/ERK pathway prevented
Ras-induced activation of RhoA and translocation of p190 Rho-GAP;
expression of constitutively active Raf-1 kinase or MEK was sufficient
to induce p190 Rho-GAP translocation. We conclude that in NIH 3T3 cells
oncogenic Ras activates RhoA through the Raf/MEK/ERK pathway by
decreasing the cytosolic activity and changing the subcellular
localization of p190 Rho-GAP.
Oncogenic Ras Leads to Rho Activation by Activating the
Mitogen-activated Protein Kinase Pathway and Decreasing
Rho-GTPase-activating Protein Activity*
,,
*
This work was supported in part by United States Public
Health Service Grants GM55586 (to R. B. P.) and CA89828 and CA90932 (to G. R. B.) and by a University of California Cancer Coordinating Committee grant (to R. B. P.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
To whom correspondence should be addressed: Dept. of Medicine,
University of California at San Diego, 9500 Gilman Dr., Basic Science
Bldg. 5080, La Jolla, CA 92093-0652. Tel.: 858-534-8805; Fax:
858-534-1421; E-mail: rpilz@ucsd.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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