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Molecular and Cellular Biology, October 2001, p. 6706-6717, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6706-6717.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Raf-MEK-Erk Cascade in Anoikis Is Controlled by Rac1 and Cdc42 via Akt

Olivier Zugasti,1 Wilfrid Rul,1 Pierre Roux,2 Carole Peyssonnaux,3 Alain Eychene,3 Thomas F. Franke,4 Philippe Fort,2 and Urszula Hibner1,*

Institut de Génétique Moléculaire, CNRS UMR5535,1 and Centre de Recherche en Biochimie Macromoléculaire, CNRS UPR1086,2 F-34293 Montpellier Cedex 5, and UMR 146 CNRS/Institut Curie-Recherche, Centre Universitaire, F-91405 Orsay,3 France, and Department of Pharmacology, Columbia University, New York, New York 100324

Received 7 May 2001/Accepted 15 June 2001

Signals from the extracellular matrix are essential for the survival of many cell types. Dominant-negative mutants of two members of Rho family GTPases, Rac1 and Cdc42, mimic the loss of anchorage in primary mouse fibroblasts and are potent inducers of apoptosis. This pathway of cell death requires the activation of both the p53 tumor suppressor and the extracellular signal-regulated mitogen-activated protein kinases (Erks). Here we characterize the proapoptotic Erk signal and show that it differs from the classically observed survival-promoting one by the intensity of the kinase activation. The disappearance of the GTP-bound forms of Rac1 and Cdc42 gives rise to proapoptotic, moderate activation of the Raf-MEK-Erk cascade via a signaling pathway involving the kinases phosphatidlyinositol 3-kinase and Akt. Moreover, concomitant activation of p53 and inhibition of Akt are both necessary and sufficient to signal anoikis in primary fibroblasts. Our data demonstrate that the GTPases of the Rho family control three major components of cellular signal transduction, namely, p53, Akt, and Erks, which collaborate in the induction of apoptosis due to the loss of anchorage.

* Corresponding author. Mailing address: Institut de Génétique Moléculaire, CNRS UMR5535, 1919 Rt. de Mende, F-34293 Montpellier Cedex 5, France. Phone: 33 467613655. Fax: 33 467040231. E-mail: hibner{at}igm.cnrs-mop.fr.

Molecular and Cellular Biology, October 2001, p. 6706-6717, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6706-6717.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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