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MBC in Press, published online ahead of print December 10, 2003
Mol. Biol. Cell 10.1091/mbc.E03-05-0301

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Submitted on May 15, 2003
Revised on August 13, 2003
Accepted on October 24, 2003

Rac GTPase instructs NF-kB activation by conveying the SCF complex and IkB{alpha} to the ruffling membranes

Laurent Boyer1, Sara Travaglione2, Loredana Falzano2, Nils C. Gauthier1, Michel R. Popoff3, Emmanuel Lemichez1, Carla Fiorentini4, and Alessia Fabbri4*

1 INSERM U452, IFR50, Faculté de Médecine, 28 Avenue de Valombrose, 06107 Nice, France
2 Laboratory of Ultrastructures, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy; New affiliation: Department of Drug Research and Evaluation
3 CNR Anaerobies, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France
4 Laboratory of Ultrastructures, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy; New affiliation: Department of Drug Research and Evaluation; C. Fiorentini and A. Fabbri were principal investigators

* Corresponding author. E-mail address: alessia.fabbri{at}iss.it.

NF-{kappa}B is an ubiquitously expressed transcription factor that plays a central role in directing a vast range of cellular functions. Its activation is controlled by the Rac GTPase and relies on the coordinated cooperation of the E3-ligase complex SCF{beta}{beta}TrCP, composed by Skp-1/Cullin-1, Rbx/Roc1 and the {beta}-TrCP proteins. Recently, Cullin-1 has been reported to form a complex with the activated Rac GTPase. Here we show that the specific activation of the Rac GTPase, besides directing its own positioning, induces the relocalization of the SCF component Cullin-1 to the ruffling membranes. This occurred only if the ruffles were stimulated by the Rac GTPase and was accompanied by the repositioning to the same intracellular compartment of the SCF protein Skp-1 and the ubiquitin-like molecule Nedd-8. The SCF substrate IkB{alpha} was also directed to the ruffling membranes in a Rac-dependent way. The novelty of these findings is in respect to the demonstration that the correct positioning at the ruffling membranes is crucial for the subsequent series of events that leads to IkB{alpha} proteasomal degradation and the resultant activation of NF-{kappa}B. Consequently, this points to the role of Rac as a docking molecule in NF-{kappa}B activation.




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