Rac GTPase instructs nuclear factor-kappaB activation by conveying the SCF complex and IkBalpha to the ruffling membranes.

Nuclear factor-kappaB (NF-kappaB) is a 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(betaTrCP), 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 IkBalpha 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 IkBalpha proteasomal degradation and the resultant activation of NF-kappaB. Consequently, this points to the role of Rac as a docking molecule in NF-kappaB activation.