Dbl and the Rho GTPases Activate NFκB by IκB Kinase (IKK)-dependent and IKK-independent Pathways

Dbl is a guanine nucleotide exchange factor that activates the Rho family GTPases Cdc42, Rac, and Rho. Dbl and all three GTPases are strong activators of transcription factor NFκB, which has been shown to have an important role in Dbl-induced oncogenic transformation. Here we show that although Dbl activation of NFκB requires Cdc42, Rac, and Rho, the different GTPases activate NFκB by different mechanisms. Whereas Rac stimulates the activity of the IκB kinase IKKβ, Cdc42 and Rho activate NFκB without activating either IKKα or IKKβ. Like Dbl, Rac activation of IKKβ is mediated by the serine/threonine kinases NIK but not MEKK. This differs from Rac activation of the JNK pathway, which was previously shown to be mediated by MEKK. The pathway leading from Rho and Cdc42 to NFκB is more elusive, but our results suggest that it involves an IKKα/IKKβ-independent mechanism. Finally, we show that the signaling enzymes that mediate NFκB activation by Dbl and the Rho GTPases are also necessary for malignant transformation induced by oncogenic Dbl.