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 NF kappaB, which has been shown to have an important role in Dbl-induced oncogenic transformation, Here we show that although Dbl activation of NF kappaB requires Cdc42, Rac, and Rho, the different GTPases activate NF kappaB by different mechanisms. Whereas Rac stimulates the activity of the I kappaB kinase IKK beta, Cdc42 and Rho activate NF kappaB without activating either IKK alpha or IKK beta, Like Dbl, Rac activation of IKK beta 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 NF kappaB is more elusive, but our results suggest that it involves an IKK alpha /IKK beta -independent mechanism. Finally, we show that the signaling enzymes that mediate NF kappaB activation by Dbl and the Rho GTPases are also necessary for malignant transformation induced by oncogenic Dbl.