Dbl and the Rho GTPases activate NF kappa B by I kappa B kinase (IKK)-dependent and IKK-independent pathways

Abstract

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 kappa B, which has been shown to have an important role in Dbl-induced oncogenic transformation. Here we show that although Dbl activation of NF kappa B requires Cdc42, Rac, and Rho, the different GTPases activate NF kappa B by different mechanisms. Whereas Rac stimulates the activity of the I kappa B kinase IKK beta, Cdc42 and Rho activate NF kappa B 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 kappa B 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 kappa B activation by Dbl and the Rho GTPases are also necessary for malignant transformation induced by oncogenic Dbl.