Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF alpha and IL-1, and by the Epstein-Barr virus transforming protein LMP1

Cdc42, a Rho-family GTPase, has been implicated in several signal transduct ion pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear tra nscription factor kappa B (NF kappa B). We report here that exposure of fib roblasts to the inflammatory cytokines tumor necrosis factor a (TNF alpha) and interleukin-1 (IL-I) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Pac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but n ot activation of JNK or NF kappa B. The latent membrane protein 1 of Epstei n-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors, When expressed in fibroblasts, LMP1 stimulates Cdc42-dependent filopodia formation as well as JNK and NF kappa B activation, Using LMP1 mu tants, we show that activation of Cdc42 and JNK/NF kappa B occur through di stinct pathways and that Cdc42 activation is independent of LMPI's interact ion with TRADD and TRAF proteins.