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 transduction pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear transcription factor kappa B (NF(kappa)B). We report here that exposure of fibroblasts to the inflammatory cytokines tumor necrosis factor (alpha) (TNF(alpha)) and interleukin-1 (IL-1) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Rac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but not activation of JNK or NF(kappa)B. The latent membrane protein 1 of Epstein-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 mutants, we show that activation of Cdc42 and JNK/NF(kappa)B occur through distinct pathways and that Cdc42 activation is independent of LMP1's interaction with TRADD and TRAF proteins.