ACTIVATION OF THE NUCLEAR FACTOR-KAPPA-B BY RHO, CDC42, AND RAC-1 PROTEINS

The Rho family of small GTPases are critical elements involved in the regulation of signal transduction cascades from extracellular stimuli to the cell nucleus, including the JNK/SAPK signaling pathway, the c-f os serum response factor, and the p70 S6 kinase. Here we report a nove l signaling pathway activated by the Rho proteins that may be responsi ble for their biological activities, including cytoskeleton organizati on, transformation, apoptosis, and metastasis. The human RhoA, CDC42, and Rac-1 proteins efficiently induce the transcriptional activity of nuclear factor kappa B (NF-kappa B) by a mechanism that involves phosp horylation of I kappa B alpha and translocation of p50/p50 and p50/p65 dimers to the nucleus, but independent of the Ras GTPase and the Raf- 1 kinase. We also show that activation of NF-kappa B by TNF alpha depe nds on CDC42 and RhoA, but not Rac-1 proteins, because this activity i s drastically inhibited by their respective dominant-negative mutants. In contrast, activation of NF-kappa B by UV light was not affected by Rho, CDC42, or Rac-1 dominant-negative mutants. Thus, members of the Rho family of GTPases are involved specifically in the regulation of N F-kappa B-dependent transcription.