Stimulation of NF kappa B activity by multiple signaling pathways requiresPAK1

The p21-activated kinase (PAK1) is a serine-threonine protein kinase that i s activated by binding to the Rho family small G proteins Rac and Cdc42hs. Both Rac and Cdc42hs have been shown to regulate the activity of the transc ription factor NF kappa B. Here we show that expression of active Ras, Raf- 1, or Rad in fibroblasts stimulates NF kappa B in a PAK1-dependent manner a nd that expression of active PAK1 can stimulate NF kappa B on its own. Simi larly, in macrophages activation of NF kappa B as well as transcription fro m the tumor necrosis factor alpha promoter depends on PAK1. In these cells lipopolysaccharide is a potent activator of PAK1 kinase activity. We also d emonstrate that expression of active PAK1 stimulates the nuclear translocat ion of the p65 subunit of NF kappa B but does not activate the inhibitor of kappa B kinases alpha or beta. These data demonstrate that PAK1 is a cruci al signaling molecule involved in NF kappa B activation by multiple stimuli .