Stimulation of NFκB activity by multiple signaling pathways requires PAK1

The p21-activated kinase (PAK1) is a serine-threonine protein kinase that is 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 transcription 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 and that expression of active PAK1 can stimulate NF kappa B on its own. Similarly, in macrophages activation of NF kappa B as well as transcription from the tumor necrosis factor alpha promoter depends on PAK1. In these cells lipopolysaccharide is a potent activator of PAK1 kinase activity. We also demonstrate that expression of active PAK1 stimulates the nuclear translocation 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 crucial signaling molecule involved in NF kappa B activation by multiple stimuli.