Protein kinase C-α is an upstream activator of the IκB kinase complex in the TPA signal transduction pathway to NF-κB in U2OS cells

Inactive nuclear factor kappaB (NF-kappaB) complexes are retained in the cytoplasm by binding to inhibitory proteins, such as I kappaB alpha. Various stimuli lead to phosphorylation and subsequent processing of I kappaB alpha in the 26S proteasome and import of the active NF-kappaB transcription factor into the nucleus. In agreement with our previous finding that p90(rsk1) is essential for TPA-induced activation of NF-kappaB in Adenovirus 5E1-transformed Baby Rat Kidney cells, we now report that the MEK/ERK/p90(rsk1) inhibitor U0126 efficiently blocks TPA-induced I kappaB alpha processing in these cells. However, in U2OS cells, the cytokine-inducible I kappaB kinase complex (IKK) is the essential component of the TPA signal transduction pathway. Activation of the Wt complex in response to TPA is mediated by PKC-alpha, since both the PKC inhibitor GF109203 and a catalytically inactive PKC-alpha mutant inhibit activation of endogenous IKK by TPA, but not by tumor necrosis factor-alpha (TNF-alpha). We conclude that IKK is an integrator of TNF-alpha and TPA signal transduction pathways in U2OS cells. (C) 2000 Elsevier Science Inc. All rights reserved.