Ribosomal S6 kinase-1 modulates interleukin-1 -induced persistent activation of NF- B through phosphorylation of I B

Xu, Shanqin, Hossein Bayat, Xiuyun Hou, and Bingbing Jiang. Ribosomal S6 kinase-1 modulates interleukin-1 -induced persistent activation of NFB through phosphorylation of I B . Am J Physiol Cell Physiol 291: C1336–C1345, 2006. First published July 5, 2006; doi:10.1152/ajpcell.00552.2005.—Activation of NFB requires the phosphorylation and degradation of its associated inhibitory proteins, I B. Previously, we reported that the extracellular signal-regulated kinase (ERK) is required for IL-1 to induce persistent activation of NFB in cultured rat vascular smooth muscle cells (VSMCs). The present study examined the mechanism by which the ERK signaling cascade modulates the duration of NFB activation. In cultured rat VSMCs, IL-1 activated ERK and induced degradation of both I B and I B , which was associated with nuclear translocation of both ribosomal S6 kinase (RSK)1 and NFB p65. RSK1, a downstream kinase of ERK, was associated with an I B /NFB complex, which was independent of the phosphorylation status of RSK1. Treatment of VSMCs with IL-1 decreased I B in the RSK1/I B /NFB complex, an effect that was attenuated by inhibition of ERK activation. Knockdown of RSK1 by small interference RNA attenuated the IL-1 -induced I B decrease without influencing ether ERK phosphorylation or the earlier I B degradation. By using recombinant wild-type and mutant I B proteins, both active ERK2 and RSK1 were found to directly phosphorylate I B , but only active RSK1 phosphorylated I B on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. In conclusion, in the ERK signaling cascade, RSK1 is a key component that directly phosphorylates I B and contributes to the persistent activation of NFB by IL-1 .