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RECEPTORS AND SIGNAL TRANSDUCTION

Phosphorylation of SIMPL modulates RelA-associated NF-B-dependent transcription

¹Department of Biochemistry and Molecular Biology, ²Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana; and ³Institute of Life Science and Biotechnology, Yonsei University, Seoul, South Korea

Submitted 25 August 2006 ; accepted in final form 31 October 2006

Epidemiological data have implicated perturbations in the regulation of NF-B activity to diseases that affect a large number of Americans today. Specifically, chronic activation of genes involved in the inflammatory response is associated with the progression of and complications in diabetes, arthritis, atherosclerosis, and cancer. Insight into the mechanisms governing the regulation of NF-B transcriptional activity will provide the molecular link between NF-B and these pathological states. SIMPL (signaling molecule that associates with mouse Pelle-like kinase) is a component of a signaling pathway through which tumor necrosis factor- (TNF-) induces NF-B-controlled gene transcription. SIMPL interacts with the nuclear pool of the NF-B subunit, p65, in a TNF--dependent manner to enhance p65-dependent gene transcription. How SIMPL activity is regulated is unknown. Under basal as well as TNF--stimulated conditions, SIMPL phosphopeptides were identified. SIMPL mutants lacking sites that are phosphorylated under basal conditions diminished p65 transactivation activity but had no effect on SIMPL nuclear localization. SIMPL mutants lacking sites of TNF--enhanced phosphorylation impaired nuclear localization and prevented TNF--induced p65 transactivation activity. Together, these studies reveal that phosphorylation of the SIMPL protein plays a critical role in SIMPL regulation by affecting both SIMPL subcellular localization and the p65 coactivator function of SIMPL.

cytokines; inflammation; signal transduction; nuclear factor-B

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