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

Yong Luo, Hyung Joo Kwon, Sherwin Montano, Millie Georgiadis, Mark G. Goebl, Maureen A. Harrington

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Epidemiological data have implicated perturbations in the regulation of NF-κB 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-κB transcriptional activity will provide the molecular link between NF-κB 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-α (TNF-α) induces NF-κB-controlled gene transcription. SIMPL interacts with the nuclear pool of the NF-κB subunit, p65, in a TNF-α-dependent manner to enhance p65-dependent gene transcription. How SIMPL activity is regulated is unknown. Under basal as well as TNF-α-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-α-enhanced phosphorylation impaired nuclear localization and prevented TNF-α-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.

Original languageEnglish (US)
Pages (from-to)C1013-C1023
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number3
DOIs
StatePublished - Mar 1 2007

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Keywords

  • Cytokines
  • Inflammation
  • Nuclear factor-κB
  • Signal transduction

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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