Tristetraprolin (TTP)-14-3-3 complex formation protects TTP from dephosphorylation by protein phosphatase 2a and stabilizes tumor necrosis factor-α mRNA

Lei Sun, Georg Stoecklin, Susan Van Way, Vania Hinkovska-Galcheva, Ren Feng Guo, Paul Anderson, Thomas Patrick Shanley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

163 Scopus citations


Tumor necrosis factor (TNF)-α is a major cytokine produced by alveolar macrophages in response to pathogen-associated molecular patterns such as lipopolysaccharide. TNF-α secretion is regulated at both transcriptional and post-transcriptional levels. Posttranscriptional regulation occurs by modulation of TNF-α mRNA stability via the binding of tristetraprolin (TTP) to the adenosine/uridine-rich elements found in the 3′-untranslated region of the TNF-α transcript. Phosphorylation plays important roles in modulating mRNA stability, because activation of p38 MAPK by lipopolysaccharide stabilizes TNF-α mRNA. We hypothesized that the protein phosphatase 2A (PP2A) regulates this signaling pathway. Our results show that inhibition of PP2A by okadaic acid or small interference RNA significantly enhanced the stability of TNF-α mRNA. This result was associated with increased phosphorylation of p38 MAPK and MAPK-activated kinase 2 (MK-2). PP2A inhibition increased TTP phosphorylation and enhanced complex formation with chaperone protein 14-3-3. TTP physically interacted with PP2A in transfected mammalian cells. A functional consequence of TTP-14-3-3 complex formation appeared to be protection of TTP from dephosphorylation by inhibition of the binding of PP2A to phosphorylated TTP. Mutation of the MK-2 phosphorylation sites of TTP did not influence TNF-α adenosine/uridine- rich element binding and did not alter the increased TNF-α 3′-untranslated region-dependent luciferase activity induced by PP2A-small interference RNA silencing. Our data indicate that, although phosphorylation stabilizes TNF-α mRNA, PP2A regulates them RNA stability by modulating the phosphorylation state of members of the p38/MK-2/TTP pathway.

Original languageEnglish (US)
Pages (from-to)3766-3777
Number of pages12
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Jan 9 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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