Activation-induced degradation of FLIPL is mediated via the phosphatidylinositol 3-kinase/Akt signaling pathway in macrophages

Bo Shi, Tri Tran, Rudina Sobkoviak, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Cellular FLIP (Flice-like inhibitory protein) is critical for the protection against death receptor-mediated cell apoptosis. In macrophages, FLIP long (FLIPL) and FLIP short (FLIPS) mRNA was induced by tumor necrosis factor (TNF) α, mediated through NF-κB. However, we observed TNFα reduced the protein level of FLIPL, but not FLIPS, at 1 and 2 h. Similar results were observed with lipopolysaccharide. The reduction of FLIPL by TNFα was not mediated by caspase 8, or through JNK or Itch, but was suppressed by inhibition of the phosphatidylinositol 3-kinase/Akt pathway employing chemical inhibitors, a dominant negative Akt-1, or Akt-1 small interfering RNA. The reduction of FLIPL resulted in the short term induction of caspase 8-like activity, which augmented NF-κB activation. A co-immunoprecipitation assay demonstrated that Akt-1 physically interacts with FLIPL. Moreover, TNFα enhanced FLIPL serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIPL, was critical for the activation-induced reduction of FLIPL. Thus, these observations document a novel mechanism where by TNFα facilitates the reduction of FLIPL protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling.

Original languageEnglish (US)
Pages (from-to)14513-14523
Number of pages11
JournalJournal of Biological Chemistry
Issue number21
StatePublished - May 22 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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