Protein kinase C-δ and phosphatidylinositol 3-Kinase/Akt activate mammalian target of rapamycin to modulate NF-κB activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells

Mohd Minhajuddin, Kaiser M. Bijli, Fabeha Fazal, Antonella Sassano, Keiichi I. Nakayama, Nissim Hay, Leonidas C. Platanias, Arshad Rahman

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

We have shown that the mammalian target of rapamycin (mTOR) down-regulates thrombin-induced ICAM-1 expression in endothelial cells by suppressing the activation of NF-κB. However, the mechanisms by which mTOR is activated to modulate these responses remain to be addressed. Here, we show that thrombin engages protein kinase C (PKC)-δ and phosphattidylinositol 3-kinase (PI3K)/Akt pathways to activate mTOR and thereby dampens NF-κB activation and intercellular adhesion molecule 1 (ICAM-1) expression. Stimulation of human vascular endothelial cells with thrombin induced the phosphorylation of mTOR and its downstream target p70 S6 kinase in a PKC-δ- and PI3K/Akt-dependent manner. Consistent with this, thrombin-induced phosphorylation of p70 S6 kinase was defective in embryonic fibroblasts from mice with targeted disruption of PKC-δ (Pkc-δ-/-), p85α and p85β subunits of the PI3K (p85α-/-β-/-), or Akt1 and Akt2 (Akt1-/-2-/-). Furthermore, we observed that expression of the constitutively active form of PKC-δ or Akt was sufficient to induce NF-κB activation and ICAM-1 expression, and that co-expression of mTOR suppressed these responses. In reciprocal experiments, inhibition/depletion of mTOR augmented NF-κB activation and ICAM-1 expression induced by PKC-δ or Akt. In control experiments, increasing or impairing mTOR signaling by the above approaches produced similar effects on NF-κB activation and ICAM-1 expression induced by thrombin. Thus, these data reveal an important role of PKC-δ and PI3K/Akt pathways in activating mTOR as an endogenous modulator to ensure a tight regulation of NF-κB signaling of ICAM-1 expression in endothelial cells.

Original languageEnglish
Pages (from-to)4052-4061
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number7
DOIs
Publication statusPublished - Feb 13 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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