Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Protein kinase C-delta and phosphatidylinositol 3-kinase/Akt activate mammalian target of rapamycin to modulate NF-kappaB activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells.

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

Published In J Biol Chem, (2009 Feb 13)

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-kappaB. 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)-delta and phosphattidylinositol 3-kinase (PI3K)/Akt pathways to activate mTOR and thereby dampens NF-kappaB 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-delta- 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-delta (Pkc-delta(-)(/)(-)), p85alpha and p85beta subunits of the PI3K (p85alpha(-)(/)(-)beta(-)(/)(-)), or Akt1 and Akt2 (Akt1(-)(/)(-)2(-)(/)(-)). Furthermore, we observed that expression of the constitutively active form of PKC-delta or Akt was sufficient to induce NF-kappaB activation and ICAM-1 expression, and that co-expression of mTOR suppressed these responses. In reciprocal experiments, inhibition/depletion of mTOR augmented NF-kappaB activation and ICAM-1 expression induced by PKC-delta or Akt. In control experiments, increasing or impairing mTOR signaling by the above approaches produced similar effects on NF-kappaB activation and ICAM-1 expression induced by thrombin. Thus, these data reveal an important role of PKC-delta and PI3K/Akt pathways in activating mTOR as an endogenous modulator to ensure a tight regulation of NF-kappaB signaling of ICAM-1 expression in endothelial cells.

PubMed ID: 19074768 Exiting the NIEHS site

MeSH Terms: Animals; Carrier Proteins/genetics; Carrier Proteins/metabolism*; Cell Line; Embryo, Mammalian/cytology; Embryo, Mammalian/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism*; Fibroblasts/cytology; Fibroblasts/metabolism; Gene Expression Regulation/drug effects; Gene Expression Regulation/physiology*; Hemostatics/pharmacology; Humans; Intercellular Adhesion Molecule-1/biosynthesis*; Intercellular Adhesion Molecule-1/genetics; Mice; Mice, Knockout; NF-kappa B/genetics; NF-kappa B/metabolism*; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism*; Phosphorylation/drug effects; Phosphorylation/physiology; Phosphotransferases (Alcohol Group Acceptor)/genetics; Phosphotransferases (Alcohol Group Acceptor)/metabolism*; Protein Kinase C-delta/genetics; Protein Kinase C-delta/metabolism*; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism*; Ribosomal Protein S6 Kinases, 70-kDa/genetics; Ribosomal Protein S6 Kinases, 70-kDa/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; TOR Serine-Threonine Kinases; Thrombin/pharmacology

Back
to Top