A differential role for endocytosis in receptor-mediated activation of Nox1.

Miller FJ, Chu X, Stanic B, Tian X, Sharma RV, Davisson RL, Lamb FS
Antioxid Redox Signal. 2010 12 (5): 583-93

PMID: 19737091 · PMCID: PMC2861543 · DOI:10.1089/ars.2009.2857

Internalization of activated receptors to a compartment enriched with NAPDH oxidase and associated signaling molecules is expected to facilitate regulation of redox-mediated signal transduction. The aim of this study was to test the hypothesis that endocytosis is necessary for generation of reactive oxygen species (ROS) by Nox1 and for redox-dependent signaling in smooth muscle cells (SMCs). Within minutes of treatment with tumor necrosis factor (TNF)-alpha or thrombin, SMCs increased cellular levels of ROS that was inhibited by shRNA to Nox1. Treatment of SMC with TNF-alpha induced a dynamin-dependent endosomal generation of ROS, whereas thrombin-mediated ROS production did not occur within endosomes and was not prevented by dominant-negative dynamin (dn-dynamin), but instead required transactivation of the epidermal growth factor receptor (EGFR). Activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-activating transcription factor-1 (ATF-1) pathway by TNF-alpha and thrombin were both Nox1- and dynamin-dependent. In conclusion, we show that formation of specific ligand-receptor complexes results in spatially distinct mechanisms of Nox1 activation and generation of ROS. These findings provide novel insights into the role of compartmentalization for integrating redox-dependent cell signaling.

MeSH Terms (23)

Activating Transcription Factor 1 Animals Cells, Cultured Cytoplasmic Vesicles Dynamins Endocytosis Endosomes Enzyme Activation Humans Isoenzymes Membrane Microdomains Mice Mice, Inbred C57BL Muscle, Smooth, Vascular Myocytes, Smooth Muscle NADPH Oxidases Oxidation-Reduction Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Reactive Oxygen Species Signal Transduction Thrombin Tumor Necrosis Factor-alpha

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