Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases

Cell Signal. 2006 Jan;18(1):69-82. doi: 10.1016/j.cellsig.2005.03.023. Epub 2005 May 31.


Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases (Nox) homologous to Nox2 (gp91phox) of phagocyte cytochrome b558 have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22phox protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cytosol / enzymology
  • DNA Mutational Analysis
  • Epithelial Cells / metabolism
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • NADPH Oxidases / physiology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology
  • rac GTP-Binding Proteins / metabolism*


  • Membrane Transport Proteins
  • Phosphoproteins
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • CYBA protein, human
  • rac GTP-Binding Proteins