Activation of tumor necrosis factor-alpha-converting enzyme-mediated ectodomain shedding by nitric oxide

J Biol Chem. 2000 May 26;275(21):15839-44. doi: 10.1074/jbc.M000604200.


Ectodomain shedding of cell surface proteins is an important process in a wide variety of physiological and developmental events. Recently, tumor necrosis factor-alpha-converting enzyme (TACE) has been found to play an essential role in the shedding of several critical surface proteins, which is evidenced by multiple developmental defects exhibited by TACE knockout mice. However, little is known about the physiological activation of TACE. Here, we show that nitric oxide (NO) activates TACE-mediated ectodomain shedding. Using an in vitro model of TACE activation, we show that NO activates TACE by nitrosation of the inhibitory motif of the TACE prodomain. Thus, NO production activates the release of cytokines, cytokine receptors, and adhesion molecules, and NO may be involved in other ectodomain shedding processes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Animals
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Lipopolysaccharides / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Knockout
  • Nitric Oxide / pharmacology*
  • Peptide Fragments / pharmacology
  • Rats
  • Receptors, Tumor Necrosis Factor / metabolism
  • Recombinant Proteins / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism


  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Membrane Proteins
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse
  • Adam17 protein, rat
  • Tetradecanoylphorbol Acetate