Calcium-regulated intramembrane proteolysis of the RAGE receptor

Biochem Biophys Res Commun. 2008 May 23;370(1):1-5. doi: 10.1016/j.bbrc.2008.02.163. Epub 2008 Mar 18.


The receptor for advanced glycation endproducts (RAGE) interacts with several ligands and is involved in various human diseases. RAGE_v1 or sRAGE, a RAGE splice variant, is secreted and contributes to the removal of RAGE ligands. Because RAGE blockade by specific antibodies directed against RAGE extracellular domains and the use of sRAGE have been proven to be beneficial in the context of pathological settings, both RAGE and sRAGE are considered as therapeutic target. Here, we show that sRAGE is also produced through regulated intramembrane proteolysis of the RAGE receptor, which is catalyzed by ADAM10 and the gamma-secretase and that calcium is an essential regulator of RAGE processing. Furthermore, RAGE intracellular domain localizes both in the cytoplasm and the nucleus and induces apoptosis when expressed in cells. These findings reveal new aspects of RAGE regulation and signaling and also provide a new interaction between RAGE and human pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • Amyloid Precursor Protein Secretases / metabolism*
  • Antibodies / pharmacology
  • Calcium / metabolism*
  • Cell Line
  • Cell Membrane / metabolism*
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Dimethyl Sulfoxide / pharmacology
  • Humans
  • Ionomycin / pharmacology
  • Membrane Proteins / metabolism*
  • Protein Structure, Tertiary
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology


  • Antibodies
  • Membrane Proteins
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Ionomycin
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • Tetradecanoylphorbol Acetate
  • Calcium
  • Dimethyl Sulfoxide