Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ-secretase complex

Biochem Biophys Res Commun. 2012 Jan 6;417(1):462-7. doi: 10.1016/j.bbrc.2011.11.140. Epub 2011 Dec 7.


Cell adhesion molecule 1 (CADM1) is a type I transmembrane glycoprotein expressed in various tissues. CADM1 is a cell adhesion molecule with many functions, including roles in tumor suppression, apoptosis, mast cell survival, synapse formation, and spermatogenesis. CADM1 undergoes membrane-proximal cleavage called shedding, but the sheddase and mechanisms of CADM1 proteolysis have not been reported. We determined the cleavage site involved in CADM1 shedding by LC/MS/MS and showed that CADM1 shedding occurred in the membrane fraction and was inhibited by tumor necrosis factor-α protease inhibitor-1 (TAPI-1). An siRNA experiment revealed that ADAM10 mediates endogenous CADM1 shedding. In addition, the membrane-bound fragment generated by shedding was further cleaved by γ-secretase and generated CADM1-intracellular domain (ICD) in a mechanism called regulated intramembrane proteolysis (RIP). These results clarify the detailed mechanism of membrane-proximal cleavage of CADM1, suggesting the possibility of RIP-mediated CADM1 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM10 Protein
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • COS Cells
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Disintegrins / metabolism*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Phorbol Esters / pharmacology
  • Protease Inhibitors / pharmacology
  • Tumor Suppressor Proteins / metabolism*


  • CADM1 protein, human
  • Cadm1 protein, mouse
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • Disintegrins
  • Immunoglobulins
  • Membrane Proteins
  • Phorbol Esters
  • Protease Inhibitors
  • Tumor Suppressor Proteins
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • Adam10 protein, mouse