TY - JOUR
T1 - Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ-secretase complex
AU - Nagara, Yusuke
AU - Hagiyama, Man
AU - Hatano, Naoya
AU - Futai, Eugene
AU - Suo, Satoshi
AU - Takaoka, Yutaka
AU - Murakami, Yoshinori
AU - Ito, Akihiko
AU - Ishiura, Shoichi
N1 - Funding Information:
We thank Dr. Bart De Strooper (Vlaams Instituut voor Biotechnologie) for Presenilin 1/2 double knockout cells and Dr. Philip C. Wong (The Johns Hopkins University) for Nicastrin −/− cells. Y.N. is supported by a JSPS Research Fellowship for Young Scientists.
PY - 2012/1/6
Y1 - 2012/1/6
N2 - 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.
AB - 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.
KW - ADAM10
KW - CADM1
KW - RIP
KW - Shedding
KW - Tumor suppressor gene
KW - γ-Secretase
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U2 - 10.1016/j.bbrc.2011.11.140
DO - 10.1016/j.bbrc.2011.11.140
M3 - Article
C2 - 22172944
AN - SCOPUS:84855781402
SN - 0006-291X
VL - 417
SP - 462
EP - 467
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -