title: Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ-secretase complex.
abstract: 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.
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nagara
authors.forename: Man
authors.initials: M
authors.lastname: Hagiyama
authors.forename: Naoya
authors.initials: N
authors.lastname: Hatano
authors.forename: Eugene
authors.initials: E
authors.lastname: Futai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suo
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D019483:Disintegrins / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010703:Phorbol Esters / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D019483:Disintegrins; D007136:Immunoglobulins; D008565:Membrane Proteins; D010703:Phorbol Esters; D011480:Protease Inhibitors; D025521:Tumor Suppressor Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse