Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ-secretase complex
Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ-secretase complex
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DOI：
10.1016/j.bbrc.2011.11.140
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发表时间：
2012-01-06
影响因子：
3.1
通讯作者：
Ishiura, Shoichi
中科院分区：
文献类型：
--
作者：
Nagara, Yusuke;Hagiyama, Man;Ishiura, Shoichi
细胞粘附分子1（CADM 1）是一种I型跨膜糖蛋白，在多种组织中表达。CADM 1是一种具有多种功能的细胞粘附分子，包括在肿瘤抑制、凋亡、肥大细胞存活、突触形成和精子发生中的作用。CADM 1经历称为脱落的近膜切割，但CADM 1蛋白水解的脱落酶和机制尚未报道。我们通过LC/MS/MS确定了参与CADM 1脱落的切割位点，并表明CADM 1脱落发生在膜部分中，并被肿瘤坏死因子-α蛋白酶抑制剂-1（TAPI-1）抑制。siRNA实验显示，ADAM 10介导内源性CADM 1脱落。此外，脱落产生的膜结合片段进一步被γ-分泌酶切割，并在称为调节性膜内蛋白水解（RIP）的机制中产生CADM 1-胞内结构域（ICD）。这些结果阐明了CADM 1近膜切割的详细机制，提示RIP介导的CADM 1信号转导的可能性。(C)2011 Elsevier Inc. All rights reserved.
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-alpha 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 gamma-secretase and generated CADM1-intracellular domain (ICD) in a mechanism called regulated intra-membrane proteolysis (RIP). These results clarify the detailed mechanism of membrane-proximal cleavage of CADM1, suggesting the possibility of RIP-mediated CADM1 signaling. (C) 2011 Elsevier Inc. All rights reserved.