Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme.
Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme.
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DOI：
10.1042/bj3570787
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发表时间：
2001-08
期刊：
影响因子：
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通讯作者：
Barbara E. Slack;Leona K. Ma;Ching Ching Seah-Ching
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文献类型：
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作者：
Barbara E. Slack;Leona K. Ma;Ching Ching Seah-Ching
阿尔茨海默病的淀粉样前体蛋白（APP）是一种跨膜蛋白，在其细胞外结构域内被切割，释放出可溶性N-末端片段（sAPP α）。该过程的假定介质包括ADAM（去整合素和金属蛋白酶）家族的三个成员，ADAM 9、ADAM 10和ADAM 17/TACE（肿瘤坏死因子-α转化酶）。肿瘤坏死因子-α蛋白酶抑制剂（TAPI-1）是一种亚当斯抑制剂，可减少稳定表达M3毒蕈碱受体的HEK-293细胞中组成型和毒蕈碱受体刺激的sAPP α释放。然而，前者对TAPI-1（IC（50）=8.09 μ M）的敏感性低于后者（IC（50）=3.61 μ M），表明这些过程可能由不同的金属蛋白酶介导。在用TACE瞬时转染的细胞中，组成性sAPP α释放增加数倍，并且这种增加与TACE表达成比例。相比之下，毒蕈碱受体激活的sAPP α释放在TACE转染子中没有改变。TAPI-1抑制共转染APP（695）的TACE依赖性组成型释放，IC（50）为0.92 μ m，该值显著低于内源性分泌酶介导的组成型或受体调节的sAPP α脱落抑制的IC（50）。结果表明，TACE能够催化APP的组成型α分泌裂解，但ADAM家族的其他成员可能介导HEK-293细胞中sAPP α的内源性组成型和受体偶联释放。
The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved within its extracellular domain, liberating a soluble N-terminal fragment (sAPP alpha). Putative mediators of this process include three members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10 and ADAM17/TACE (tumour necrosis factor-alpha converting enzyme). Tumour necrosis factor-alpha protease inhibitor (TAPI-1), an inhibitor of ADAMs, reduced constitutive and muscarinic receptor-stimulated sAPP alpha release in HEK-293 cells stably expressing M3 muscarinic receptors. However, the former was less sensitive to TAPI-1 (IC(50)=8.09 microM) than the latter (IC(50)=3.61 microM), suggesting that these processes may be mediated by different metalloproteases. Constitutive sAPP alpha release was increased several-fold in cells transiently transfected with TACE, and this increase was proportional to TACE expression. In contrast, muscarinic-receptor-activated sAPP alpha release was not altered in TACE transfectants. TACE-dependent constitutive release of co-transfected APP(695) was inhibited by TAPI-1 with an IC(50) of 0.92 microm, a value significantly lower than the IC(50)s for inhibition of either constitutive or receptor-regulated sAPP alpha shedding mediated by endogenous secretases. The results indicate that TACE is capable of catalysing constitutive alpha-secretory cleavage of APP, but it is likely that additional members of the ADAM family mediate endogenous constitutive and receptor-coupled release of sAPP alpha in HEK-293 cells.