ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α
ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α
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DOI：
10.1091/mbc.e08-11-1135
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发表时间：
2009-03-15
影响因子：
3.3
通讯作者：
Blobel, Carl P.
中科院分区：
文献类型：
--
作者：
Le Gall, Sylvain M.;Bobe, Pierre;Blobel, Carl P.
蛋白质胞外域脱落是许多膜蛋白的关键调节剂，包括表皮生长因子受体-配体和肿瘤坏死因子（TNF）-α，为定义负责的脱落酶提供了强烈的动机。先前的研究确定了ADAM 17作为转化生长因子（TGF）-α和肝素结合表皮生长因子的主要脱落酶，但Ca++内流激活了Adam 17-/-细胞中这些表皮生长因子受体配体的额外脱落酶。在这里，我们表明，Ca++内流和P2 X7 R信号通路的刺激激活ADAM 10作为脱落酶的许多ADAM 17底物在Adam 17-/-成纤维细胞和原代B细胞。重要的是，尽管在Adam 17-/-细胞中，ADAM 10可以释放本文测试的ADAM 17的所有底物，但用高度选择性的ADAM 17抑制剂（SP26）对野生型细胞的急性处理表明，当亚当斯10和17都存在时，ADAM 17仍然是主要的释放酶。然而，用SP26长期处理野生型细胞促进了ADAM 10对ADAM 17底物的加工，从而产生了如Adam 17-/-细胞中的条件。这些结果具有普遍的影响，了解两个主要的细胞脱落酶，亚当斯10和17的底物选择性。
Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-alpha, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-alpha and heparin-binding epidermal growth factor, but Ca++ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17-/- cells. Here, we show that Ca++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17-/- fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17-/- cells, acute treatment of wild-type cells with a highly selective ADAM17 inhibitor (SP26) showed that ADAM17 is nevertheless the principal sheddase when both ADAMs 10 and 17 are present. However, chronic treatment of wild-type cells with SP26 promoted processing of ADAM17 substrates by ADAM10, thus generating conditions such as in Adam17-/- cells. These results have general implications for understanding the substrate selectivity of two major cellular sheddases, ADAMs 10 and 17.