Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways
Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways
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DOI：
10.1073/pnas.1307478110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Herrlich, Andreas
中科院分区：
文献类型：
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作者：
Dang, Michelle;Armbruster, Nicole;Herrlich, Andreas
解整合素和金属蛋白酶（亚当斯）对细胞表面蛋白的胞外结构域切割受到高度调节，其失调与许多疾病有关。ADAM 10和ADAM 17切割大多数疾病相关底物。广谱金属蛋白酶抑制剂在临床上已经失败，并且靶向特定底物的切割仍然是不可能的。因此，有必要鉴定决定切割底物特异性的信号传导中间体。我们在这里表明，佛波酯或血管紧张素II诱导的EGF家族成员的蛋白水解释放可能不需要在ADAM 17蛋白酶活性显着增加。相反，诱导剂使用PKC-α和PKC调节的蛋白磷酸酶1抑制剂14 D激活信号传导途径，这是ADAM 17切割TGF-α、肝素结合EGF和双调蛋白所必需的。涉及PKC-δ的第二途径是神经调节蛋白（NRG）裂解所需的，并且实际上，NRG胞质结构域中丝氨酸286的PKC-δ磷酸化对于诱导的NRG裂解是必需的。因此，信号传导介导的底物选择明显不同于酶活性的调节，酶活性的调节是一种重要的机制，可用于疾病。
Ectodomain cleavage of cell-surface proteins by A disintegrin and metalloproteinases (ADAMs) is highly regulated, and its dysregulation has been linked to many diseases. ADAM10 and ADAM17 cleave most disease-relevant substrates. Broad-spectrum metalloprotease inhibitors have failed clinically, and targeting the cleavage of a specific substrate has remained impossible. It is therefore necessary to identify signaling intermediates that determine substrate specificity of cleavage. We show here that phorbol ester or angiotensin II-induced proteolytic release of EGF family members may not require a significant increase in ADAM17 protease activity. Rather, inducers activate a signaling pathway using PKC-alpha and the PKC-regulated protein phosphatase 1 inhibitor 14D that is required for ADAM17 cleavage of TGF-alpha, heparin-binding EGF, and amphiregulin. A second pathway involving PKC-delta is required for neuregulin (NRG) cleavage, and, indeed, PKC-delta phosphorylation of serine 286 in the NRG cytosolic domain is essential for induced NRG cleavage. Thus, signaling-mediated substrate selection is clearly distinct from regulation of enzyme activity, an important mechanism that offers itself for application in disease.