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首页> 外文期刊>FEBS Open Bio >ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin
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ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

机译：ADAM17对于EGF受体配体双调蛋白的胞外域脱落至关重要

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The epidermal growth factor (EGF)‐receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8‐, ADAM15‐, and batimastat (broad metalloprotease inhibitor)‐sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2cub) mouse model that shows loss‐of‐hair, enlarged sebaceous gland, and rapid cutaneous wound‐healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2cub mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound‐healing phenotype observed in Rhbdf2cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG.
机译：表皮生长因子（EGF）受体配体双调蛋白（AREG）是有效的生长因子，与增生性皮肤病以及原发性和转移性上皮癌有关。合成为前肽的AREG需要通过金属蛋白酶通过称为胞外域脱落的过程转化为活性肽。尽管（ADAM17）整联蛋白和金属蛋白酶17是AREG的主要脱壳酶，但AREG脱落也与ADAM8‐，ADAM15‐和batimastat（广泛的金属蛋白酶抑制剂）敏感的金属蛋白酶有关。在本研究中，我们使用卷曲的裸鼠（Rhbdf2cub）模型显示脱毛，皮脂腺增大和由增强的Areg mRNA和蛋白质水平介导的快速皮肤伤口愈合表型，我们试图确定主要的胞外域棚户蛋白酶的AREG。为此，我们生成了在皮肤中特异性缺乏ADAM17的Rhbdf2cub小鼠，并检查了Rhbdf2cub小鼠的上述表型。我们发现Rhbdf2cub小鼠皮肤中的ADAM17缺乏可恢复完整的毛发，防止皮脂腺增大，并损害Rhbdf2cub小鼠中观察到的快速伤口愈合表型。此外，在体外，缺乏ADAM17的Rhbdf2cub小鼠胚胎角质形成细胞废除了AREG的刺激性脱落。因此，我们的数据支持了先前的发现，表明ADAM17是AREG的主要胞外脱落酶。

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