Hosur Vishnu, Farley Michelle L, Burzenski Lisa M, Shultz Leonard D, Wiles Michael V
The Jackson Laboratory Bar Harbor ME USA.
FEBS Open Bio. 2018 Mar 12;8(4):702-710. doi: 10.1002/2211-5463.12407. eCollection 2018 Apr.
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 ( ) mouse model that shows loss-of-hair, enlarged sebaceous gland, and rapid cutaneous wound-healing phenotypes mediated by enhanced mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated mice lacking ADAM17 specifically in the skin and examined the above phenotypes of mice. We find that ADAM17 deficiency in the skin of mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound-healing phenotype observed in mice. Furthermore, , stimulated shedding of AREG is abolished in mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG.
表皮生长因子（EGF）受体配体双调蛋白（AREG）是一种强效生长因子，与增殖性皮肤病以及原发性和转移性上皮癌有关。AREG最初作为前体肽合成，需要通过一种称为胞外域脱落的过程，由金属蛋白酶转化为活性肽。尽管解整合素和金属蛋白酶17（ADAM17）是AREG的关键脱落酶，但ADAM8、ADAM15以及batimastat（一种广泛的金属蛋白酶抑制剂）敏感的金属蛋白酶也与AREG的脱落有关。在本研究中，我们使用了一种卷毛裸鼠模型，该模型表现出毛发脱落、皮脂腺肿大以及由增强的mRNA和蛋白质水平介导的快速皮肤伤口愈合表型，旨在确定AREG的主要胞外域脱落酶。为此，我们构建了皮肤中特异性缺乏ADAM17的小鼠，并检查了这些小鼠的上述表型。我们发现，小鼠皮肤中ADAM17的缺乏恢复了完整的毛发覆盖，防止了皮脂腺肿大，并损害了在小鼠中观察到的快速伤口愈合表型。此外，在缺乏ADAM17的小鼠胚胎角质形成细胞中，AREG的刺激脱落被消除。因此，我们的数据支持了先前的研究结果，即ADAM17是AREG的主要胞外域脱落酶。
