The TspanC8 Subgroup of Tetraspanins Interacts with A Disintegrin and Metalloprotease 10 (ADAM10) and Regulates Its Maturation and Cell Surface Expression
The TspanC8 Subgroup of Tetraspanins Interacts with A Disintegrin and Metalloprotease 10 (ADAM10) and Regulates Its Maturation and Cell Surface Expression
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DOI：
10.1074/jbc.m112.416503
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发表时间：
2012-11-16
影响因子：
4.8
通讯作者：
Tomlinson, Michael G.
中科院分区：
文献类型：
--
作者：
Haining, Elizabeth J.;Yang, Jing;Tomlinson, Michael G.
解整合素和金属蛋白酶10（ADAM 10）是一种普遍存在的跨膜金属蛋白酶，其从超过40种不同的跨膜靶蛋白（包括Notch和淀粉样前体蛋白）切割细胞外区域。ADAM 10对胚胎发育至关重要，在炎症、癌症和阿尔茨海默病中也很重要。然而，对ADAM 10的调控仍然知之甚少。ADAM 10被划分成由四跨膜蛋白形成的膜微结构域，四跨膜蛋白是人类中33种跨膜蛋白的超家族，其调节某些其他跨膜“伴侣”蛋白的聚集和运输。这是通过特定的四跨膜蛋白-伴侣相互作用实现的，但尚不清楚哪些四跨膜蛋白特异性地与ADAM 10相互作用。本研究的目的是确定哪些四跨膜蛋白与ADAM 10相互作用，以及它们如何调节这种金属蛋白酶。免疫共沉淀鉴定了ADAM 10与Tspan 5、Tspan 10、Tspan 14、Tspan 15、Tspan 17和Tspan 33/Penumbra的特异性相互作用。这些是大部分未研究的四跨膜蛋白TspanC 8亚组的成员，所有六种都促进了ADAM 10的成熟。不同的细胞类型表达不同的TspanC 8四跨膜蛋白库。人脐静脉内皮细胞表达相对高水平的Tspan 14，其敲低降低了ADAM 10表面表达和活性。小鼠红细胞主要表达Tspan 33，而在缺乏这种四跨膜蛋白的情况下，ADAM 10的表达显著降低。与此相反，ADAM 10的表达是正常的Tspan 33缺陷型小鼠血小板，其中Tspan 14是主要的TspanC 8四跨膜蛋白。这些结果将TspanC 8四跨膜蛋白定义为ADAM 10成熟和运输至细胞表面的必要调节剂。这一发现具有治疗意义，因为专注于特定的TspanC 8-ADAM 10复合物可能允许细胞类型和/或底物特异性的ADAM 10靶向。
A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions from over 40 different transmembrane target proteins, including Notch and amyloid precursor protein. ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. However, ADAM10 regulation remains poorly understood. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which are a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane "partner" proteins. This is achieved by specific tetraspanin-partner interactions, but it is not clear which tetraspanins specifically interact with ADAM10. The aims of this study were to identify which tetraspanins interact with ADAM10 and how they regulate this metalloprotease. Co-immunoprecipitation identified specific ADAM10 interactions with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the largely unstudied TspanC8 subgroup of tetraspanins, all six of which promoted ADAM10 maturation. Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33-deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. These results define TspanC8 tetraspanins as essential regulators of ADAM10 maturation and trafficking to the cell surface. This finding has therapeutic implications because focusing on specific TspanC8-ADAM10 complexes may allow cell type- and/or substrate-specific ADAM10 targeting.