iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding
iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding
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DOI：
10.1073/pnas.1302553110
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发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Blobel, Carl P.
中科院分区：
文献类型：
--
作者：
Maretzky, Thorsten;McIlwain, David R.;Blobel, Carl P.
由ADAM 17（一种去整合素和金属蛋白酶17）（EGF受体信号传导和TNF α释放的主要调节剂）引起的蛋白质胞外结构域脱落被多种信号传导途径快速地和事后地激活，但对潜在的机制知之甚少。在这里，我们报告说，无活性菱形蛋白2（iRhom 2），最近被确定为在造血细胞中的ADAM 17的成熟所必需的，是至关重要的快速激活脱落的一些，但不是所有的底物的ADAM 17。成熟的ADAM 17存在于缺乏iRhom 2的小鼠胚胎成纤维细胞（mEF）中，但ADAM 17不能支持其几种底物的刺激脱落，包括肝素结合EGF和Kit配体2。其他ADAM 17底物（如TGF α）的刺激脱落在iRhom 2（-/-）EFs中不受影响，但可通过用针对iRhom 1的siRNA处理iRhom 2（-/-）EFs强烈降低。在iRhom 2（-/-）EFs中由ADAM 17引起的肝素结合EGF或Kit配体2脱落的激活可以被野生型iRhom 2拯救，但不能被缺乏其N-末端胞质结构域的iRhom 2拯救。iRhom 2的胞质结构域对ADAM 17刺激脱落的需求可能有助于解释为什么ADAM 17的胞质结构域对刺激脱落不需要。iRhom 2在调节EGF受体（EGFR）配体脱落中的功能相关性通过在iRhom 2（-/-）mEF中缺乏与ERK 1/2的溶血磷脂酸/ADAM 17/EGFR依赖性串扰以及iRhom 2（-/-）角质形成细胞的FGF 7/ADAM 17/EGFR刺激的迁移的显著减少来建立。综上所述，这些发现揭示了iRhom 2在EGFR信号传导调节和控制ADAM 17依赖性脱落事件的活化和底物选择性中的功能。
Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNF alpha release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGF alpha, is not affected in iRhom2(-/-) EFs but can be strongly reduced by treating iRhom2(-/-) EFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2(-/-) EFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2(-/-) mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2(-/-) keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.