PDF(Pubmed)
Abstract：
The protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a non-canonical, phosphorylation-independent 14-3-3 interaction site that encompasses all known TOC mutations. Disruption of this site dysregulates ADAM17 activity. The larger cub deletion also includes the TOC site and thus also dysregulated ADAM17 activity. The cub deletion, but not the TOC mutation, also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, demonstrating the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences, and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17.
摘要：
蛋白酶ADAM17在炎症和癌症中起重要作用，并受iRhom2调控。人iRhom2的胞浆N末端突变会导致食管癌（TOC）。在老鼠身上,N-末端的部分缺失导致卷发表型(幼崽)。这些病理结果与我们的发现一致，即iRhom2在角质形成细胞和食道癌中高表达。Cub和TOC与ADAM17依赖性EGFR信号的过度激活有关。然而,潜在的分子机制尚不清楚。我们已经确定了一个非规范的，不依赖磷酸化的14-3-3相互作用位点，包括所有已知的TOC突变。该位点的破坏使ADAM17活性失调。较大的幼崽缺失还包括TOC位点,因此也包括失调的ADAM17活性。幼崽的缺失，但不是TOC突变,也会导致刺激脱落的严重减少，绑定,和ADAM17的稳定性,证明在iRhom2的N端存在额外的调节位点。总的来说,这项研究对比了TOC和幼崽的突变，说明了它们不同的分子后果，并揭示了iRhom2N端在调节ADAM17中的重要关键功能。
