文章：

ADAMs：肿瘤微环境中的信号剪刀

The ADAMs: signalling scissors in the tumour microenvironment

原文发布日期：2008-11-01

DOI: 10.1038/nrc2459

类型: Review Article

开放获取: 否

要点：

1. ADAMs (a disintegrin and metalloproteinase) are membrane-associated metalloproteinases with a complex multi-domain structure. About half of the family have proteolytic potential, as well as domains with adhesive properties and a cytoplasmic domain involved in cell signalling.
2. The upregulation of proteolytic ADAMs has been documented for a number of cancers, with some correlation to parameters of disease progression.
3. The 'shedding' activities of ADAMs — cleaving transmembrane proteins and solubilizing the complete ectodomain of cytokines, growth factors, receptors and adhesion molecules — places them in pivotal positions in the extracellular regulation of cellular signalling. They can potentially regulate many activities within the tumour microenvironment, including inflammatory responses, immune regulation, angiogenesis, and cell migration and proliferation.
4. ADAM proteolysis has been implicated in key signalling pathways identified in many tumour cells. The generation of soluble ligands for the family of Erbb receptors, including in response to the activation of G-protein-coupled receptors and leading to epidermal growth factor receptor transactivation, have been described. ADAM sheddase activity appears to modulate the process of regulated intramembrane proteolysis (RIPping) by γ-secretase: the intracellular portions of transmembrane proteins are released either into proteasomal degradation pathways or into the cytosol prior to nuclear trafficking where they function as transcription factors.
5. ADAM activity is regulated in part by cellular trafficking and changes in the interaction with the membrane-bound substrate. Numerous protein adaptors and modulators that alter either enzyme activity or substrate availability have been documented and these may build specificity into ADAM sheddase activities in vivo.
6. The data from cell and animal models of cancer indicate that ADAM proteolytic activities could drive aspects of tumorigenesis. Before their consideration as therapeutic targets it will be necessary to further define the correlation of their expression in relation to different aspects of tumour development, and the mechanism by which they do this. Furthermore, the design of specific inhibitors, possibly targeting extracatalytic sites or adaptor proteins, will be essential.

要点翻译：

1. ADAMs（解整合素-金属蛋白酶）是一类具有复杂多结构域的膜结合金属蛋白酶。该家族约半数成员具有蛋白水解潜能，同时兼具粘附特性结构域及参与细胞信号转导的胞质结构域。
2. 多种癌症中均观察到蛋白水解型ADAMs的上调现象，且其表达水平与疾病进展参数存在一定相关性。
3. ADAMs的"脱落"活性——通过切割跨膜蛋白并将细胞因子、生长因子、受体及粘附分子的完整胞外域可溶化——使其在细胞信号转导的胞外调控中处于关键地位。它们可能调控肿瘤微环境中的多种活动，包括炎症反应、免疫调节、血管生成、细胞迁移与增殖。
4. 研究显示ADAM蛋白水解作用参与多种肿瘤细胞的关键信号通路。包括响应G蛋白偶联受体激活并导致表皮生长因子受体反式激活的Erbb受体家族可溶性配体的生成过程。ADAM脱落酶活性似乎通过γ-分泌酶调节受控膜内蛋白水解过程：跨膜蛋白的胞内区段被释放后，或进入蛋白酶体降解途径，或转运至胞质继而进行核转运发挥转录因子功能。
5. ADAM活性部分受细胞运输及与膜结合底物相互作用变化的调控。多种能改变酶活性或底物可用性的蛋白质衔接子和调节因子已被证实，这些元件可能赋予体内ADAM脱落酶活性特异性。
6. 来自癌症细胞和动物模型的数据表明，ADAM蛋白水解活性可能驱动肿瘤发生的某些环节。在将其作为治疗靶点前，需进一步明确其表达与肿瘤发展不同阶段的关联性及具体作用机制。此外，开发针对催化外位点或衔接蛋白的特异性抑制剂也至关重要。

英文摘要：

Over the last few years disintegrin metalloproteinases of the Adam (a disintegrin and metalloproteinase) family have been associated with the process of proteolytic 'shedding' of membrane-associated proteins and hence the rapid modulation of key cell signalling pathways in the tumour microenvironment. Furthermore, numerous members of the Adam family have been associated with tumorigenesis and tumour progression. The question now arises of whether pharmacological manipulation of their functions would be a useful adjunct to therapies targeting intercellular communications. To learn from the lessons of matrix metalloproteinase inhibitors as anticancer agents, there are many facets of the biological and clinical relevance of the ADAMs that need to be understood before embarking with confidence on such an approach.

摘要翻译： 

近年来，Adam（a disintegrin and metalloproteinase）家族的去整合素金属蛋白酶被发现与膜相关蛋白的蛋白水解“脱落”过程有关，从而能够快速调控肿瘤微环境中的关键细胞信号通路。此外，Adam家族的众多成员也与肿瘤发生和肿瘤进展相关。现在的问题是，对其功能进行药理学干预是否可作为靶向细胞间通讯治疗的有用辅助手段。借鉴基质金属蛋白酶抑制剂作为抗癌药物的经验，在 confidently 采取这种方法之前，仍需了解ADAMs在生物学和临床相关性方面的诸多层面。

原文链接：

The ADAMs: signalling scissors in the tumour microenvironment