Jacobsen J, Wewer U M
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Curr Pharm Des. 2009;15(20):2300-10. doi: 10.2174/138161209788682389.
ADAM12/meltrin alpha is a type I transmembrane multidomain protein involved in tumor progression and other severe diseases, including osteoarthritis, and as such could be considered as a potential drug target. In addition to protease activity, ADAM12 possesses cell binding and cell signaling properties. This functional trinity is reflected in the structure of ADAM12, which can be divided into head, body, and tail. The head of the protein (consisting of the pro and catalytic domains) mediates processing of growth factors and cytokines and has been implicated in epidermal growth factor (EGF) and insulin-like growth factor receptor signaling. The body of the protein (consisting of the disintegrin, cysteine-rich, and EGF-like domains) is involved in contacts with the extracellular matrix and other cells through interactions with integrins and syndecans. Finally, the tail of the protein (consisting of the cytoplasmic domain) is engaged in interactions with intracellular signaling molecules. In many studies, ADAM12 overexpression has been correlated with disease, and ADAM12 has been shown to promote tumor growth and progression in cancer. On the other hand, protective effects of ADAM12 in disease have also been reported. Future investigations should address the precise mechanisms of ADAM12 in disease and biology in order to counterbalance the benefits from targeting ADAM12 therapeutically with possible side effects. This review describes the biology of ADAM12, its association with disease, and evaluates the possible approaches to targeting ADAM12 in human disease.
ADAM12/解聚素金属蛋白酶12α是一种I型跨膜多结构域蛋白，参与肿瘤进展及包括骨关节炎在内的其他严重疾病，因此可被视为一种潜在的药物靶点。除蛋白酶活性外，ADAM12还具有细胞结合和细胞信号传导特性。这种功能三位一体体现在ADAM12的结构中，其可分为头部、主体和尾部。该蛋白的头部（由前结构域和催化结构域组成）介导生长因子和细胞因子的加工，并与表皮生长因子（EGF）和胰岛素样生长因子受体信号传导有关。该蛋白的主体（由解聚素结构域、富含半胱氨酸结构域和EGF样结构域组成）通过与整合素和多配体蛋白聚糖相互作用，参与与细胞外基质和其他细胞的接触。最后，该蛋白的尾部（由细胞质结构域组成）参与与细胞内信号分子的相互作用。在许多研究中，ADAM12的过表达与疾病相关，并且已证明ADAM12在癌症中促进肿瘤生长和进展。另一方面，也有报道称ADAM12在疾病中具有保护作用。未来的研究应探讨ADAM在疾病和生物学中的精确机制，以便在治疗上靶向ADAM12带来的益处与可能的副作用之间取得平衡。本综述描述了ADAM12的生物学特性、其与疾病的关联，并评估了在人类疾病中靶向ADAM12的可能方法。
