Mercurio Flavia A, Leone Marilisa
National Research Council (CNR) - Institute of Biostructures and Bioimaging, Via Mezzocannone 16, Naples 80134, Italy.
Curr Med Chem. 2016;23(42):4718-4734. doi: 10.2174/0929867323666161101100722.
Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be engaged against tumor malignancy.
We critically analyzed literature related to a) Eph receptors with particular emphasis on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions involving EphA2-Sam.
While literature data indicate that binding of EphA2-Sam to Ship2-Sam should largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2- Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due to the lack of a native like fold.
Molecule antagonists of heterotypic EphA2-Sam associations could work as potential anticancer agents or be implemented as tools to further clarify receptor functions and eventually validate its role as a novel target in the field of anti-cancer drug discovery. Due to the failure of linear peptides there is a crucial need for novel approaches, based on cyclic or helical molecules, to target Sam-Sam interfaces.
Eph受体在发育过程和疾病中发挥重要作用，其中EphA2因其在癌症中的争议性作用而广为人知。药物发现策略主要集中在EphA2细胞外配体结合域，然而，该受体在C端还含有一个很大程度上未被探索的胞质Sam（无活性α基序）结构域。EphA2-Sam与脂质磷酸酶Ship2的Sam结构域以及Odin的第一个Sam结构域结合。Sam-Sam相互作用对于调节配体诱导的受体内吞和降解可能很重要，即这些过程可能与肿瘤恶性程度相关。
我们批判性地分析了与以下方面相关的文献：a）Eph受体，特别强调EphA2及其在癌症中的作用；b）Sam结构域；c）涉及EphA2-Sam的异型Sam-Sam相互作用。
虽然文献数据表明EphA2-Sam与Ship2-Sam的结合在很大程度上应在癌细胞中产生促癌作用，但EphA2-Sam/Odin-Sam1复合物与疾病之间的相关性尚不清楚。最近，一些包含来自Ship2-Sam和Odin-Sam1结合界面的线性肽已被表征，但由于缺乏天然样折叠，未能有效阻断涉及EphA2-Sam的异型Sam-Sam相互作用。
异型EphA2-Sam关联的分子拮抗剂可作为潜在的抗癌药物，或用作进一步阐明受体功能并最终验证其作为抗癌药物发现领域新靶点作用的工具。由于线性肽的失败，迫切需要基于环状或螺旋状分子的新方法来靶向Sam-Sam界面。
