Leung Kam
National Center for Biotechnology Information, NLM, NIH
The ephrin (Eph) receptors constitute the largest member of the receptor tyrosine kinase family (1, 2). The Eph receptors and their ligands (ephrins) mediate numerous biological processes in normal development, particularly in the nervous and cardiovascular systems (3-5). Based on their structures and sequence relationships, ephrins are divided into the ephrin-A class, which are anchored to the cell membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B class, which are transmembrane proteins. The Eph family of receptors is divided into two groups, EphA and EphB, on the basis of the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. The Eph receptors transmit forward signals their kinase domain and reverse signals their transmembrane ephrin ligands (6). EphB–ephrin-B interactions are capable of mediating bi-directional signaling events upon cell–cell contact, either into the receptor-expressing cell as "forward signaling" or into the ligand-expressing cell as "reverse signaling" (7). Ephrin-2 is expressed on arterial and activated endothelial cells, whereas EphB4 is normally expressed on venous endothelial cells and various blood cells (8). EphB4 selectively binds to ephrin-2 to promote cell signaling and angiogenesis. EphB4 has been implicated in cancer progression and in pathological forms of angiogenesis. Overexpression of EphB4 has been observed in cancer cells and is associated with tumorigenesis forward signaling and angiogenesis reverse signaling through ephrin-2 interaction (9). EphB4 forward signaling stimulates cellular proliferation. Koolpe et al. (10) identified a 15-mer peptide, Tyr-Asn-Tyr-Leu-Phe-Ser-Pro-Asn-Gly-Pro-Ile-Ala-Arg-Ala-Trp (TNYL-RAW), to be a selective antagonist of EphB4 using phage display screening. Xiong et al. (11) reported the development of Cu-tetraazacyclododecane-,','','''-tetraacetic acid-TNYL-RAW (Cu-DOTA-TNYL-RAW) for positron emission tomography (PET) imaging of EphB4 in nude mice bearing tumor xenografts. Zhang et al. (12) conjugated TNYL-RAW to polyethylene glycol–coated core-cross-linked polymeric micelles (CCPMs) labeled with Cy7 and In (In-TNYL-RAW-CCPM) for multimodality detection of EphB4 in tumors.
Eph受体是受体酪氨酸激酶家族中最大的成员（1, 2）。Eph受体及其配体（ephrin）在正常发育过程中，尤其是在神经和心血管系统中，介导众多生物学过程（3 - 5）。根据其结构和序列关系，ephrin分为A类ephrin，通过糖基磷脂酰肌醇连接锚定在细胞膜上；以及B类ephrin，为跨膜蛋白。Eph受体家族根据其胞外结构域序列的相似性以及与ephrin - A和ephrin - B配体结合的亲和力，分为EphA和EphB两组。Eph受体通过其激酶结构域传递正向信号，通过其跨膜ephrin配体传递反向信号（6）。EphB - ephrin - B相互作用能够在细胞 - 细胞接触时介导双向信号事件，要么作为“正向信号”传入表达受体的细胞，要么作为“反向信号”传入表达配体的细胞（7）。Ephrin - 2在动脉和活化的内皮细胞上表达，而EphB4通常在静脉内皮细胞和各种血细胞上表达（8）。EphB4选择性地与ephrin - 2结合以促进细胞信号传导和血管生成。EphB4与癌症进展和血管生成的病理形式有关。在癌细胞中观察到EphB4过表达，并且通过与ephrin - 2相互作用与肿瘤发生（正向信号传导）和血管生成（反向信号传导）相关（9）。EphB4正向信号传导刺激细胞增殖。Koolpe等人（10）通过噬菌体展示筛选鉴定出一种15肽，酪氨酸 - 天冬酰胺 - 酪氨酸 - 亮氨酸 - 苯丙氨酸 - 丝氨酸 - 脯氨酸 - 天冬酰胺 - 甘氨酸 - 脯氨酸 - 异亮氨酸 - 丙氨酸 - 精氨酸 - 丙氨酸 - 色氨酸（TNYL - RAW），作为EphB4的选择性拮抗剂。熊等人（11）报道了铜 - 四氮杂环十二烷 - 四乙酸 - TNYL - RAW（Cu - DOTA - TNYL - RAW）的开发，用于在携带肿瘤异种移植的裸鼠中对EphB4进行正电子发射断层扫描（PET）成像。张等人（12）将TNYL - RAW偶联到用Cy7和铟标记的聚乙二醇包被的核交联聚合物胶束（CCPMs）上（铟 - TNYL - RAW - CCPM），用于肿瘤中EphB4的多模态检测。
