Agonistic monoclonal antibodies potentiate tumorigenic and invasive activities of splicing variant of the RON receptor tyrosine kinase
Agonistic monoclonal antibodies potentiate tumorigenic and invasive activities of splicing variant of the RON receptor tyrosine kinase
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DOI：
10.4161/cbt.5.9.3073
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发表时间：
2006-09-01
影响因子：
3.6
通讯作者：
Wang, Ming-Hai
中科院分区：
文献类型：
--
作者：
Yao, Hang-Ping;Luo, Yu-Lan;Wang, Ming-Hai
罗恩受体酪氨酸激酶的配体依赖性或非依赖性活化在转导导致致瘤活性增加的侵袭性信号中是必不可少的。在这项研究中，我们的特点是两个单克隆抗体（单克隆抗体）的细胞外结构域的人罗恩和研究其对致癌活性的激动作用介导的致癌变异罗恩德尔塔160。mAb Zt/g4和Zt/c1对人罗恩具有特异性。它们以高亲和力结合罗恩并识别罗恩胞外结构域上的不同表位。由于它们与天然罗恩的反应性，Zt/g 4和Zt/c1可用于各种应用，例如免疫沉淀、免疫荧光分析和免疫组织化学染色。功能研究表明，Zt/g4和Zt/c1能够诱导罗恩磷酸化，从而激活信号蛋白如Erk 1/2和Akt。在表达罗恩Delta 160的NIH 3 T3细胞中，两种mAb均显著增强罗恩Delta 160介导的致瘤活性，包括细胞增殖、病灶形成和锚定非依赖性生长。同时观察到细胞形态改变，运动和侵袭活动增加。体内研究进一步证明，Zt/g4和Zt/c1增加裸鼠中罗恩Delta 160介导的肿瘤生长，具有缩短的发病时间和增大的肿瘤体积。因此，通过识别罗恩胞外结构域上的特异性表位，Zt/g4和Zt/c1具有引发一系列RON介导的应答的能力。这些单克隆抗体将有助于研究罗恩激活导致致瘤活性增加的潜在机制。
Ligand-dependent or independent activation of the RON receptor tyrosine kinase is essential in transducing invasive signals leading to increased tumorigenic activities. In this study, we characterized two monoclonal antibodies (mAbs) specific to the extracellular domains of human RON and studied their agonistic effect on tumorigenic activities mediated by oncogenic variant RON Delta 160. The mAb Zt/g4 and Zt/c1 are specific to human RON. They bind to RON with high affinities and recognized different epitopes on the RON extracellular domain. Because of their reactivity with native RON, Zt/g4 and Zt/c1 are useful in various applications such as immunoprecipitation, immunofluorescent analysis, and immunohistochemical staining. Functional studies revealed that Zt/g4 and Zt/c1 are capable of inducing RON phosphorylation which activates signaling proteins such as Erk1/2 and Akt. In NIH3T3 cells expressing RON Delta 160, both mAbs significantly enhanced RON Delta 160-mediated tumorigenic activities including cell proliferation, focus formation, and anchorage-independent growth. Cell shape changes with increased motile and invasive activities were also observed. Studies in vivo further demonstrated that Zt/g4 and Zt/c1 increase RON Delta 160-mediated tumor growth in nude mice with a shortened time of onset and enlarged tumor volume. Thus, by recognizing specific epitopes on the RON extracellular domains, Zt/g4 and Zt/c1 have abilities to elicit a full array of RON-mediated responses. These mAbs will be useful in studying mechanisms underlying RON activation which lead to increased tumorigenic activities.