Deletion of the ectodomain unleashes the transforming, invasive, and tumorigenic potential of the MET oncogene
Deletion of the ectodomain unleashes the transforming, invasive, and tumorigenic potential of the MET oncogene
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DOI：
10.1111/j.1349-7006.2008.01079.x
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发表时间：
2009-04-01
期刊：
影响因子：
5.7
通讯作者：
Prat, Maria
中科院分区：
文献类型：
--
作者：
Merlin, Simone;Pietronave, Stefano;Prat, Maria
c-MET原癌基因编码p190肝细胞生长因子酪氨酸激酶受体，可通过基因重排、扩增和过表达、点突变、异位表达等多种机制获得致癌潜能，导致其组成性激活。肝细胞生长因子受体的截断形式是由翻译后切割产生的：p140和p130缺乏激酶结构域并且不活跃。它们的c端残余片段在正常细胞中通常检测不到，但在一些人类肿瘤中，一种与膜相关的截断形式被抗c端抗体识别，这表明肝细胞生长因子受体缺乏外结构域，但保留跨膜和细胞内结构域（Met-EC-），可能获得致癌特性。本研究表明，用MET-EC-转导的NIH-3T3细胞表达了一种膜相关的组成型酪氨酸磷酸化的60 kda蛋白，并且与表达胞质癌蛋白tp - met的NIH-3T3细胞类似，显示了活化的细胞外调节激酶1/2丝裂原活化蛋白激酶和Akt下游转导。与对照NIH-3T3细胞相比，NIH-3T3- met - ec -细胞生长速度更快，表现出不依赖于锚定的生长和各方面的侵袭性，与表达转化TPR-MET的细胞相似。裸鼠雌性皮下注射NIH-3T3-Met-EC-细胞后可见肿瘤，呈典型的多角形细胞癌形态，与注射NIH-3T3-Tpr-Met细胞诱导的梭形细胞肉瘤形成鲜明对比。提示癌蛋白亚细胞定位的不同，而不是信号转导的差异，可能是导致肿瘤表型的原因。综上所述，这些数据表明外结构域的缺失激活了肝细胞生长因子受体及其下游信号通路，释放了其转化、侵袭和致瘤潜能。（癌症科学2009；100:633-638）
The c-MET proto-oncogene, encoding the p190 hepatocyte growth factor tyrosine kinase receptor, can acquire oncogenic potential by multiple mechanisms, such as gene rearrangement, amplification and overexpression, point mutation, and ectopic expression, all resulting in its constitutive activation. Hepatocyte growth factor receptor truncated forms are generated by post-translational cleavage: p140 and p130 lack the kinase domain and are inactive. Their C-terminal remnant fragments are generally undetectable in normal cells, but a membrane-associated truncated form is recognized by anti-C-terminus antibodies in some human tumors, suggesting that a hepatocyte growth factor receptor lacking the ectodomain, but retaining the transmembrane and intracellular domains (Met-EC-), could acquire oncogenic properties. Herein we show that NIH-3T3 cells transduced with MET-EC- expressed a membrane-associated constitutively tyrosine-phosphorylated 60-kDa protein and, similarly to NIH-3T3 cells expressing the cytosolic oncoprotein Tpr-Met, showed activated extracellular regulated kinase 1/2 mitogen-activated protein kinase and Akt downstream transducers. Compared to control NIH-3T3 cells, NIH-3T3-Met-EC- cells grew faster and showed anchorage-independent growth and invasive properties in all aspects similar to cells expressing the transforming TPR-MET. Nude female mice injected subcutaneously with NIH-3T3-Met-EC- cells developed visible tumors, displaying the typical morphology of carcinomas with polygonal cells, in contrast to sarcomas with spindle-shaped cells induced by the injection of NIH-3T3-Tpr-Met cells. It is suggested that the different subcellular localization of the oncoproteins, more than differences in signal transduction, could be responsible for the tumor phenotype. All together, these data show that deletion of the ectodomain activates the hepatocyte growth factor receptor and its downstream signaling pathways, unleashing its transforming, invasive, and tumorigenic potential. (Cancer Sci 2009; 100: 633-638)