A point mutation in the MET oncogene abrogates metastasis without affecting transformation
A point mutation in the MET oncogene abrogates metastasis without affecting transformation
复制标题
DOI：
10.1073/pnas.94.25.13868
复制
发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Comoglio, PM
中科院分区：
文献类型：
--
作者：
Giordano, S;Bardelli, A;Comoglio, PM
MET癌基因编码肝细胞生长因子/分散因子（NGF）的酪氨酸激酶受体，已知其刺激上皮细胞的侵入性生长。MET在相当大比例的人类癌症中过表达，并且在原发性肿瘤和转移之间的过渡期间扩增。为了研究该癌基因是否直接负责转移表型的获得，我们开发了MET的单次击中致癌版本，其能够在体外和裸鼠中转化非致瘤细胞并赋予其侵袭性和转移性，我们诱变了Met的信号转导对接位点（（YVHVX 3 YVNV）-V-1349-V-1356），其具有结合和激活含有多个src同源区2（SH 2）的细胞内效应物的不寻常性质。值得注意的是，点突变（H-1351 --> N）增加了癌基因的转化能力，但消除了其转移潜力。该突变复制了Grb 2结合位点，超激活Ras途径并促进其他细胞内转导物的结合。与另一种非转移性突变体（N-1358 --> H）反式互补，招募Met下游除Grb 2外的所有转换器，拯救了侵袭性转移性表型。它的结论是，MET癌基因的转移潜力依赖于其多功能对接站点的属性，并且影响信号转导的单个点突变可以解离肿瘤转化转移。
The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (NGF, known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis, To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, we exploited a single-hit oncogenic version of MET, able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice, We mutagenized the signal transducer docking site of Met ((YVHVX3YVNV)-V-1349-V-1356), which has the uncommon property of binding and activating multiple src homology region 2 (SH2)-containing intracellular effecters. Notably, a point mutation (H-1351 --> N) increased the transforming ability of the oncogene but abolished its metastatic potential. This mutation duplicates the Grb2 binding site, super-activating the Ras pathway and pl eventing the binding of the other intracellular transducers. Complementation in trans with another nonmetastatic mutant (N-1358 --> H), recruiting all the transducers downstream to Met except Grb2, rescued the invasive-metastatic phenotype. It is concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.