Moscatello D K, Montgomery R B, Sundareshan P, McDanel H, Wong M Y, Wong A J
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Oncogene. 1996 Jul 4;13(1):85-96.
An amino-truncated variant form of the epidermal growth factor receptor (EGFRvIII) has been identified in human brain, breast, lung and ovarian tumors. We have found that overexpression of this mutant EGF receptor in NIH3T3 cells results in transformation as a result of the activation of the receptor kinase via ligand-independent dimerization. Transformation was correlated with tyrosine phosphorylation of only a subset of the proteins observed in cells overexpressing the normal EGF receptor. This suggested that further studies on cells expressing the EGFRvIII might provide insights into the pathways most relevant to transformation. In clones expressing high levels of mutant EGF receptor, the levels of both Grb2 and SHC were decreased. Despite this decrease, much of the endogenous Grb2 immunoprecipitated with EGFRvIII. Interestingly, no increase in ras-GTP loading was found in clones expressing the EGFRvIII and MAP kinase assays indicated only a small increase in activity. These results indicate that high-level expression of the EGFRvIII induces down-regulation of the ras-MAP kinase pathway and that other components involved in EGF receptor signal transduction may play a greater role in neoplastic transformation by the EGFRvIII.
在人脑、乳腺、肺和卵巢肿瘤中已鉴定出表皮生长因子受体（EGFRvIII）的一种氨基截短变异形式。我们发现，在NIH3T3细胞中这种突变型表皮生长因子受体的过表达会导致细胞转化，这是通过配体非依赖性二聚化激活受体激酶所致。转化与在过表达正常表皮生长因子受体的细胞中观察到的仅一部分蛋白质的酪氨酸磷酸化相关。这表明，对表达EGFRvIII的细胞进行进一步研究可能会为与转化最相关的信号通路提供见解。在表达高水平突变型表皮生长因子受体的克隆中，Grb2和SHC的水平均降低。尽管有这种降低，但许多内源性Grb2仍与EGFRvIII发生免疫沉淀。有趣的是，在表达EGFRvIII的克隆中未发现ras-GTP负载增加，并且丝裂原活化蛋白激酶（MAP激酶）检测表明活性仅略有增加。这些结果表明，EGFRvIII的高水平表达诱导ras-MAP激酶信号通路的下调，并且表皮生长因子受体信号转导中涉及的其他成分可能在EGFRvIII介导的肿瘤转化中发挥更大作用。
