Transformational and altered signal transduction by a naturally occurring mutant EGF receptor.
Transformational and altered signal transduction by a naturally occurring mutant EGF receptor.
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发表时间：
1996-07
期刊：
影响因子：
8
通讯作者：
D. Moscatello;Montgomery Rb;P. Sundareshan;H. McDanel;Wong My;Albert J. Wong
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作者：
D. Moscatello;Montgomery Rb;P. Sundareshan;H. McDanel;Wong My;Albert J. Wong
表皮生长因子受体 (EGFRvIII) 的氨基截短变体形式已在人脑、乳腺、肺和卵巢肿瘤中被发现。我们发现，NIH3T3 细胞中这种突变型 EGF 受体的过度表达会导致受体激酶通过配体非依赖性二聚化激活而发生转化。转化与在过度表达正常 EGF 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 的细胞的进一步研究可能会深入了解与转化最相关的途径。在表达高水平突变型EGF受体的克隆中，Grb2和SHC的水平均下降。尽管出现这种下降，但大部分内源性 Grb2 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 负载量增加，而 MAP 激酶测定表明活性仅小幅增加。这些结果表明，EGFRvIII 的高水平表达诱导 ras-MAP 激酶途径的下调，并且参与 EGF 受体信号转导的其他成分可能在 EGFRvIII 的肿瘤转化中发挥更大的作用。
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.