Antonyak M A, Moscatello D K, Wong A J
Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Biol Chem. 1998 Jan 30;273(5):2817-22. doi: 10.1074/jbc.273.5.2817.
Epidermal growth factor receptor (EGF) variant type III (EGFRvIII) is a constitutively active, naturally occurring mutation of the EGF receptor that is found in many types of human tumors. When overexpressed in NIH3T3 fibroblasts, EGFRvIII induces transformation by enhancing cell growth and reducing apoptosis. Analysis of downstream signaling pathways has revealed that extracellular signal-regulated kinase activity is down-regulated, raising doubt as to the significance of this pathway in promoting transformation. We investigated whether the c-Jun N-terminal kinase (JNK) pathway was affected by EGFRvIII. NIH3T3 cells expressing EGFRvIII exhibited a high basal level of JNK activity, which was not present in cells overexpressing the normal EGF receptor. Treatment of cells overexpressing EGFRvIII with inhibitors of the EGF receptor or phosphatidylinositol 3-kinase resulted in the down-regulation of JNK activity. Furthermore, the down-regulation of JNK activity was associated with a loss of properties related to transformation, and there was no evidence for JNK activity in the promotion of apoptosis in these cells. These findings implicate constitutive activation of the JNK pathway in transformation by EGFRvIII.
表皮生长因子受体（EGF）III型变体（EGFRvIII）是一种组成型激活的、在许多类型人类肿瘤中自然发生的EGF受体突变。当在NIH3T3成纤维细胞中过表达时，EGFRvIII通过增强细胞生长和减少凋亡诱导细胞转化。对下游信号通路的分析表明，细胞外信号调节激酶活性被下调，这使得人们对该通路在促进转化中的重要性产生怀疑。我们研究了c-Jun氨基末端激酶（JNK）通路是否受EGFRvIII影响。表达EGFRvIII的NIH3T3细胞表现出高水平的基础JNK活性，而过表达正常EGF受体的细胞中不存在这种活性。用EGF受体或磷脂酰肌醇3激酶抑制剂处理过表达EGFRvIII的细胞会导致JNK活性下调。此外，JNK活性下调与转化相关特性的丧失有关，并且没有证据表明JNK活性在促进这些细胞凋亡中起作用。这些发现表明JNK通路的组成型激活在EGFRvIII介导的转化中起作用。
