Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor
Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor
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DOI：
10.1074/jbc.273.5.2817
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发表时间：
1998-01-30
影响因子：
4.8
通讯作者：
Wong, AJ
中科院分区：
文献类型：
--
作者：
Antonyak, MA;Moscatello, DK;Wong, AJ
表皮生长因子受体(EGF)变异型III(EGFRvIII)是一种天然存在的EGF受体的结构性活性突变，存在于多种类型的人类肿瘤中。当EGFRvIII在NIH3T3成纤维细胞中过表达时，通过促进细胞生长和减少凋亡来诱导转化，下游信号通路的分析显示细胞外信号调节的激酶活性下调，这使得人们对该途径在促进转化中的意义产生了怀疑，我们研究了c-Jun氨基末端激酶(JNK)途径是否受到EGFRvIII的影响。表达EGFRvIII的NIH3T3细胞表现出较高的基础水平的JNK活性，而正常EGF受体过表达的细胞不存在这一点，用EGF受体或磷脂酰肌醇3-激酶的抑制剂处理过表达的EGFRvIII细胞会导致JNK活性下调。此外，JNK活性的下调与与转化相关的性质的丧失有关，并且没有证据表明JNK活性促进了这些细胞的凋亡。这些发现表明，在EGFRvIII的转化过程中，JNK途径被结构性激活。
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.