EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins
EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins
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DOI：
10.1038/sj.onc.1209662
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发表时间：
2006-10-19
期刊：
影响因子：
8
通讯作者：
Lipkowitz, S.
中科院分区：
文献类型：
--
作者：
Davies, G. C.;Ryan, P. E.;Lipkowitz, S.
酪氨酸激酶（TK）如表皮生长因子受体（EGFR）的过度表达或突变可导致癌症的发展。胶质母细胞瘤中EGFR最常见的突变是外显子2-7的缺失，称为EGFRvIII。这种突变型受体不能结合EGF，而是具有组成性活性。泛素连接酶的Cbl家族（Cbl、Cbl-b和Cbl-c）靶向活化的EGFR进行降解。随着EGFRvIII的转化，我们研究了它是否可以被Cbl蛋白下调。所有三种Cbl蛋白的过表达导致EGFRvIII的泛素化和降解。与野生型EGFR一样，Cbl-b的TK结合结构域和RING指足以下调EGFRvIII。此外，我们发现Cbl-b被募集到EGFRvIII，并抑制NIH 3 T3细胞由EGFRvIII转化。EGFRvIII中Cbl结合位点（Y1045 F）的突变抑制其泛素化和通过Cbl-b的下调，并增强其转化能力。此外，EGFR TK抑制剂AG 1478防止Cbl蛋白下调EGFRvIII，并拮抗针对EGFRvIII的免疫毒素杀死表达该受体的细胞的能力。总之，EGFRvIII不会通过逃避Cbl蛋白的调节而转化，并且这种激活诱导的EGFRvIII下调在介导抗EGFRvIII免疫毒素的毒性中具有重要作用。
The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The overexpression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFRvIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.