Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling
Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling
复制标题
DOI：
10.1038/sj.onc.1210503
复制
发表时间：
2007-10-01
期刊：
影响因子：
8
通讯作者：
Yarden, Y.
中科院分区：
文献类型：
--
作者：
Shtiegman, K.;Kochupurakkal, B. S.;Yarden, Y.
表皮生长因子受体(EGFR)的激酶域中的几个不同的突变与非小细胞肺癌有关，但其致癌潜力的潜在机制尚不完全清楚。尽管正常情况下配体诱导的激酶激活以EGFR为靶标，Cbl介导的受体泛素化和随后在溶酶体中的降解，我们报告了某些EGFR突变体逃脱了这一调控。缺陷性内吞是EGFR的一个缺失突变和一个点突变(L858R-EGFR)，其与c-Cbl和泛素化的联系受到损害。我们的数据提出了这样一种可能性，即L858R-EGFR对下调的抵抗力是由于与癌基因产物HER2的异源二聚作用增强，从而导致持续刺激。
Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.