The exon 19-deleted EGFR undergoes ubiquitylation-mediated endocytic degradation via dynamin activity-dependent and -independent mechanisms

作者：Taishu Wang, Jinrui Zhang, Shanshan Wang, Xiuna Sun, Duchuang Wang, Yurou Gao, Yang Zhang, Lu Xu, Yue Wu, Yueguang Wu, Fang Liu, Xiuxiu Liu, Shuyan Liu, Yingqiu Zhang, Yang Wang, Lijuan Zou, Han Liu · 发表于：Cell Communication and Signaling · 年份：2018 · DOI：10.1186/s12964-018-0245-y · 被引用次数：24 · 研究领域：Cellular transport and secretion、HER2/EGFR in Cancer Research、Receptor Mechanisms and Signaling

BACKGROUND: The epidermal growth factor receptor (EGFR) is closely implicated in cancer, and sequencing analyses have revealed a high mutation rate of EGFR in lung cancer. Recent advances have provided novel insights into the endocytic regulation of wild-type EGFR, but that of mutated EGFR remains elusive. In the present study, we aim to investigate the endocytic degradation of a frequently occurred exon 19-deleted mutant in lung cancer. METHODS: The EGF-induced endocytic degradation of EGFR was examined in a panel of lung cancer cells using immunoblotting. The subcellular distribution of internalized EGFR was investigated using immunofluorescence and confocal microscopy. The effects of dynamin were assessed using its small molecule inhibitors, while the influence of RTN3 was tested using shRNA-mediated knockdown. Finally the ubiquitylation status of EGFR mutant was studied using immunoprecipitation under steady state and tyrosine kinase inhibitor-treated conditions. RESULTS: EGF induced various rates of EGFR endocytic degradation in lung cancer cells. Interestingly, the exon 19 deletion mutant is constantly internalized and sorted to lysosome for degradation, and this process is independent of dynamin activity. EGF stimulation and HSP90 inhibition further enhance the endocytic degradation of the exon 19 deletion mutant, in a dynamin activity-dependent and -independent manner, respectively. Albeit with different modes of internalization, the uptake of the exon 19-deleted EGFR...