Shtiegman K, Kochupurakkal B S, Zwang Y, Pines G, Starr A, Vexler A, Citri A, Katz M, Lavi S, Ben-Basat Y, Benjamin S, Corso S, Gan J, Yosef R B, Giordano S, Yarden Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 2007 Oct 25;26(49):6968-78. doi: 10.1038/sj.onc.1210503. Epub 2007 May 7.
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.
表皮生长因子受体（EGFR）激酶结构域内的几种不同突变与非小细胞肺癌相关，但其致癌潜力背后的机制尚未完全明确。虽然正常情况下，配体诱导的激酶激活会使EGFR靶向Cbl介导的受体泛素化，并随后在溶酶体中降解，但我们报告称某些EGFR突变体逃避了这种调节。内吞作用缺陷是EGFR缺失突变体以及点突变体（L858R-EGFR）的特征，它们与c-Cbl的结合及泛素化均受损。我们的数据提出了一种可能性，即L858R-EGFR对下调的难治性是由于与癌基因产物HER2的异源二聚化增强，从而导致持续刺激。
