Epidermal Growth Factor Receptor Exposed to Oxidative Stress Undergoes Src- and Caveolin-1-dependent Perinuclear Trafficking
Epidermal Growth Factor Receptor Exposed to Oxidative Stress Undergoes Src- and Caveolin-1-dependent Perinuclear Trafficking
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DOI：
10.1074/jbc.m509332200
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发表时间：
2006-05-19
影响因子：
4.8
通讯作者：
Goldkorn, Tzipora
中科院分区：
文献类型：
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作者：
Khan, Elaine M.;Heidinger, Jill M.;Goldkorn, Tzipora
表皮生长因子（EGF）受体（EGFR）在几种类型的癌细胞中被发现过表达，其致瘤潜能的调控已被广泛研究。EGFR下调的模式涉及活化的受体分子从质膜运输，通过网格蛋白包覆的凹坑，进入细胞进行溶酶体降解。我们之前已经证明H2O2产生的氧化应激会导致EGFR的异常磷酸化。这导致c- cl介导的EGFR泛素化丧失，从而阻止其降解。然而，我们发现c- cl介导的泛素化仅仅是氧化应激下EGFR降解所必需的，而不是内化所必需的。为了进一步研究氧化应激下EGFR的命运，我们使用共聚焦分析表明，受体不仅在质膜上与小泡蛋白-1共定位，而且在更长的时间点上，也通过网格蛋白独立的、小泡介导的途径被分类到核周室。我们的研究结果表明，尽管EGFR与caveolin-1构成相关，但caveolin-1仅在氧化应激下被过度磷酸化，这对于将EGFR运输到核周位置至关重要，在那里它不会被降解并保持活性。因此，氧化应激不仅通过激活EGFR，而且通过促进质膜和细胞内受体的延长激活，可能在肿瘤发生中起作用。
The epidermal growth factor (EGF) receptor (EGFR) has been found to be overexpressed in several types of cancer cells, and the regulation of its oncogenic potential has been widely studied. The paradigm for EGFR down-regulation involves the trafficking of activated receptor molecules from the plasma membrane, through clathrin-coated pits, and into the cell for lysosomal degradation. We have previously shown that oxidative stress generated by H2O2 results in aberrant phosphorylation of the EGFR. This leads to the loss of c-Cbl-mediated ubiquitination of the EGFR and, consequently, prevents its degradation. However, we have found that c-Cbl-mediated ubiquitination is required solely for degradation but not for internalization of the EGFR under oxidative stress. To further examine the fate of the EGFR under oxidative stress, we used confocal analysis to show that the receptor not only remains colocalized with caveolin-1 at the plasma membrane, but at longer time points, is also sorted to a perinuclear compartment via a clathrin-independent, caveolae-mediated pathway. Our findings indicate that although the EGFR associates with caveolin-1 constitutively, caveolin-1 is hyperphosphorylated only under oxidative stress, which is essential in transporting the EGFR to a perinuclear location, where it is not degraded and remains active. Thus, oxidative stress may have a role in tumorigenesis by not only activating the EGFR but also by promoting prolonged activation of the receptor both at the plasma membrane and within the cell.