Maisel Sabrina, Broka Derrick, Schroeder Joyce
Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA.
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
Oncotarget. 2017 Dec 29;9(5):6463-6477. doi: 10.18632/oncotarget.23766. eCollection 2018 Jan 19.
The Epidermal Growth Factor Receptor (EGFR) is frequently mutated and overexpressed in metastatic cancer. Although EGFR is a transmembrane tyrosine kinase localized to the basolateral membrane in normal epithelium, it is frequently found intracellularly localized in transformed cells. We have previously demonstrated the epithelial adaptor protein mucin 1 (MUC1) alters trafficking of EGFR, inhibiting its degradation and promoting its translocation to the nucleus, where it can directly modulate gene transcription. Here, we demonstrate that MUC1 promotes the retention of EGF-bound EGFR in Early Endosome Antigen1 (EEA1)-positive vesicles while preventing its trafficking to the lysosome. These events result in the accumulation of endosomal vesicles harboring active receptor throughout the cell and a reorganization of the actin cytoskeleton. EGF-dependent cell migration and filopodia formation is reliant upon this altered trafficking, and can be prevented by blocking retrograde trafficking. Together, these results indicate that intracellular EGFR may play an essential role in cancer metastasis and a potential mechanism for the failure of therapeutic antibodies in EGFR-driven metastatic breast cancer.
表皮生长因子受体（EGFR）在转移性癌症中经常发生突变并过度表达。尽管EGFR是一种跨膜酪氨酸激酶，在正常上皮细胞中定位于基底外侧膜，但在转化细胞中它经常定位于细胞内。我们之前已经证明，上皮衔接蛋白粘蛋白1（MUC1）会改变EGFR的运输，抑制其降解并促进其转运至细胞核，在细胞核中它可以直接调节基因转录。在此，我们证明MUC1促进结合了表皮生长因子（EGF）的EGFR保留在早期内体抗原1（EEA1）阳性囊泡中，同时阻止其运输至溶酶体。这些事件导致整个细胞中含有活性受体的内体囊泡积累以及肌动蛋白细胞骨架的重组。EGF依赖性细胞迁移和丝状伪足形成依赖于这种改变的运输，并且可以通过阻断逆向运输来防止。总之，这些结果表明细胞内EGFR可能在癌症转移中起重要作用，并且是EGFR驱动的转移性乳腺癌中治疗性抗体失效的潜在机制。
