Abstract
Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application.
Highlights
Receptor tyrosine kinases (RTKs), which contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain, mediate cellular signal transduction by extracellular ligand binding
Wang et al [37] reported that γ-COP, one of the subunits of the complex I (COPI) coatomer, associates with epidermal growth factor receptor (EGFR) and mediates EGF-dependent EGFR nuclear transport. These findings suggest that endosomal membrane-embedded cell surface EGFR in a membrane-associated environment travels from the cell surface to the nucleus within the Golgi and endoplasmic reticulum (ER) membranes via COPI-mediated vesicle trafficking
Researchers discovered a logical route for the nuclear translocation of EGFR in response to EGF, in which cell surface EGFR travels to the nucleus, all the way in a membrane-bound environment, through the Golgi-to-ER retrograde pathway and INTERNET model to the inner nuclear membrane (INM) in the nucleus [37,38]
Summary
Receptor tyrosine kinases (RTKs), which contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain, mediate cellular signal transduction by extracellular ligand binding. In line with the studies of nuclear EGFR, nuclear ErbB-2 can transactivate COX2 gene expression through binding to a specific DNA element, the HER2-associated sequence, within the promoter, whereas the transcriptional factors involved remain to be identified [68]. A series of studies showed that DNA damage pathways, such as those activated by ultraviolet irradiation or cisplatin treatment, can induce the interaction between nuclear EGFR and DNA-dependent protein kinase (DNA-PK) [15,50,60], which is a central enzyme of the nonhomologous end-joining repair of DNA double-strand breaks, contributing to DNA repair and chemo- and radio-resistance It is not yet clear but worthwhile to determine whether EGFR phosphorylates DNA-PK to regulate its activity. This Sec61β-mediated ERassociated degradation model in regulating EGFR nuclear trafficking needs to be further verified since researchers could not detect EGFR in the cytoplasm in EGF-treated cells [32]
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