Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family

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.

Figure 1

A summary of nuclear function of EGFR as a transcriptional co-activator. Nuclear EGFR can function in transcriptional regulation to enhance expression levels of target genes, including iNOS (A), cyclin D1 (B), COX-2 (C), Aurora-A (C), c-Myc (C), B-Myb (D), thymidylate synthase (E), and BCRP (E), through activation of transcriptional factors, such as STAT and E2F1. EGFR also associates with RHA in the nucleus, where the EGFR/RHA complex binds to the target gene promoter, including iNOS (A) and cyclinD1 (B), through the recruitment of RHA to the ATRS of the target gene promoter to mediate its transcriptional activation. In addition to RHA, EGFR is also recruited to the iNOS gene promoter through STAT3 to the STAT3-binding site (A). Whether RHA is involved in the nuclear EGFR-mediated activation of thymidylate synthase and BCRP (E) has not yet been explored.

Figure 2

A diagram of the EGFR family receptors trafficking to different compartments. The endocytic vesicles carrying EGFR can be transported from the cell surface to several intracellular organelles, including the Golgi apparatus, the ER, the mitochondria, and the nucleus. It has been documented recently that COPI vesicle-mediated retrograde transport from the Golgi to the ER is involved in the EGFR nuclear trafficking. Integral EGFR inserted into the ER membrane is targeted to the INM of the nuclear envelope (NE) through the ONM and NPC via a model of integral trafficking from the ER to the NE transport (INTERNET). The INM-embedded EGFR can be released from the lipid bilayer to the nucleoplasm within the nucleus by the association with the translocon Sec61β located in the INM. In addition to the nuclear import of cell surface EGFR, the internalized EGFR can also be trafficked to the mitochondria; however, the molecular mechanism underlying the cell surface-to-mitochondria trafficking of EGFR remains unclear. Whether the localization of EGFR in the mitochondria is involved in the EGFR trafficking to the Golgi, the ER, and the nucleus has not yet been explored. The scale of the diagram does not reflect the relative sizes of different molecules or subcellular structures. EV, endocytic vesicle; COPI: coat protein complex I; NPC, nuclear pore complex; ER, endoplasmic reticulum; ONM, outer nuclear membrane; INM, inner nuclear membrane.