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Review
. 2010 Jul 15;29(28):3997-4006.
doi: 10.1038/onc.2010.157. Epub 2010 May 17.

Nuclear trafficking of the epidermal growth factor receptor family membrane proteins

Y-N Wang  1 , H Yamaguchi, J-M Hsu, M-C Hung
Affiliations
Review

Nuclear trafficking of the epidermal growth factor receptor family membrane proteins

Y-N Wang et al. Oncogene. .

Abstract

Multiple membrane-bound receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR) and ErbB-2, have been reported to be localized in the nucleus, where emerging evidence suggests that they are involved in transcriptional regulation, cell proliferation, DNA repair and chemo- and radio-resistance. Recent studies have shown that endocytosis and endosomal sorting are involved in the nuclear transport of cell surface RTKs. However, the detailed mechanism by which the full-length receptors embedded in the endosomal membrane travel all the way from the cell surface to the early endosomes and pass through the nuclear pore complexes is unknown. This important area has been overlooked for decades, which has hindered progress in our understanding of nuclear RTKs' functions. Here, we discuss the putative mechanisms by which EGFR family RTKs are shuttled into the nucleus. Understanding the trafficking mechanisms as to how RTKs are transported from the cell surface to the nucleus will significantly contribute to understanding the functions of the nuclear RTKs.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A diagram of the EGFR family receptors trafficking. The endocytic vesicles carrying EGFR derived from either clathrin-dependent or clathrin-independent endocytosis subsequently fuse with the early endosomes. There are three possibilities of the internalized EGFR decided in the early endosomes. First, EGFR can be recycled back to the cell surface either through a rapid recycling or sorted to the recycling endosomes. Second, EGFR can also be sorted to the late endosomes and then degraded by lysosomes. The third and novel pathway is shown, by which the internalized EGFR embedded within the early endosomes is transported to the nucleus. Several potential mechanisms may be involved in the nuclear trafficking of the EGFR family receptors. For example, EGFR localized in the ER is extracted from lipid layers to the cytoplasm through the ERAD pathway, and the cytoplasmic EGFR is transported to the nucleus through the NPC. In addition to the ERAD pathway, other mechanisms such as retrograde transport from the early endosomes to the Golgi/ER may also exist. Furthermore, it is unexplored yet whether the nuclear transport of EGFR occurs from the recycling endosomes or the late endosomes. The scale of the diagram does not reflect the relative sizes of different molecules or subcellular structures. EV, endocytic vesicle; EE, early endosomes; LE, late endosomes; RE, recycling endosomes; NPC, nuclear pore complex; ER, endoplasmic reticulum.
Figure 2
Figure 2
A model of integral trafficking from the ER to the NE transport (INTERNET). Integral INM proteins initially inserted into the ER membrane are targeted to the INM of the NE through the ONM and NPC. This INTERNET model may be involved in the nuclear transport of other integral membrane proteins such as cell surface EGFR RTKs (see Table 1). The cognate receptor may also serve as an active transporter and form a ligand–receptor complex to transport the ligand into the nucleus. The scale of the diagram does not reflect the relative sizes of different molecules or subcellular structures. ONM, outer nuclear membrane; INM, inner nuclear membrane.
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