Abstract
Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease.
Highlights
Numerous Cell Surface Receptors Traffic to The NucleusDespite being comparatively understudied, the presence of cell surface receptors in the nucleus was reported as early as the 80s for the Insulin receptor (IR) and the epidermal growth factor receptor (EGFR) [1,2,3]
The nuclear localization concerns a great number of receptor tyrosine kinases (RTKs) with essential biological functions, such as the EGFR, its paralog ERB2, the fibroblast growth factor receptor 1 (FGFR-1), the vascular endothelial growth factor receptor 1 (VEGFR1) and the platelet derived growth factor receptor beta (PGDFR-b) [1,5,6,7]
A better knowledge of this trafficking pathway would provide the tools to better separate the effects of the nuclear pool of EGFR and those induced by the signal transduction cascades initiated from the plasma membrane or endosomal pools of the receptor
Summary
The presence of cell surface receptors in the nucleus was reported as early as the 80s for the Insulin receptor (IR) and the epidermal growth factor receptor (EGFR) [1,2,3]. Nuclear VEGFR2 has been shown to amplify angiogenic responses and regulates its own transcription This process requires phosphorylation of the receptor and stimulation by the VEGF ligand [27]. EGFR could regulate DNA repair and synthesis through the phosphorylation of Histone H4 [32] Consistent with these functions in the DNA repair, EGFR has reproducibly been shown to translocate to the nucleus after DNA damaging treatments such as cisplatin or radiation [18,31,33]. Overall, these proposed functions can explain why the nuclear accumulation of EGFR seems to be selected in cancer cells, especially in relapsing tumors. A better knowledge of this trafficking pathway would provide the tools to better separate the effects of the nuclear pool of EGFR and those induced by the signal transduction cascades initiated from the plasma membrane or endosomal pools of the receptor
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