Membrane-bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2

Abstract

Background: EGFR is translocated to the inner nuclear membrane through the INTERNET (integral trafficking from the ER to the nuclear envelope transport) pathway. Results: INTERNET regulates EGFR and ErbB-2 but not FGFR-1. Conclusion: At least two different pathways of nuclear transport exist for cell surface receptors.Significance: This provides a new direction for investigating the trafficking mechanisms of various nuclear RTKs.

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…In addition to recycling back to plasma membrane or undergoing lysosome-mediated degradation, a subset of EGFR molecules may be transported into the nucleus. Cell surface EGFRs are trafficked to the nucleus through a retrograde pathway from the Golgi to ER, and then to the inner nuclear membrane (584). The juxtamembrane region of EGFR harbors a putative nuclear localization signal (NLS) with three clusters of basic amino acids [RRRHIVRKRTLRR (amino acids 645-657)] that mediate the nuclear localization of EGFR (229).…”

Nuclear EGFR Suppresses Ribonuclease Activity of Polynucleotide Phosphorylase through DNAPK-mediated Phosphorylation at Serine 776

“…The isolated nuclei in the nuclear fractions extracted using cellular fractionation were resuspended in buffer A (0.25 M sucrose, 50 mM Tris-HCl, pH 7.4, 10 mM MgCl 2 , 1 mM dithiothreitol, and protease inhibitor mixture), incubated with 1% (w/v) sodium citrate at 4°C with gentle rotation for 30 min, and centrifuged at 500 ϫ g for 15 min. The pellet was resuspended in buffer A and digested with DNase I (250 mg/ml; Sigma) at 4°C for 14 h. After centrifugation at 10,000 ϫ g for 2 h, the supernatant was collected as an NP fraction, and the digested pellet was then recentrifuged at 100,000 ϫ g for 20 min in a sucrose gradient to obtain purified INM fractions (30,31). The membrane fraction collected at the 0.25-1.60 M sucrose interface contained the purified INM.…”

EGFR Modulates DNA Synthesis and Repair through Tyr Phosphorylation of Histone H4

“…Although it is conceptually difficult to accept that an integral membrane-embedded RTK can escape from the lipid bilayer and enter the nucleus, recent studies have provided a comprehensive model of integral membrane-embedded EGFR trafficking to the nucleus in a vesicle via COPI-mediated retrograde trafficking (Wang et al, 2012; Wang et al, 2010a; Wang et al, 2010c), which enables EGFR to stay in its membrane-embedded form throughout the entire trafficking pathway from the cell surface to the nucleus (Wang and Hung, 2012; Wang et al, 2010b). The current study further provides a comprehensive molecular mechanism governing the function of nEGFR, namely, the regulation of DNA synthesis and DNA repair through nEGFR-mediated H4-Y72 phosphorylation to enhance recruitment of SET8 and SUV4-20H for methylation at K20 of histone H4.…”