Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin β1 and CRM1

Hui Wen Lo, Mohamed Ali-Seyed, Yadi Wu, Geoffrey Bartholomeusz, Sheng Chieh Hsu, Mien Chie Hung

Research output: Contribution to journalArticle

171 Citations (Scopus)

Abstract

Many receptor tyrosine kinases (RTKs) can be detected in the cell nucleus, such as EGFR, HER-2, HER-3, HER-4, and fibroblast growth factor receptor. EGFR, HER-2 and HER-4 contain transactivational activity and function as transcription co-factors to activate gene promoters. High EGFR in tumor nuclei correlates with increased tumor proliferation and poor survival in cancer patients. However, the mechanism by which cell-surface EGFR translocates into the cell nucleus remains largely unknown. Here, we found that EGFR co-localizes and interacts with importins α1/β1, carriers that are critical for macromolecules nuclear import. EGFR variant mutated at the nuclear localization signal (NLS) is defective in associating with importins and in entering the nuclei indicating that EGFR's NLS is critical for EGFR/ importins interaction and EGFR nuclear import. Moreover, disruption of receptor internalization process using chemicals and forced expression of dominant-negative Dynamin II mutant suppressed nuclear entry of EGFR. Additional evidences suggest an involvement of endosomal sorting machinery in EGFR nuclear translocalization. Finally, we found that nuclear export of EGFR may involve CRM1 exportin as we detected EGFR/CRM1 interaction and markedly increased nuclear EGFR following exposure to leptomycin B, a CRM1 inhibitor. Collectively, these data suggest the importance of receptor endocytosis, endosomal sorting machinery, interaction with importins α1/β1, and exportin CRM1 in EGFR nuclear-cytoplasmic trafficking. Together, our work sheds light into the nature and regulation of the nuclear EGFR pathway and provides a plausible mechanism by which cells shuttle cell-surface EGFR and potentially other RTKs through the nuclear pore complex and into the nuclear compartment.

Original languageEnglish
Pages (from-to)1570-1583
Number of pages14
JournalJournal of Cellular Biochemistry
Volume98
Issue number6
DOIs
Publication statusPublished - 15 Aug 2006
Externally publishedYes

Fingerprint

Karyopherins
Cell Nucleus Active Transport
Endocytosis
Nuclear Localization Signals
Receptor Protein-Tyrosine Kinases
Cell Nucleus
Sorting
Machinery
Tumors
Receptor, Fibroblast Growth Factor, Type 4
Dynamin II
Chemical Phenomena
Cells
Nuclear Pore
Neoplasms
Transcription
Macromolecules
Transcription Factors
Genes
Survival

Keywords

  • Cancer
  • CRM1
  • EGF receptor
  • Endocytosis
  • Endosomal sorting
  • Importin β1

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Lo, H. W., Ali-Seyed, M., Wu, Y., Bartholomeusz, G., Hsu, S. C., & Hung, M. C. (2006). Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin β1 and CRM1. Journal of Cellular Biochemistry, 98(6), 1570-1583. https://doi.org/10.1002/jcb.20876

Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin β1 and CRM1. / Lo, Hui Wen; Ali-Seyed, Mohamed; Wu, Yadi; Bartholomeusz, Geoffrey; Hsu, Sheng Chieh; Hung, Mien Chie.

In: Journal of Cellular Biochemistry, Vol. 98, No. 6, 15.08.2006, p. 1570-1583.

Research output: Contribution to journalArticle

Lo, HW, Ali-Seyed, M, Wu, Y, Bartholomeusz, G, Hsu, SC & Hung, MC 2006, 'Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin β1 and CRM1', Journal of Cellular Biochemistry, vol. 98, no. 6, pp. 1570-1583. https://doi.org/10.1002/jcb.20876
Lo, Hui Wen ; Ali-Seyed, Mohamed ; Wu, Yadi ; Bartholomeusz, Geoffrey ; Hsu, Sheng Chieh ; Hung, Mien Chie. / Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin β1 and CRM1. In: Journal of Cellular Biochemistry. 2006 ; Vol. 98, No. 6. pp. 1570-1583.
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