Endosomal transport of ErbB-2: Mechanism for nuclear entry of the cell surface receptor

Dipak K. Giri, Mohamed Ali-Seyed, Long Yuan Li, Dung Fang Lee, Pin Ling, Geoffrey Bartholomeusz, Shao Chun Wang, Mien Chie Hung

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165 Citations (Scopus)


The cell membrane receptor ErbB-2 migrates to the nucleus. However, the mechanism of its nuclear translocation is unclear. Here, we report a novel mechanism of its nuclear localization that involves interaction with the transport receptor importin β1, nuclear pore protein Nup358, and a host of players in endocytic internalization. Knocking down importin β1 using small interfering RNA oligonucleotides or inactivation of small GTPase Ran by RanQ69L, a dominant-negative mutant of Ran, causes a nuclear transport defect of ErbB-2. Mutation of a putative nuclear localization signal in ErbB-2 destroys its interaction with importin β1 and arrests nuclear translocation, while inactivation of nuclear export receptor piles up ErbB-2 within the nucleus. Additionally, blocking of internalization by a dominant-negative mutant of dynamin halts its nuclear localization. Thus, the cell membrane-embedded ErbB-2, through endocytosis using the endocytic vesicle as a vehicle, importin β1 as a driver and Nup358 as a traffic light, migrates from the cell surface to the nucleus. This novel mechanism explains how a receptor tyrosine kinase on the cell surface can be translocated into the nucleus. This pathway may serve as a general mechanism to allow direct communication between cell surface receptors and the nucleus, and our findings thus open a new era in understanding direct trafficking between the cell membrane and nucleus.

Original languageEnglish
Pages (from-to)11005-11018
Number of pages14
JournalMolecular and Cellular Biology
Issue number24
Publication statusPublished - 2005 Dec 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Giri, D. K., Ali-Seyed, M., Li, L. Y., Lee, D. F., Ling, P., Bartholomeusz, G., Wang, S. C., & Hung, M. C. (2005). Endosomal transport of ErbB-2: Mechanism for nuclear entry of the cell surface receptor. Molecular and Cellular Biology, 25(24), 11005-11018. https://doi.org/10.1128/MCB.25.24.11005-11018.2005