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Molecular and Cellular Biology, December 2005, p. 11005-11018, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.11005-11018.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endosomal Transport of ErbB-2: Mechanism for Nuclear Entry of the Cell Surface Receptor{dagger}

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

Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Received 20 April 2005/ Returned for modification 3 June 2005/ Accepted 21 September 2005

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 ß1, nuclear pore protein Nup358, and a host of players in endocytic internalization. Knocking down importin ß1 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 ß1 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 ß1 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.

* Corresponding author. Mailing address: Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 79, Houston, TX 77030. Phone: (713) 792-3668. Fax: (713) 794-0209. E-mail: mhung{at}mdanderson.org.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally.

Molecular and Cellular Biology, December 2005, p. 11005-11018, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.11005-11018.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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