Open AccessEndosomal Transport of ErbB-2: Mechanism for Nuclear Entry of the Cell Surface Receptor
Author(s) -
Dipak K. Giri,
Mohamed Ali-Seyed,
Long-yuan Li,
DungFang Lee,
Pin Ling,
Geoffrey Bartholomeusz,
ShaoChun Wang,
MienChie Hung
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.24.11005-11018.2005
Subject(s) - importin , nuclear transport , microbiology and biotechnology , biology , endocytic cycle , nucleoporin , internalization , ran , nuclear pore , nuclear localization sequence , cell nucleus , endocytosis , heterogeneous ribonucleoprotein particle , clathrin , nucleus , cell , biochemistry , rna binding protein , rna , gene
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.