title: Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor.
abstract: 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 beta1, nuclear pore protein Nup358, and a host of players in endocytic internalization. Knocking down importin beta1 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 beta1 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 beta1 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Giri
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ali-Seyed
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Pin
authors.initials: P
authors.lastname: Ling
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bartholomeusz
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Wang
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D028961:beta Karyopherins / Q000032:analysis / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D002966:Clathrin; D028884:Karyopherins; D018832:Molecular Chaperones; D019913:Nuclear Localization Signals; D028861:Nuclear Pore Complex Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D028961:beta Karyopherins; D020931:ran GTP-Binding Protein; D000097606:Exportin 1 Protein; C424166:KPNB1 protein, human; C094493:ran-binding protein 2