title: Activated ErbB3 Translocates to the Nucleus via Clathrin-independent Endocytosis, Which Is Associated with Proliferating Cells.
abstract: Members of the receptor tyrosine kinase family (RTK) have been shown to be present in the nucleus of cells; however, the mechanisms underlying their trafficking to the nucleus, and their relevance once there are poorly understood. In the present study, we focus on the RTK ErbB3 and elucidate the mechanisms regulating its trafficking. We show that heregulin-stimulation induces trafficking of phosphorylated ErbB3 from the plasma membrane to the nucleus via a clathrin-independent mechanism. Nuclear import of ErbB3 occurs via importin β1, which drives the receptor through the nuclear pore complex. In the nucleus, ErbB3 interacts with transcription complexes, and thereby has a role in transcriptional regulation. Our results also demonstrate that ErbB3 nuclear localization is transient as it is exported out of the nucleus by the nuclear receptor protein crm-1. Analysis of normal, regenerating tissues, and tumors showed that ErbB3 nuclear translocation is a common event in proliferating tissues.
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany, reif@ifado.de.
authors.forename: Raymond
authors.initials: R
authors.lastname: Reif
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors.forename: Alshaimaa
authors.initials: A
authors.lastname: Adawy
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors.forename: Nachiket
authors.initials: N
authors.lastname: Vartak
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schröder
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Günther
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany, Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ghallab
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, 55131 Mainz, Germany, and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Biological Sciences, Sunnybrook Research Institute and Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Schormann
authors.affiliation: From the Leibniz Research Centre for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002966:Clathrin / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology; D022022:Nuclear Pore / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000097606:Exportin 1 Protein
chemical_list: D002966:Clathrin; D028884:Karyopherins; D020890:Neuregulin-1; D020893:Receptor, ErbB-3; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C581292:ERBB3 protein, human
keywords: nuclear translocation; proliferation; receptor endocytosis; receptor tyrosine kinase; signal transduction