title: Analysis of the cellular uptake and nuclear delivery of insulin-like growth factor binding protein-3 in human osteosarcoma cells.
abstract: Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF-I. Beyond that, IGF-independent actions mediated by intracellular IGFBP-3 including nuclear-IGFBP-3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP-3 to living cells results in rapid uptake and nuclear delivery of IGFBP-3, by yet partly unknown mechanisms. IGFBP-3 is internalized through a dynamin-dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP-3 containing structures to the nuclear envelope and found IGFBP-3 containing dot-like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.
authors.affiliation: Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
authors.forename: Lucia
authors.initials: L
authors.lastname: Micutkova
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Martin
authors.initials: M
authors.lastname: Offterdinger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hess
authors.forename: Andrea
authors.initials: A
authors.lastname: Matscheski
authors.forename: Haymo
authors.initials: H
authors.lastname: Pircher
authors.forename: Christoph
authors.initials: C
authors.lastname: Mück
authors.forename: Hannes-Leonhard
authors.initials: HL
authors.lastname: Ebner
authors.forename: Andreas
authors.initials: A
authors.lastname: Laich
authors.forename: Elisa
authors.initials: E
authors.lastname: Ferrando-May
authors.forename: Werner
authors.initials: W
authors.lastname: Zwerschke
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism*; D002458:Cell Fractionation / Q000379:methods; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism* / Q000493:pharmacokinetics; D018613:Microscopy, Confocal / Q000379:methods; D008854:Microscopy, Electron / Q000379:methods; D012516:Osteosarcoma / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins