title: Cytoplasmic transport of Stat3 by receptor-mediated endocytosis.
abstract: Signal transducer and activator of transcription (STAT) proteins are cytoplasmic transcription factors that translocate to the nucleus and regulate gene expression upon activation of cytokine or growth factor receptors. While this translocation event is essential for gene regulation by STATs, their mechanism of transport through the cytoplasm to the nucleus has remained elusive. We now report that cytoplasmic transport of Stat3 is an active process that requires receptor-mediated endocytosis. Stat3 co-localizes with endocytic vesicles in transit from the cell membrane to the perinuclear region in response to growth factor stimulation. Consistent with a role for receptor endocytosis in growth factor signaling, disruption of endocytosis with specific inhibitors blocks Stat3 nuclear translocation and Stat3-dependent gene regulation. These results indicate that receptor-mediated endocytosis may be a general mechanism of transport through the cytoplasm for a subset of cytoplasmic signaling proteins destined for the nucleus.
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D017930:Genes, Reporter; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001152:Arsenicals; D002352:Carrier Proteins; D002966:Clathrin; D004268:DNA-Binding Proteins; C486204:EPN2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011506:Proteins; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C029341:oxophenylarsine; C075637:amphiphysin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors