title: Tyrosine residues within the intracellular domain of the erythropoietin receptor mediate activation of AP-1 transcription factors.
abstract: Binding of erythropoietin (Epo) to the Epo receptor (EpoR) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of AP-1 transcription factor(s). While Epo is known to activate c-fos gene expression, the mechanism of AP-1 activation is unknown. Here we show that AP-1 activation by Epo requires tyrosine kinase activity and also de novo protein synthesis. Using a mutant EpoR containing no cytosolic tyrosine residues, and a set of eight mutants containing a single cytosolic tyrosine residue, we show that multiple EpoR tyrosines, thought to activate multiple intracellular signal transduction proteins, can mediate AP-1 activation. An EpoR containing only tyrosine 343 or tyrosine 464 supports a maximal level of AP-1 activation. We also show that AP-1 activation does not require maximal STAT5 activation and may occur via a STAT5-independent signaling pathway.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bergelson
authors.forename: U
authors.initials: U
authors.lastname: Klingmüller
authors.forename: M
authors.initials: M
authors.lastname: Socolovsky
authors.forename: J G
authors.initials: JG
authors.lastname: Hsiao
authors.forename: H F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008894:Milk Proteins; D016297:Mutagenesis, Site-Directed; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000737:chemistry* / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000032:analysis*
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011500:Protein Synthesis Inhibitors; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014443:Tyrosine; D004247:DNA; D003513:Cycloheximide