title: Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis.
abstract: Signaling networks play important roles in cancer progression. For example, overexpression of the epidermal growth factor receptor (EGFR) is a poor prognostic indicator in multiple tumor types. Recent studies have postulated that the EGFR functions as a central conduit for signaling by different classes of cell surface receptors. In this study, we demonstrated that c-Src-dependent phosphorylation of tyrosine 845 (Tyr 845) on EGFR was required for DNA synthesis induced by the G protein-coupled agonists, endothelin (ET) and lysophosphatidic acid (LPA), and the cytokine, growth hormone (GH), in murine fibroblast and breast cancer model systems. In addition, we showed that a dominant interfering form of signal transducer and activator of transcription (STAT)5b (a downstream effector of phospho-Tyr 845 [pY845] in fibroblasts) abrogates DNA synthesis induced by all agonists in the breast cancer model. To further characterize the role of Tyr 845, a pY845-containing peptide was microinjected into SKBr3 breast cancer cells and murine fibroblasts, and was found to ablate EGF-stimulated S-phase entry in both cell systems. Taken together, these findings suggested that pY845 is critical for DNA synthesis induced by a variety of mitogens and that its signaling effectors may include but are not limited to STAT5b.
authors.affiliation: Department of Microbiology, The Cancer Center, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boerner
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Biscardi
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Silva
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parsons
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine; D002478:Cells, Cultured; D002645:Chickens; D004247:DNA / Q000096:biosynthesis*; D016232:Endothelins / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D013006:Growth Hormone / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D010446:Peptide Fragments / Q000008:administration & dosage; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D016196:S Phase; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D016232:Endothelins; D008246:Lysophospholipids; D010446:Peptide Fragments; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D013006:Growth Hormone; D004247:DNA; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D001973:Bromodeoxyuridine; C032881:lysophosphatidic acid