Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis.
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.
Boerner
Julie L
JL
Department of Microbiology, The Cancer Center, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Biscardi
Jacqueline S
JS
Silva
Corinne M
CM
Parsons
Sarah J
SJ
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*
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