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 cla...

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Bibliographic Details
Published in:Molecular carcinogenesis 2005-12, Vol.44 (4), p.262-273
Main Authors: Boerner, Julie L., Biscardi, Jacqueline S., Silva, Corinne M., Parsons, Sarah J.
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Bromodeoxyuridine
c-Src
Cells, Cultured
Chickens
DNA - biosynthesis
EGF receptor
endothelin
Endothelins - pharmacology
Fibroblasts - cytology
Fibroblasts - metabolism
growth hormone
Growth Hormone - pharmacology
Humans
Immunoprecipitation
lysophosphatidic acid
Lysophospholipids - pharmacology
Mice
Mice, Inbred C3H
Peptide Fragments - administration & dosage
Phosphorylation
Proto-Oncogene Proteins pp60(c-src) - physiology
Receptor, Epidermal Growth Factor - agonists
Receptor, Epidermal Growth Factor - metabolism
S Phase
STAT5 Transcription Factor - metabolism
Trans-Activators - physiology
Tyrosine - metabolism
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Summary: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. © 2005 Wiley‐Liss, Inc.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.20138