Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis

Mol Carcinog. 2005 Dec;44(4):262-73. doi: 10.1002/mc.20138.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Bromodeoxyuridine
  • Cells, Cultured
  • Chickens
  • DNA / biosynthesis*
  • Endothelins / pharmacology
  • ErbB Receptors / agonists*
  • ErbB Receptors / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Growth Hormone / pharmacology
  • Humans
  • Immunoprecipitation
  • Lysophospholipids / pharmacology
  • Mice
  • Mice, Inbred C3H
  • Peptide Fragments / administration & dosage
  • Phosphorylation
  • Proto-Oncogene Proteins pp60(c-src) / physiology
  • S Phase
  • STAT5 Transcription Factor / metabolism
  • Trans-Activators / physiology*
  • Tyrosine / metabolism*


  • Endothelins
  • Lysophospholipids
  • Peptide Fragments
  • STAT5 Transcription Factor
  • Stat5b protein, mouse
  • Trans-Activators
  • Tyrosine
  • Growth Hormone
  • DNA
  • ErbB Receptors
  • Proto-Oncogene Proteins pp60(c-src)
  • Bromodeoxyuridine
  • lysophosphatidic acid