Tyrosine phosphorylation of Grb2: role in prolactin/epidermal growth factor cross talk in mammary epithelial cell growth and differentiation

Mol Cell Biol. 2009 May;29(10):2505-20. doi: 10.1128/MCB.00034-09. Epub 2009 Mar 9.

Abstract

Characterizing mechanisms regulating mammary cell growth and differentiation is vital, as they may contribute to breast carcinogenesis. Here, we examine a cross talk mechanism(s) downstream of prolactin (PRL), a primary differentiation hormone, and epidermal growth factor (EGF), an important proliferative factor, in mammary epithelial cell growth and differentiation. Our data indicate that EGF exerts inhibitory effects on PRL-induced cellular differentiation by interfering with Stat5a-mediated gene expression independent of the PRL-proximal signaling cascade. Additionally, our data show that PRL is a potent inhibitor of EGF-induced cell proliferation. We identify tyrosine phosphorylation of the growth factor receptor-bound protein 2 (Grb2) as a critical mechanism by which PRL antagonizes EGF-induced cell proliferation by attenuating the activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Together, our results define a novel negative cross-regulation between PRL and EGF involving the Jak2/Stat5a and Ras/MAPK pathways through tyrosine phosphorylation of Grb2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Communication / physiology
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Proliferation
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology*
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • GRB2 Adaptor Protein / genetics
  • GRB2 Adaptor Protein / metabolism*
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • MAP Kinase Signaling System / physiology*
  • Mammary Glands, Human / cytology*
  • Mammary Glands, Human / physiology
  • Phosphorylation
  • Prolactin / metabolism*
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tyrosine / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • GRB2 Adaptor Protein
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Tumor Suppressor Proteins
  • Tyrosine
  • Epidermal Growth Factor
  • Prolactin
  • JAK2 protein, human
  • Janus Kinase 2
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins