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Src-dependent phosphorylation of the EGF receptor Tyr-845 mediates Stat-p21waf1 pathway in A431 cells

Ken-ichi Sato1, Tomomi Nagao, Tetsushi Iwasaki

  • 1Research Centre for Environmental Genomics, Department of Biology, Faculty of Science, Kobe University, Nada, Kobe 657-8501, Japan. kksato@kobe-u.ac.jp

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|January 31, 2004
PubMed
Abstract

Insights

The adaptor protein p52shc and epidermal growth factor (EGF) activate c-Src kinase, leading to the phosphorylation of the epidermal growth factor receptor (EGFR) at Tyr 845. This process promotes signal transducer and activator of transcription (Stat) 3/5 phosphorylation.

Area of Science:

  • Cellular signaling pathways
  • Receptor tyrosine kinases
  • Signal transduction

Background:

  • Epidermal growth factor receptor (EGFR) and c-Src tyrosine kinase cooperate in cellular processes.
  • Previous work showed p52shc/p66shc expression or EGF stimulation activates c-Src, leading to Stat phosphorylation in A431 cells.

Purpose of the Study:

  • Investigate the role of p52shc, EGF, and H2O2 in EGFR phosphorylation.
  • Determine the specific site of EGFR phosphorylation and its relationship with c-Src and Stat activation.

Main Methods:

  • Utilized A431 cells as a model system.
  • Employed phospho-Tyr 845-specific antibodies and dominant-negative c-Src.
  • Performed in vitro kinase assays with purified c-Src and EGFR.

Main Results:

  • p52shc expression, EGF, or H2O2 induced EGFR phosphorylation at Tyr 845, sensitive to PP2 but not AG1478.
  • EGFR Tyr 845 phosphorylation correlated with c-Src activation and Stat 3/5 phosphorylation, independent of MAP kinase.
  • Direct phosphorylation of EGFR Tyr 845 by c-Src was demonstrated in vitro.

Conclusions:

  • Src-dependent phosphorylation of EGFR at Tyr 845 is a key mechanism for Stat 3/5 activation.
  • Multiple signaling inputs converge on c-Src to regulate EGFR phosphorylation and downstream signaling.

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