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Updated: May 16, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src

Kenichi Ishibashi1, Yasunori Fukumoto, Hitomi Hasegawa

  • 1Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.

Journal of Cell Science
|December 12, 2012
PubMed

Insights

Epidermal growth factor receptor (EGFR) signaling antagonizes ErbB4 nuclear signaling. Epidermal growth factor (EGF) activates c-Src, which inhibits the nuclear accumulation of the ErbB4 intracellular domain (4ICD), thereby blocking gene expression changes.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Epigenetics

Background:

  • The ErbB family of receptor tyrosine kinases, including EGFR and ErbB4, are crucial for signal transduction.
  • Neuregulin-1 (NRG-1) stimulation leads to ErbB4 cleavage, releasing the intracellular domain (4ICD) that regulates gene expression in the nucleus.
  • The regulation of 4ICD nuclear signaling via tyrosine phosphorylation remains poorly understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms of ErbB4 nuclear signaling, specifically focusing on tyrosine phosphorylation.
  • To elucidate the role of EGFR and associated signaling pathways in modulating 4ICD nuclear functions.

Main Methods:

  • Investigated the interplay between NRG-1-induced ErbB4 activation and EGF-induced EGFR signaling.
  • Utilized techniques to assess nuclear accumulation of 4ICD and its tyrosine kinase activity.
  • Examined the impact of c-Src activation on histone modifications (H3K9me3) and gene expression (hTERT).

Main Results:

  • NRG-1 stimulation increases nuclear 4ICD accumulation and trimethylated histone H3 on lysine 9 (H3K9me3).
  • EGF-induced c-Src activation, downstream of EGFR, phosphorylates 4ICD at Tyr950 and Tyr1056.
  • c-Src phosphorylation of 4ICD inhibits its nuclear accumulation and H3K9me3 levels, consequently repressing hTERT transcription.

Conclusions:

  • c-Src acts as a negative regulator of ErbB4 nuclear signaling.
  • EGFR activation antagonizes NRG-1-mediated ErbB4 nuclear functions through c-Src.
  • This study reveals a novel inhibitory crosstalk between EGFR and ErbB4 nuclear signaling pathways.

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