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p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047

Seiji Adachi1, Hideo Natsume, Junichi Yamauchi

  • 1Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.

Cancer Letters
|January 14, 2009
PubMed

Insights

p38 mitogen-activated protein kinase (MAPK) directs epidermal growth factor receptor (EGFR) desensitization. This occurs through specific phosphorylation at Ser1046/7, impacting cancer cell regulation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR) desensitization is crucial for regulating cancer cell proliferation.
  • EGFR phosphorylation at Tyr1045 and Ser1046/1047 is implicated in desensitization, but the exact mechanism is unclear.
  • Understanding upstream signals controlling EGFR phosphorylation is vital for targeted cancer therapies.

Purpose of the Study:

  • To investigate the upstream signaling pathways regulating EGFR phosphorylation at Tyr1045 and Ser1046/1047.
  • To elucidate the specific roles of p38 MAPK and SAPK/JNK in EGFR desensitization.
  • To determine the contribution of p38 MAPK to EGFR internalization and degradation.

Main Methods:

  • Utilized SW480 colon cancer cells treated with anisomycin (kinase activator) and EGF.
  • Employed p38 MAPK inhibitor (SB203580) and p38 MAPK-siRNA for gene silencing.
  • Analyzed EGFR phosphorylation, internalization, and degradation using specific assays.

Main Results:

  • Anisomycin activated p38 MAPK and SAPK/JNK, leading to EGFR degradation, which was blocked by SB203580.
  • EGF induced EGFR phosphorylation at Tyr1045, while anisomycin induced phosphorylation at Ser1046/7.
  • Anisomycin-induced EGFR internalization was independent of c-Cbl, unlike EGF-induced internalization.

Conclusions:

  • p38 MAPK activation is essential for anisomycin-induced EGFR phosphorylation at Ser1046/7.
  • p38 MAPK signaling pathway mediates EGFR desensitization through Ser1046/7 phosphorylation.
  • This study identifies a novel mechanism for EGFR regulation in colon cancer cells.

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