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Engrailed 2 triggers the activation of multiple phosphorylation-induced signaling pathways in both

Yong Cao1, Jie Jiang2, Xueqin Song1

  • 1Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Luzhou Key Laboratory of Molecular Cancer, Luzhou, 646000, Sichuan, China.

Biochemical and Biophysical Research Communications
|September 22, 2023
PubMed

Insights

Engrailed 2 (EN2) protein, beyond its transcription factor role, activates cancer signaling pathways. Blocking these pathways, including NF-κB and AKT, shows therapeutic promise for esophageal squamous cell carcinoma (ESCC).

Area of Science:

  • Molecular biology
  • Cancer research
  • Signal transduction

Background:

  • Homeodomain (HD)-containing proteins, like Engrailed 2 (EN2), are known transcription factors.
  • EN2 is highly expressed in various cancers, but its precise biological functions remain unclear.
  • Understanding EN2's mechanisms is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the transcription-independent functions of Engrailed 2 (EN2).
  • To identify signaling pathways regulated by EN2.
  • To explore therapeutic strategies targeting EN2 in cancer, specifically esophageal squamous cell carcinoma (ESCC).

Main Methods:

  • Phosphoproteomic analysis to identify altered protein phosphorylation sites upon EN2 expression.
  • Immunoprecipitation-mass spectrometry (IP-MS) to detect protein interactions.
  • Validation of EN2 interaction with PP2A-B55α complex and assessment of its phosphatase activity.
  • Pharmacological inhibition of EN2-activated NF-κB and AKT signaling pathways.

Main Results:

  • EN2 exhibits transcription-independent functions, activating multiple signaling pathways via phosphorylation cascades.
  • EN2 interacts with numerous proteins involved in phosphorylation signaling, including B55α, suppressing PP2A-B55α phosphatase activity.
  • Simultaneous inhibition of EN2-activated NF-κB and AKT pathways demonstrated synergistic effects.

Conclusions:

  • EN2 possesses significant transcription-independent roles in cancer progression.
  • EN2's interaction with PP2A-B55α and subsequent pathway activation contribute to malignancy.
  • Targeting EN2-mediated signaling pathways offers a potential therapeutic strategy for ESCC.
Keywords:
Engrailed 2Esophageal squamous cell carcinomaHomeobox genesProtein phosphorylation modification

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