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Updated: Oct 28, 2025

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Phosphorylation of intestine-specific homeobox by ERK1 modulates oncogenic activity and sorafenib resistance

Li-Ting Wang1, Kwei-Yan Liu2, Shyh-Shin Chiou3

  • 1Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.

Cancer Letters
|July 15, 2021
PubMed

Insights

Extracellular signal-regulated kinase 1 (ERK1) phosphorylates intestine-specific homeobox (ISX), promoting its nuclear entry and driving hepatocellular carcinoma (HCC) progression. This ERK1/ISX pathway is a potential therapeutic target for HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Mitogen-activated protein kinases (MAPKs) regulate nuclear translocation for target gene access, but their role in oncogenesis is not fully understood.
  • Mechanisms linking MAPK signaling to cancer-driving gene expression require elucidation.

Purpose of the Study:

  • To investigate the role of extracellular signal-regulated kinase 1 (ERK1) and intestine-specific homeobox (ISX) in hepatocellular carcinoma (HCC) progression.
  • To identify the specific phosphorylation site and downstream effects of ERK1 on ISX.

Main Methods:

  • Phosphorylation assays to identify the target site of ERK1 on ISX.
  • In vitro and in vivo experiments using hepatoma cells with dominant-negative ERK1 or mutated ISX.
  • Analysis of ERK1 and ISX expression in clinical HCC samples.

Main Results:

  • ERK1 specifically phosphorylates serine 183 of ISX, promoting its nuclear translocation and oncogenic signaling.
  • Inhibition of ERK1 reduces ISX nuclear translocation and downstream gene expression linked to proliferation, transformation, and epithelial-mesenchymal transition.
  • Mutated ISX (S183D) shows constitutive nuclear localization and sorafenib resistance.
  • ERK1 and ISX are co-expressed in HCC tissues and correlate with tumor progression and patient survival.

Conclusions:

  • The ERK1-mediated phosphorylation of ISX is a critical driver of HCC progression.
  • The ERK1/ISX signaling pathway represents a potential prognostic biomarker and therapeutic target for HCC.
Keywords:
Hepatocellular carcinoma (HCC)ISXMAPKNuclear translocationTyrosine kinase inhibitors (TKIs)

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