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Updated: Jun 7, 2025

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GADD45β-MTK1 signaling axis mediates oncogenic stress-induced activation of the p38 and JNK pathways

Saeko Kawataki1,2, Yuji Kubota1, Kotoe Katayama3

  • 1Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Cancer Science
|November 11, 2024
PubMed

Insights

Normal cells prevent cancer by activating stress pathways (p38/JNK) in response to abnormal ERK signaling. This study identifies GADD45β/MTK1 as crucial for this tumor suppression, revealing their downregulation in many cancers.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • The ERK pathway is vital for cell functions but its hyperactivation drives cancer.
  • Normal cells counter oncogenic ERK signaling via p38/JNK pathways, inducing cell cycle arrest or apoptosis.
  • The exact molecular mechanisms of this tumor-suppressive ERK-p38/JNK cross-talk are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mediators of oncogene-induced, ERK-dependent activation of p38/JNK signaling.
  • To investigate the role of MAP three kinase 1 (MTK1) in this stress response.
  • To explore the implications of this pathway in carcinogenesis and cancer development.

Main Methods:

  • Utilized gene knockout and transcriptome analyses.
  • Investigated the role of early growth response protein 1 (EGR1) and GADD45β in mediating signaling cross-talk.
  • Examined the expression patterns of key pathway components in cancer cells.

Main Results:

  • Demonstrated that MTK1 acts as a key mediator for p38/JNK activation by oncogenic ERK signaling.
  • Revealed that aberrant ERK signaling sustains EGR1 expression, promoting GADD45β production and activating MTK1-p38/JNK signaling.
  • Found that GADD45β/MTK1-mediated cross-talk upregulates genes involved in apoptosis and immune response.
  • Observed frequent downregulation of EGR1, GADD45β, and MTK1 in cancers with high ERK activity, disrupting tumor suppression.
  • Showed that restoring GADD45β expression suppresses tumorigenesis in cancer cells.

Conclusions:

  • Identified a novel GADD45β/MTK1-mediated mechanism for sensing and responding to oncogenic ERK stress.
  • Highlighted the disruption of this tumor-suppressive pathway as a critical event in cancer development.
  • Established the potential of targeting this pathway for cancer therapy by restoring GADD45β expression.
Keywords:
ERKJNKoncogeneoncogenic stressp38

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