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JNK signaling is converted from anti- to pro-tumor pathway by Ras-mediated switch of Warts activity

Masato Enomoto1, Daisuke Kizawa1, Shizue Ohsawa1

  • 1Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Developmental Biology
|May 14, 2015
PubMed

Insights

Hyperactive Ras signaling switches the c-Jun N-terminal kinase (JNK) pathway

Area of Science:

  • Cellular signaling pathways
  • Oncogenesis
  • Developmental biology

Background:

  • The c-Jun N-terminal kinase (JNK) pathway exhibits dual roles in tumor development, acting as both an anti- and pro-tumorigenic factor.
  • The precise mechanisms governing JNK's context-dependent oncogenic functions remain unclear.
  • Understanding this switch is critical for comprehending tumorigenesis and normal tissue growth.

Purpose of the Study:

  • To elucidate the mechanism by which hyperactive Ras signaling modulates the JNK pathway's function.
  • To investigate how JNK signaling transitions between anti- and pro-tumorigenic roles.
  • To explore the role of Ras-mediated JNK switching in tissue growth and cancer.

Main Methods:

  • Utilized Drosophila melanogaster genetics to study signaling pathways in vivo.
  • Investigated the interplay between Ras, JNK, and Hippo signaling pathways.
  • Analyzed the regulation of Hippo pathway effectors, such as Yorkie (Yki).

Main Results:

  • Hyperactive Ras acts as a signaling switch, converting JNK's role from anti-tumor to pro-tumorigenic.
  • In normal epithelium, JNK antagonizes Hippo signaling by increasing Warts activity, suppressing growth.
  • In the presence of hyperactive Ras, JNK promotes tissue growth by enhancing Yorkie activation via Ajuba-mediated F-actin accumulation.
  • Epidermal growth factor receptor (EGFR) signaling utilizes this Ras-mediated JNK switch for growth promotion.

Conclusions:

  • Ras-mediated signaling dictates whether JNK suppresses or promotes tumor growth.
  • The JNK pathway's dual function is regulated by cellular context, particularly Ras activity.
  • This Ras-JNK-Hippo axis is crucial for both normal development and tumorigenesis.
Keywords:
Hippo signalingJNKRasTumor progression

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