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CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer

Marie C Wesener1, Sofia M E Weiler1, Michaela Bissinger1

  • 1Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

International Journal of Molecular Sciences
|August 10, 2024
PubMed

Insights

Researchers identified CRKL as a new YAP regulator in liver cancer. Targeting CRKL or the JNK/JUN pathway may suppress YAP and improve outcomes for hepatocarcinoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The Hippo pathway, particularly YAP and TAZ, is crucial in liver tumorigenesis.
  • Inhibitors targeting YAP/TAZ are in clinical trials, but upstream regulators also present therapeutic targets.
  • Hepatocellular carcinoma (HCC) progression is linked to dysregulated YAP/TAZ activity.

Purpose of the Study:

  • To identify novel regulators of YAP/TAZ activity in HCC cells.
  • To investigate the role of CRKL in YAP regulation and HCC progression.
  • To explore therapeutic strategies targeting CRKL or downstream pathways.

Main Methods:

  • Proximity labeling (BioID) coupled with mass spectrometry to identify YAP interaction partners.
  • In vitro experiments to assess CRKL's function in cell survival and YAP binding.
  • Analysis of CRKL expression in HCC patient data and correlation with survival prognosis.

Main Results:

  • CRKL was identified as a YAP-exclusive interaction partner in HCC cells.
  • High CRKL expression in HCC patients correlates with YAP activity and poor survival.
  • CRKL promotes HCC cell survival and YAP transcription via JNK/JUN pathway activation.
  • Actin disruption disrupts the CRKL-YAP interaction.

Conclusions:

  • CRKL is a significant regulator of YAP activity in HCC, acting through direct binding and JNK/JUN pathway activation.
  • Targeting CRKL or the JNK/JUN pathway offers a potential therapeutic strategy for HCC.
  • CRKL represents a promising biomarker for YAP activity and patient prognosis in liver cancer.
Keywords:
AP1BioIDCRKHCCHippoMSTEADc-Junproteomicssurvival

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