Related Experiment Video

Updated: Jun 19, 2025

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MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer

Olaf Klingbeil1, Damianos Skopelitis1, Claudia Tonelli1

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Cancer Discovery
|July 26, 2024
PubMed

Insights

Researchers identified MARK2/3 kinases as essential for YAP/TAZ function in cancer. Targeting these kinases with a CagA-based inhibitor regressed tumors, suggesting a new therapeutic strategy for Hippo pathway-dysregulated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • The Hippo signaling pathway is frequently dysregulated in human cancers, creating a dependency on YAP/TAZ transcriptional coactivators.
  • Understanding the regulatory mechanisms of YAP/TAZ is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To identify kinases critical for YAP/TAZ function using CRISPR screens.
  • To investigate MARK2/3 kinases as potential therapeutic targets in YAP/TAZ-driven cancers.

Main Methods:

  • Paralog cotargeting CRISPR screens were employed to identify essential kinases for YAP/TAZ activity.
  • The Helicobacter pylori CagA protein was adapted as a catalytic inhibitor of MARK2/3 kinases.
  • Tumor regression was assessed in vivo following inhibition of MARK2/3.

Main Results:

  • MARK2/3 kinases were identified as essential for YAP/TAZ function across various carcinoma and sarcoma types.
  • MARK2/3 directly phosphorylates NF2 and YAP/TAZ, counteracting the tumor-suppressive activity of LATS1/2.
  • Inhibition of MARK2/3 using the CagA-based strategy led to the regression of established tumors in vivo.

Conclusions:

  • MARK2/3 kinases represent key dependencies for YAP/TAZ in cancer.
  • Targeting MARK2/3 offers a potential therapeutic avenue to restore Hippo pathway tumor suppression in YAP/TAZ-dysregulated cancers.
  • This study highlights how genetic redundancy can mask critical signaling dependencies in cancer therapy.

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