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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

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Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway

Jung-Soon Mo1, Zhipeng Meng1, Young Chul Kim2

  • 1Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

Nature Cell Biology
|March 10, 2015
PubMed

Insights

Cellular energy stress activates AMPK, which inhibits the Hippo-YAP pathway by phosphorylating YAP. This finding reveals a new mechanism linking energy status to cancer cell growth and YAP activity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The Hippo-YAP pathway regulates cell growth and organ size, and its dysregulation is implicated in cancer.
  • Yes-associated protein (YAP) is a key co-activator in this pathway, promoting gene expression through interaction with TEAD transcription factors.
  • YAP activity is normally controlled by the kinase Lats, which phosphorylates YAP, leading to its degradation.

Purpose of the Study:

  • To investigate the role of cellular energy status in regulating the Hippo-YAP pathway.
  • To elucidate the molecular mechanisms by which energy stress affects YAP activity.
  • To explore the potential of targeting this pathway for cancer therapy.

Main Methods:

  • Investigated the effect of cellular energy stress on YAP phosphorylation and activity.
  • Utilized biochemical assays to determine the interaction between AMPK, Lats, and YAP.
  • Assessed the impact of AMPK-mediated YAP inhibition on oncogenic transformation in cancer cells.

Main Results:

  • Cellular energy stress triggers YAP phosphorylation via AMPK-dependent Lats activation, inhibiting YAP.
  • AMP-activated protein kinase (AMPK) directly phosphorylates YAP at Serine 94, disrupting YAP-TEAD interactions.
  • AMPK-induced YAP inhibition suppresses the oncogenic transformation of Lats-null cells with elevated YAP activity.

Conclusions:

  • AMPK acts as a crucial link between cellular energy status and the Hippo-YAP pathway.
  • AMPK-mediated YAP inhibition represents a novel mechanism to suppress cancer progression.
  • Targeting the AMPK-YAP axis could offer therapeutic strategies for cancers with dysregulated Hippo-YAP signaling.

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