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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Insulin receptor substrate 2: a bridge between Hippo and AKT pathways

Sun-Hye Jeong1, Dae-Sik Lim1

  • 1National Creative Research Initiatives Center, Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

BMB Reports
|April 28, 2018
PubMed

Insights

Non-alcoholic fatty liver disease (NAFLD) and liver cancer are linked. Disrupting the Hippo pathway and PTEN-AKT signaling promotes NAFLD and cancer by upregulating IRS2, but targeting AKT can prevent these conditions.

Area of Science:

  • Hepatology and molecular biology research.
  • Investigating liver disease mechanisms and cancer development.

Background:

  • Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH) and liver cancer.
  • Understanding NAFLD pathogenesis is crucial for prevention and treatment strategies.
  • The interplay between the Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis is not fully understood.

Discussion:

  • Depletion of PTEN and SAV1 in hepatocytes promotes NAFLD and liver cancer via AKT hyperactivity, driven by YAP/TAZ-mediated IRS2 upregulation.
  • NAFLD progression is reversed by YAP/TAZ ablation or Hippo pathway activation.
  • Human hepatocellular carcinoma (HCC) patients with NAFLD exhibit correlations between YAP/TAZ, IRS2, and phospho-AKT expression.

Key Insights:

  • The Hippo pathway and AKT signaling crosstalk through IRS2 to influence liver homeostasis and prevent NAFLD and cancer.
  • Hyperactive AKT signaling, driven by YAP/TAZ, promotes NAFLD and liver tumorigenesis.
  • Targeting AKT signaling with inhibitors like MK-2206 can attenuate NAFLD and cancer development.

Outlook:

  • Further elucidation of the Hippo-AKT-IRS2 axis in NAFLD and HCC.
  • Potential therapeutic strategies targeting this axis for NAFLD and liver cancer treatment.
  • Investigating the role of SAV1 in liver disease progression and cancer development.

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