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Insulin receptor substrate 2: a bridge between Hippo and AKT pathways
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
Summary
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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