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The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Daqian Xu1,2, Zheng Wang3, Yan Xia4,5

  • 1Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xudaqian@zju.edu.cn.

Nature
|April 24, 2020
PubMed

Insights

Activated AKT in cancer cells phosphorylates PCK1, which then activates SREBP proteins, promoting lipogenesis, tumor growth, and poor prognosis in hepatocellular carcinoma (HCC).

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • Cancer cells rely on increased lipogenesis for proliferation, a process centrally regulated by sterol regulatory element-binding proteins (SREBPs).
  • SREBP activation is normally inhibited by a complex involving INSIG proteins, SCAP, and sterols in the endoplasmic reticulum.
  • The precise regulatory mechanisms of this complex, particularly concerning oncogenic signaling, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of oncogenic signaling, specifically activated AKT, in regulating SREBP activation and lipogenesis in hepatocellular carcinoma (HCC).
  • To elucidate the molecular mechanism by which activated AKT influences the INSIG-SCAP interaction and subsequent SREBP activation.

Main Methods:

  • Utilized human hepatocellular carcinoma (HCC) cells and mouse models.
  • Investigated protein phosphorylation events using specific antibodies and cellular localization studies.
  • Analyzed the interaction between INSIG proteins and SCAP.
  • Assessed SREBP activation, lipogenesis-related gene transcription, cell proliferation, and tumorigenesis.
  • Correlated molecular findings with clinical data from HCC patients.

Main Results:

  • Activated AKT in HCC cells phosphorylates phosphoenolpyruvate carboxykinase 1 (PCK1) at Ser90.
  • Phosphorylated PCK1 translocates to the endoplasmic reticulum and phosphorylates INSIG1 and INSIG2, disrupting their interaction with SCAP.
  • This disruption leads to SCAP-SREBP complex translocation to the Golgi, SREBP activation, and increased lipogenesis-related gene expression.
  • PCK1, INSIG1, and INSIG2 phosphorylation correlates with SREBP1 nuclear accumulation and predicts poor HCC prognosis.
  • Inhibition of this pathway suppressed tumor growth in mice.

Conclusions:

  • Oncogenic AKT signaling activates SREBP-mediated lipogenesis in HCC through PCK1-dependent phosphorylation of INSIG proteins.
  • This pathway is crucial for tumor cell proliferation and tumorigenesis in HCC.
  • PCK1's kinase activity is highlighted as a key regulator in SREBP activation, lipogenesis, and HCC development.
  • Targeting this pathway presents a potential therapeutic strategy for HCC.

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