The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Nature. 2020 Apr;580(7804):530-535. doi: 10.1038/s41586-020-2183-2.

Daqian Xu ^# ¹ ², Zheng Wang ^# ³, Yan Xia ⁴ ⁵, Fei Shao ⁶, Weiya Xia ⁷, Yongkun Wei ⁷, Xinjian Li ⁸, Xu Qian ⁹, Jong-Ho Lee ¹⁰, Linyong Du ¹¹, Yanhua Zheng ⁴, Guishuai Lv ¹², Jia-Shiun Leu ¹³, Hongyang Wang ¹², Dongming Xing ⁶ ¹⁴, Tingbo Liang ¹⁵, Mien-Chie Hung ¹⁶, Zhimin Lu ¹⁷ ¹⁸

Affiliations

1 Department 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. [email protected].
2 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
3 The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
4 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6 The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China.
7 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
9 Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
10 Department of Biological Sciences, Dong-A University, Busan, South Korea.
11 Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
12 International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
13 Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
14 School of Life Sciences, Tsinghua University, Beijing, China.
15 Department 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.
16 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President, China Medical University, Taichung, Taiwan. [email protected].
17 The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China. [email protected].
18 Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
# Contributed equally.

PMID: 32322062 DOI: 10.1038/s41586-020-2183-2

Abstract

Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs^1,2. However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated Akt in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting Enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.

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