The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Daqian Xu (), Zheng Wang, Yan Xia, Fei Shao, Weiya Xia, Yongkun Wei, Xinjian Li, Xu Qian, Jong-Ho Lee, Linyong Du, Yanhua Zheng, Guishuai Lv, Jia-shiun Leu, Hongyang Wang, Dongming Xing, Tingbo Liang, Mien-Chie Hung () and Zhimin Lu ()
Additional contact information
Daqian Xu: Zhejiang University School of Medicine
Zheng Wang: The University of Texas Health Science Center at Houston
Yan Xia: The University of Texas MD Anderson Cancer Center
Fei Shao: The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute
Weiya Xia: The University of Texas MD Anderson Cancer Center
Yongkun Wei: The University of Texas MD Anderson Cancer Center
Xinjian Li: Chinese Academy of Sciences
Xu Qian: Nanjing Medical University
Jong-Ho Lee: Dong-A University
Linyong Du: Wenzhou Medical University
Yanhua Zheng: The University of Texas MD Anderson Cancer Center
Guishuai Lv: Second Military Medical University
Jia-shiun Leu: Houston Methodist Research Institute
Hongyang Wang: Second Military Medical University
Dongming Xing: The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute
Tingbo Liang: Zhejiang University School of Medicine
Mien-Chie Hung: China Medical University
Zhimin Lu: The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute

Nature, 2020, vol. 580, issue 7804, 530-535

Abstract: 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 SREBPs1,2. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2183-2

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