The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Xu, Daqian; Zheng, Wei; Xia, Yan; Shao, Fei; Xia, Weiya; Wei, Yongkun; Li, Xinjian; Qian, Xu; Lee, Jong Ho; Du, Linyong; Zheng, Yanhua; Lv, Guishuai; Leu, Jia-Shiun; Wang, Hongyang; Xing, Dongming; Liang, Tingbo; Hung, Mien‐Chie; Lu, Zhimin

doi:10.1038/s41586-020-2183-2

Cited by 229 publications

(178 citation statements)

References 36 publications

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“…We recently, for the first time, reported that PCK1 translocates to the ER and acts as a protein kinase phosphorylating Insigs for activating SREBP‐dependent lipogenesis and promoting tumor growth [29]. To determine how cancer cells regulate SREBP activation under sterol‐sufficient conditions, we treated Huh7 human hepatocellular carcinoma (HCC) cells with the insulin‐like growth factor 1 (IGF1), which induces the signaling that is critical for HCC development [30].…”

Section: Figurementioning

confidence: 99%

“…Notably, only AKT‐phosphorylated purified wide‐type PCK1, but not purified PCK1 S90A, interacted with purified Insig1/2. The expression of Insig1/2 truncation mutants revealed that the Insig1/2 loop 1 bound to PCK1 [29]. These results indicate that PCK1 S90 phosphorylation is required for PCK1's binding to Insig1/2.…”

Section: Figurementioning

confidence: 99%

“…In line with our previous report that metabolic enzymes could function as protein kinases, we revealed that PCK1 used GTP as the phosphate donor and phosphorylated Insig1 S207 and Insig2 S151 in vitro . This phosphorylation induced by IGF1 was abolished by knock‐in expression of PCK1 S90A [29], demonstrating that AKT‐phosphorylated PCK1 acts as a protein kinase to phosphorylate Insig1/2.…”

Section: Figurementioning

confidence: 99%

“…In addition, phosphorylation of AKT, PCK1 S90, Insig1 S207, and Insig2 S151 as well as SREBP1 cleavage were dramatically enhanced in normal liver from the mice refed with glucose after fasting, suggesting that blood glucose level in vivo regulates PCK1‐mediated Insig1/2 phosphorylation and SREBP1 activation in the liver, revealing a potential mechanism underlying overnutrition‐promoted non‐alcoholic fatty liver diseases. Notably, phosphorylation of AKT, PCK1 S90, Insig1 S207, and Insig2 S151 as well as SREBP1 cleavage were substantially increased in HCC cells compared with normal human hepatocytes [29], supporting that HCC cells with highly activated AKT have much elevated PCK1‐mediated SREBP1 activation.…”

Section: Figurementioning

confidence: 99%

“…The clinical relevance of PCK1‐regulated SREBP1 activation was demonstrated by analyses of primary HCC and adjacent normal tissue samples, which showed that PCK1 S90 and Insig1 S207/Insig2 S151 phosphorylation and nuclear SREBP1 expression were markedly increased in the HCC specimens and correlated with each other in HCC tumors. Importantly, the levels of PCK1 S90, Insig1 S207/Insig2 S151 phosphorylation, and nuclear SREBP1 expression in HCC samples were inversely correlated with overall survival durations of HCC patients [29].…”

Section: Figurementioning

confidence: 99%

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A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis

Jiang

Zhu

et al. 2020

Cancer Communications

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Highly active lipogenesis is essential for rapid tumor growth. Sterol regulatory element‐binding protein (SREBP) is a key transcriptional factor for lipogenesis and activated by reduced sterol and oxysterol levels. However, the mechanism by which cancer cells activate SREBP without altering these sterol/oxysterol levels remains elusive. In one of our recent studies published in Nature entitled “The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis”, we demonstrated that activated AKT‐mediated phosphoenolpyruvate carboxykinase 1 (PCK1) S90 phosphorylation reduces the gluconeogenic activity of PCK1 and triggers its translocation to the endoplasmic reticulum (ER), where PCK1 acts as a protein kinase and uses GTP, rather than ATP, as a phosphate donor to phosphorylate Insig1/2 thereby reducing oxysterol's binding to Insig1/2 and activating SREBP‐mediated lipogenesis for tumor growth. These findings elucidate a coordinated regulation between gluconeogenesis and lipogenesis and uncover a critical role of the protein kinase activity of PCK1 in SREBP‐dependent lipid synthesis.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis

Jiang

Zhu

et al. 2020

Cancer Communications

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Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies

Liu,

Hong,

Hou

et al. 2024

Advanced Biology

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Organelles, substructures in the cytoplasm with specific morphological structures and functions, interact with each other via membrane fusion, membrane transport, and protein interactions, collectively termed organelle interaction. Organelle interaction is a complex biological process involving the interaction and regulation of several organelles, including the interaction between mitochondria‐endoplasmic reticulum, endoplasmic reticulum‐Golgi, mitochondria‐lysosomes, and endoplasmic reticulum‐peroxisomes. This interaction enables intracellular substance transport, metabolism, and signal transmission, and is closely related to the occurrence, development, and treatment of many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Herein, the mechanisms and regulation of organelle interactions are reviewed, which are critical for understanding basic principles of cell biology and disease development mechanisms. The findings will help to facilitate the development of novel strategies for disease prevention, diagnosis, and treatment opportunities.

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Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

Shao,

Bai,

Zhu

et al. 2023

Adv Healthcare Materials

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Natural killer (NK) cells have emerged as an important contributor to cancer immunotherapy, but their antitumor efficacy remains suboptimal. While cytokine‐based priming shows promise in enhancing NK‐cell activity, its clinical translation faces many challenges, including co‐activation of multiple cytokines, poor pharmacokinetics, and limited mechanistic understanding. Here, we developed a polymeric micelle‐based IL‐15/IL‐2 codelivery system (IL‐15/2‐PEG‐PTMC) for NK‐cell activation. In vivo studies demonstrated that the half‐life of IL‐15 and IL‐2 as well as the recruitment of NK cell within tumor tissue was significantly increased after PEG‐PTMC loading. Coupled with the coactivation effect of IL‐15 and IL‐2 conferred by this polymeric micelle‐based system, it noticeably delayed the growth of tumors in mice compared to conventional NK cell activation approach, that was free IL‐15 and IL‐2. We also surprisingly found that cholesterol metabolism was highly involved in the NK cell activation by IL‐15/2‐PEG‐PTMC. Following stimulation with IL‐15/2‐PEG‐PTMC or IL‐15, NK cells underwent a series of cholesterol metabolism reprogramming, which elevated the cholesterol levels on the NK cell membrane. This in turn promoted the formation of lipid rafts and actived immune synapse, effectively contributing to the enhancement of the NK cell's anti‐tumor activity. We believe this will open a new avenue for improving the efficacy of NK cell immunotherapy by regulating cholesterol metabolism.This article is protected by copyright. All rights reserved

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The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Cited by 229 publications

References 36 publications

A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis

A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis

Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies

Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

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