# PCK2

## Overview
Phosphoenolpyruvate carboxykinase 2 (PCK2) is a gene that encodes a mitochondrial enzyme involved in critical metabolic processes, particularly gluconeogenesis. The protein product of PCK2, phosphoenolpyruvate carboxykinase 2, is a key enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate, a pivotal step in glucose production from non-carbohydrate sources. This enzyme is predominantly expressed in the liver and kidney, where it integrates the tricarboxylic acid cycle with glycolysis, thereby playing a vital role in energy homeostasis (Yu2021Phosphoenolpyruvate). Beyond its metabolic functions, PCK2 is implicated in cellular stress responses and has been associated with various cancers, where its expression levels and mutations can influence tumor progression and patient prognosis (Xiong2020Restoring; Tang2023PCK2).

## Function
Phosphoenolpyruvate carboxykinase 2 (PCK2) is a mitochondrial enzyme that plays a crucial role in gluconeogenesis, the metabolic pathway that generates glucose from non-carbohydrate substrates. In healthy human cells, PCK2 catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) within the mitochondria. This conversion is essential for maintaining glucose homeostasis, particularly during periods of fasting or increased energy demand (Yu2021Phosphoenolpyruvate).

PCK2 is predominantly expressed in the liver and kidney, where it links the tricarboxylic acid (TCA) cycle with glycolysis, facilitating the cataplerotic processes that help maintain energy balance in cells (Yu2021Phosphoenolpyruvate). In pancreatic β-cells, PCK2 is involved in glucose-stimulated insulin secretion (GSIS) by utilizing mitochondrial GTP as a phosphate donor, providing a K+-ATP-independent mechanism for insulin release (Yu2021Phosphoenolpyruvate; Stark2009Phosphoenolpyruvate).

PCK2 also plays a role in the adaptation of cells to stress conditions, such as amino acid deprivation and endoplasmic reticulum stress, by participating in the integrated stress response (ISR) pathways. This function is crucial for maintaining cell survival under stress by reprogramming gene expression and metabolic functions (MéndezLucas2014Mitochondrial).

## Clinical Significance
PCK2 has been implicated in several types of cancer due to its altered expression and mutations. In renal cell carcinoma (RCC), PCK2 is significantly downregulated, which is associated with poor prognosis and shorter overall survival times. This downregulation is primarily due to DNA methylation, an epigenetic modification that silences the gene. Restoring PCK2 expression in RCC cells has been shown to suppress tumor progression and increase sensitivity to the drug sunitinib by promoting endoplasmic reticulum stress, which is crucial for inhibiting tumor growth and overcoming drug resistance (Xiong2020Restoring).

In hepatocellular carcinoma (HCC), a non-synonymous mutation in PCK2 was identified, which affects GTP binding and kinase activity. This mutation is associated with carcinoma cell proliferation, suggesting a potential role in HCC progression (LIU2012Wholeexome).

In lung adenocarcinoma, PCK2 expression is lower in tumor tissues compared to non-cancerous tissues. Higher PCK2 expression correlates with better overall survival and disease-specific survival. PCK2 is involved in preventing immune escape by tumor cells through oxidative stress-induced senescence, highlighting its potential as a therapeutic target (Tang2023PCK2).


## References


[1. (LIU2012Wholeexome) YAN-XUAN LIU, SHU-FANG ZHANG, YING-HUA JI, SHENG-JU GUO, GENG-FU WANG, and GUANG-WEN ZHANG. Whole-exome sequencing identifies mutated pck2 and huwe1 associated with carcinoma cell proliferation in a hepatocellular carcinoma patient. Oncology Letters, 4(4):847–851, July 2012. URL: http://dx.doi.org/10.3892/ol.2012.825, doi:10.3892/ol.2012.825. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/ol.2012.825)

[2. (MéndezLucas2014Mitochondrial) Andrés Méndez-Lucas, Petra Hyroššová, Laura Novellasdemunt, Francesc Viñals, and Jose C. Perales. Mitochondrial phosphoenolpyruvate carboxykinase (pepck-m) is a pro-survival, endoplasmic reticulum (er) stress response gene involved in tumor cell adaptation to nutrient availability. Journal of Biological Chemistry, 289(32):22090–22102, August 2014. URL: http://dx.doi.org/10.1074/jbc.M114.566927, doi:10.1074/jbc.m114.566927. This article has 207 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M114.566927)

[3. (Xiong2020Restoring) Zhiyong Xiong, Changfei Yuan, Jian shi, Wei Xiong, Yu Huang, Wen Xiao, Hongmei Yang, Ke Chen, and Xiaoping Zhang. Restoring the epigenetically silenced pck2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. Theranostics, 10(25):11444–11461, 2020. URL: http://dx.doi.org/10.7150/thno.48469, doi:10.7150/thno.48469. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.7150/thno.48469)

[4. (Yu2021Phosphoenolpyruvate) Shuo Yu, Simin Meng, Meixiang Xiang, and Hong Ma. Phosphoenolpyruvate carboxykinase in cell metabolism: roles and mechanisms beyond gluconeogenesis. Molecular Metabolism, 53:101257, November 2021. URL: http://dx.doi.org/10.1016/j.molmet.2021.101257, doi:10.1016/j.molmet.2021.101257. This article has 94 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.molmet.2021.101257)

[5. (Tang2023PCK2) Mingming Tang, Jianjun Sun, and Zhigang Cai. Pck2 inhibits lung adenocarcinoma tumor cell immune escape through oxidative stress-induced senescence as a potential therapeutic target. Journal of Thoracic Disease, 15(5):2601–2615, May 2023. URL: http://dx.doi.org/10.21037/jtd-23-542, doi:10.21037/jtd-23-542. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.21037/jtd-23-542)

[6. (Stark2009Phosphoenolpyruvate) Romana Stark, Francisco Pasquel, Adina Turcu, Rebecca L. Pongratz, Michael Roden, Gary W. Cline, Gerald I. Shulman, and Richard G. Kibbey. Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial gtp with insulin secretion. Journal of Biological Chemistry, 284(39):26578–26590, September 2009. URL: http://dx.doi.org/10.1074/jbc.m109.011775, doi:10.1074/jbc.m109.011775. This article has 130 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m109.011775)