Emerging evidence suggests that some of the metabolic enzymes that catalyze the phosphorylation of metabolites can also act as protein kinases to phosphorylate various protein substrates, thereby regulating the cell cycle, apoptosis, and many other cellular processes. However, little is known about whether metabolic enzymes can act as dephosphorylated protein phosphatase proteins.
Yang Weiwei Research Group of Chinese Center for Excellence and Innovation in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology), Li Guohui Research Group of Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Professor Wang Xiongjun of Guangzhou University and Professor Li Quanlin of Zhongshan Hospital of Fudan University jointly published in Cell Research journal: Fructose-1, And 6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis's research paper.
This study revealed that the key gluconeogenic metabolic enzyme, fructose 1,6-diphosphatase 1 (FBP 1), can function as a protein phosphatase, and defined the key role of FBP 1-mediated dephosphorylation of I κ B α in colorectal carcinogenesis.
In this study, the research team conducted a high-throughput screening of metabolic phosphatases through molecular docking and molecular dynamics (MD) simulations, and found that FBP 1, a key metabolic enzyme in the gluconeogenic pathway, could be used as a protein phosphatase. FBP 1 is responsible for catalyzing the hydrolysis of fructose 1,6-diphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P).
The research team further identified I κ B α as a protein substrate for FBP 1 dephosphorylation by phosphoproteomic analysis. Mechanistically, under the stimulation of inflammatory factors such as TNF α, FBP 1 asparagine 213 (N213) directly interacts with I κ B α and dephosphorylates serine 32 / 36 of I κ B α (S32 / 36), thus inhibiting the activation of NF- κ B signaling. MD simulations show that the catalytic mechanism of FBP 1-mediated I κ B α dephosphorylation is similar to F-1,6-BP dephosphorylation, except that I κ B α dephosphorylation has a higher energy barrier.
Functionally, FBP 1-dependent inactivation of NF- κ B inhibits colorectal tumorigenesis by increasing the sensitivity of tumor cells to inflammatory stimuli and preventing the mobilization of bone marrow-derived suppressor cells (MDSCs). Moreover, FBP 1 expression in tumor tissues of colorectal cancer patients was correlated with NF- κ B activation, survival of tumor cells, and infiltration of MDSCs.
This work reveals the metabolic enzyme FBP 1 to exercise a novel function of protein phosphatase, identifies I κ B α as a protein substrate for FBP 1 dephosphorylation, and establishes the critical role and mechanism of FBP 1-mediated dephosphorylation of I κ B α in colorectal tumorigenesis.
Prof. Yang Weiwei of Molecular Cell Excellence Center of Chinese Academy of Sciences, Prof. Li Guohui of Dalian Institute of Chemical Physics, Professor Wang Xiongjun Wang of Guangzhou University, and Professor Li Quanlin from Zhongshan Hospital affiliated to Fudan University are the co-corresponding authors of the paper. Dr. Zhu Wencheng of Center of Excellence for Molecular Cell, Dr. Chu Huiying, associate researcher of Dalian Institute of Chemical Physics, Prof. Zhang Yajuan of Center of Excellence for Molecular Cells, Luo Tianhang, chief physician of Shanghai Changhai Hospital, and Dr. Yu Hua of Guangzhou University are co-first authors of this paper. The research work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program, and the Youth Basic Research Program of the Chinese Academy of Sciences. This research work was supported by the Molecular Cell Center of Excellence Cell Biology Technology platform, molecular biology technology platform, and animal experiment technology platform.
