title: Identification of protein tyrosine phosphatase SHP-2 as a new target of perfluoroalkyl acids in HepG2 cells.
abstract: Perfluoroalkyl acids (PFAAs) are widespread environmental contaminants which have been detected in humans and linked to adverse health effects. Previous toxicological studies mostly focused on nuclear receptor-mediated pathways and did not support the observed toxic effects. In this study, we aimed to investigate the molecular mechanisms of PFAA toxicities by identifying their biological targets in cells. Using a novel electrochemical biosensor, 16 PFAAs were evaluated for inhibition of protein tyrosine phosphatase SHP-2 activity. Their potency increased with PFAA chain length, with perfluorooctadecanoic acid (PFODA) showing the strongest inhibition. Three selected PFAAs, 25 μM perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid, and PFODA, also inhibited SHP-2 activity in HepG2 cells and increased paxillin phosphorylation level. PFOA was detected in the immunoprecipitated SHP-2 from the cells exposed to 250 μM PFOA, providing unequivocal evidence for the direct binding of PFOA with SHP-2 in the cell. Molecular docking rationalized the formation of PFAA/SHP-2 complex and chain length-dependent inhibition potency. Our results have established SHP-2 as a new cellular target of PFAAs.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Yu
authors: Y
authors: Yang
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Qi-Yan
authors: QY
authors: Lv
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China. LHGuo@rcees.ac.cn.|Institute of Environment and Health, Jianghan University, Wuhan, 430056, China. LHGuo@rcees.ac.cn.
authors: Liang-Hong
authors: LH
authors: Guo
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Bin
authors: B
authors: Wan
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Xiao-Min
authors: XM
authors: Ren
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Ya-Li
authors: YL
authors: Shi
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China.
authors: Ya-Qi
authors: YQ
authors: Cai
mesh_terms: D017738:Alkanesulfonic Acids / Q000737:chemistry / Q000633:toxicity*; D015374:Biosensing Techniques; D002210:Caprylates / Q000737:chemistry / Q000633:toxicity*; D055664:Electrochemical Techniques; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D005466:Fluorocarbons / Q000737:chemistry / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D051419:Paxillin; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Cellular target; Inhibition; Perfluoroalkyl acids; Protein tyrosine phosphatase