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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.

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Acknowledgments

This work was supported by the Chinese Academy of Sciences (XDB14040100) and National Natural Science Foundation of China (Nos. 21321004, 21577163, 21377142, 21377145, 21477146, 21407168, 91543203).

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Correspondence to Liang-Hong Guo.

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Yu Yang and Qi-Yan Lv contributed equally to this work.

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Yang, Y., Lv, QY., Guo, LH. et al. Identification of protein tyrosine phosphatase SHP-2 as a new target of perfluoroalkyl acids in HepG2 cells. Arch Toxicol 91, 1697–1707 (2017). https://doi.org/10.1007/s00204-016-1836-2

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  • DOI: https://doi.org/10.1007/s00204-016-1836-2

Keywords

  • Perfluoroalkyl acids
  • Protein tyrosine phosphatase
  • Inhibition
  • Cellular target