國家衛生研究院 NHRI:Item 3990099045/10182
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    題名: Src-homology 2 domain-containing tyrosine phosphatase (SHP-2) controls aryl hydrocarbon receptor-mediated mitochondrial and ER stress response in mast cells
    作者: Wang, SK;Zhou, Y;Huang, SK
    貢獻者: National Institute of Environmental Health Sciences
    摘要: Background: Exposure of mast cells to AhR ligands resulted in activation of mast cells in vitro and in vivo. However, the underlying mechanisms remain to be fully elucidated. We tested a hypothesis that SHP-2 may integrate AhR-mediated Ca 2+ and ROS signals and control mast cell’s functions. Method: Mitochondrial membrane potential was measured with MitoHealth staining, and ROS production was determined with mitoSOX. Mitochondrial Ca 2+ was measured with genetically encoding probe and cytosolic Ca 2+ with Fluo-4/fura-red staining. ER stress response, including eIF2a phosphorylation, was assessed with Western blotting analysis. Physical interaction between adenylate kinase 2(AK2) and SHP-2 was examined by coimmunoprecipitation and Western blotting analysis. Results: We found that an AhR ligand, FICZ, induced a transient increase in mitochondrial SHP-2 activity and significant functional alteration in mitochondria, including decreased ATP synthesis, enhanced membrane potential loss and ROS generation, concomitant with a reduction of intracellular GSH. Significantly, we showed that in FICZ-treated mast cells, SHP-2 promoted, in a ROS-dependent manner, mitochondrial Ca 2+ uptake through Ca 2+ mobilization from the ER. This resulted in ER stress response involving primarily the PERK signaling pathway, ATF4 activation and eIF2a phosphorylation, which could be reversed by the addition of an anti-oxidant, NAC, and was inhibited in cells with SHP-2 knockdown. Moreover, SHP-2 was found to target AK2 in mitochondria and regulate AK2-dependent Ca 2+ entry into mitochondria. Conclusion: Our findings suggested that SHP-2 is critical in controlling ER and mitochondrial stress signals in response to AhR activation, providing a new regulatory pathway in mast cells.
    日期: 2016-08
    關聯: Allergy. 2016 Aug;71(Suppl. S102):126-127.
    Link to: http://dx.doi.org/10.1111/all.12972
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0105-4538&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000383679801026
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