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Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization
Author(s) -
Lee So Young,
Lee Yun Young,
Choi Joong Sub,
Kim Kyeong Soo,
Min Do Sik,
Park ShinYoung,
Han Joong Soo
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001212r
Subject(s) - decidualization , microbiology and biotechnology , protein phosphatase 2 , chemistry , phosphorylation , biology , phosphatase , embryo
Decidualization of the endometrial stroma is an essential differentiation process for embryo implantation and maintenance of pregnancy. We previously reported that protein phosphatase 2A (PP2A) acts as a key mediator during cAMP‐induced decidualization of human endometrial stromal cells (hESCs). However, the mechanism underlying its activation has remained obscure in hESCs. In the present study, we aimed to reveal the mechanism that induces the nitration of PP2A catalytic subunit (PP2Ac) during cAMP‐induced decidualization of hESCs. First, cAMP‐induced PP2Ac nitration was significantly repressed using L‐NAME, an inhibitor of nitric oxide synthase (NOS). Among several NOS isoforms, only inducible NOS (iNOS) was highly expressed in hESCs, indicating that iNOS directly induces the nitration of PP2Ac. Second, cAMP‐induced iNOS expression and PP2Ac nitration were decreased by treatment with TSA, an inhibitor of histone deacetylase 5 (HDAC5). cAMP‐induced phosphorylation of CaMKII and HDAC5 was suppressed by treatment with U73122 (an inhibitor of phospholipase C) or transfection of PLCε siRNA. Finally, small G protein Rap1 and its guanine nucleotide exchange factor Epac1 were found to be involved in cAMP‐induced PP2A activation. Taken together, our results suggest that PP2Ac nitration during cAMP‐induced decidualization of hESCs is induced through the Epac1‐Rap1‐PLCε‐CaMKII‐HDAC5‐iNOS signaling pathway.