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PAR 1&2 driven placenta EVT invasion act via LRP5/6 as coreceptors
Author(s) -
GrisaruGranovsky Sorina,
Kumar Nag Jeetendra,
Zakar Liat,
Rudina Tatyana,
Lal Gupta Chhedi,
Maoz Myriam,
Kozlova Daria,
Bar Shavit Rachel
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.202000306r
Subject(s) - microbiology and biotechnology , cytotrophoblast , small hairpin rna , wnt signaling pathway , gene silencing , biology , receptor , catenin , trophoblast , signal transduction , gene knockdown , placenta , cell culture , genetics , gene , pregnancy , fetus
While the involvement of protease‐activated receptors (PARs) in the physiological regulation of human placenta development, as in tumor biology, is recognized, the molecular pathway is unknown. We evaluated the impact of PAR 1 and PAR 2 function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell‐lines. Activation of PAR 1 ‐ and PAR 2 ‐induced EVT invasion and proliferation, while the sh RNA silencing of low‐density lipoprotein receptor‐related protein 5/6 (LRP5/6) inhibited these processes. PAR 1 and PAR 2 effectively induce β‐catenin stabilization in a manner similar to that shown for the canonical β‐catenin stabilization pathway yet independent of Wnts. Immunoprecipitation analyses and protein‐protein docking demonstrated the co‐association between either PAR 1 or PAR 2 with LRP5/6 forming an axis of PAR‐LRP5/6‐Axin. Noticeably, in PAR 1 ‐PAR 2 heterodimers a dominant role is assigned to PAR 2 over PAR 1 as shown by inhibition of PAR 1 ‐induced β‐catenin levels, and Dvl nuclear localization. This inhibition takes place either by sh RNA silenced hPar2 or in the presence of a TrPAR 2 devoid its cytoplasmic tail. Indeed, TrPAR 2 cannot form the PAR 1 ‐PAR 2 complex, obstructing thereby the flow of signals downstream. Elucidation of the mechanism of PAR‐induced invasion contributes to therapeutic options highlighting key partners in the process.