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PAR 1&2 driven placenta EVT invasion act via LRP5/6 as coreceptors
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 and PAR function in cytotrophoblast (CTB) proliferation and invasion in a s...
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Published in: | The FASEB journal 2020-12, Vol.34 (12), p.15701-15717 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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
and PAR
function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell-lines. Activation of PAR
- and PAR
-induced EVT invasion and proliferation, while the shRNA silencing of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) inhibited these processes. PAR
and PAR
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
or PAR
with LRP5/6 forming an axis of PAR-LRP5/6-Axin. Noticeably, in PAR
-PAR
heterodimers a dominant role is assigned to PAR
over PAR
as shown by inhibition of PAR
-induced β-catenin levels, and Dvl nuclear localization. This inhibition takes place either by shRNA silenced hPar2 or in the presence of a TrPAR
devoid its cytoplasmic tail. Indeed, TrPAR
cannot form the PAR
-PAR
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. |
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ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fj.202000306R |