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Sorina Grisaru-Granovsky - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel. 
Jeetendra Kumar Nag - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
 
Liat Zakar - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel.
 
Tatyana Rudina - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Chhedi Lal Gupta - Institute of Soil, Water and Environmental Sciences, Volcani Research Center, Agriculture Research Organization, Rishon Lezion, Israel.  
Myriam Maoz - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
 
Daria Kozlova - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel.
 
Rachel Bar-Shavit - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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 PAR1 and PAR2 function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell-lines. Activation of PAR1 - and PAR2 -induced EVT invasion and proliferation, while the shRNA silencing of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) inhibited these processes. PAR1 and PAR2 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 PAR1 or PAR2 with LRP5/6 forming an axis of PAR-LRP5/6-Axin. Noticeably, in PAR1 -PAR2 heterodimers a dominant role is assigned to PAR2 over PAR1 as shown by inhibition of PAR1 -induced β-catenin levels, and Dvl nuclear localization. This inhibition takes place either by shRNA silenced hPar2 or in the presence of a TrPAR2 devoid its cytoplasmic tail. Indeed, TrPAR2 cannot form the PAR1 -PAR2 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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PAR 1&2 driven placenta EVT invasion act via LRP5/6 as coreceptors

Sorina Grisaru-Granovsky - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel. 
Jeetendra Kumar Nag - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
 
Liat Zakar - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel.
 
Tatyana Rudina - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Chhedi Lal Gupta - Institute of Soil, Water and Environmental Sciences, Volcani Research Center, Agriculture Research Organization, Rishon Lezion, Israel.  
Myriam Maoz - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
 
Daria Kozlova - Department of Obstetrics and Gynecology, Hebrew-University, Shaare Zedek Medical Center, Jerusalem, Israel.
 
Rachel Bar-Shavit - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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 PAR1 and PAR2 function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell-lines. Activation of PAR1 - and PAR2 -induced EVT invasion and proliferation, while the shRNA silencing of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) inhibited these processes. PAR1 and PAR2 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 PAR1 or PAR2 with LRP5/6 forming an axis of PAR-LRP5/6-Axin. Noticeably, in PAR1 -PAR2 heterodimers a dominant role is assigned to PAR2 over PAR1 as shown by inhibition of PAR1 -induced β-catenin levels, and Dvl nuclear localization. This inhibition takes place either by shRNA silenced hPar2 or in the presence of a TrPAR2 devoid its cytoplasmic tail. Indeed, TrPAR2 cannot form the PAR1 -PAR2 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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