Despite extensive efforts toward elucidation of the molecular pathway controlling cytotrophoblast (CTB) invasion to the uterine decidua, it remains poorly defined. There are striking similarities between tumor cell invasion and cytotrophoblast implantation to the deciduas whereby the role of Protease Activated Receptors (PARs) and wnt signaling is well recognized. We examine here consequences of modulation of PAR1 and PAR2 expression and function on CTB invasion and β-catenin stabilization. Toward this end, we utilized a model system of extravillous trophoblast (EVT) organ culture and various placenta cell lines (e.g., JAR and HTR-8/Svneo). Activation of PAR1 induces EVT invasion while hPar1-SiRNA and PAR1 antagonist SCH79797—effectively inhibited it. In parallel, the Wnt inhibitor Dickkopf-1 (Dkk1) similarly inhibited it. Nuclear localization of β-catenin is seen only after PAR1 activation, and is markedly reduced following the application of hPar1-SiRNA construct and PAR1 antagonist in CTBs. In contrast, PAR2 elicited a low cytoplasmic β-catenin level as also proliferation and invasion. In the non-activated CTBs in-comparison, β-catenin appeared limited to the membrane pools. Concomitantly, a temporal regulated pattern of Wnt-4, 5a, 7b, 10a, 10b expression is seen along PAR1 appearance. Enforced expression of Wnt antagonists, Secreted Frizzled Related Proteins; SFRP2 & 5; into HTR-8/Svneo, resulted with a markedly reduced nuclear β-catenin levels, similar to the effect obtained by hPar1-SiRNA treatment. Identification of PAR1 downstream target/s may nonetheless contribute to the formation of a future platform system for eliciting a firm placenta-uterus interactions and to the definition of late pregnancy outcomes. J. Cell. Physiol. 218: 512–521, 2009. © 2008 Wiley-Liss, Inc.