Emerging tasks of thrombin and its receptors in epithelial tumor development

The family of mammalian protease-activated receptors (PARs), belonging to the G protein-coupled receptors (GPCRs) - is composed of four genes. PAR₁ is emerging with central assignments in epithelia derived tumors, including breast, ovarian, colon, prostate, melanoma and endometrial carcinoma. In-fact, PAR₁ serves as a delicate cell sensor to mediate the function of enzyme/s, centrally involved in thrombosis and hemostasis (e.g., thrombin, plasmin). PAR₂, the second family member which is not considered a thrombin-receptor (in contrast to PAR_1,3&4) was found connected to coagulation by virtue of its activation by other proteases involved in hemostasis such as tissue factor (TF) bound to FVIIa (factor VIIa); TF-FVIIa. Therefore, the hallmark of coagulation-associated cancer involves also PAR₂. Indeed, PAR₂ comes into view as a potent cell-receptor that acts in promoting breast cancer. While PAR₁ is over-expressed in epithelia tumor malignancies, regulated at-large on the transcription level, little is known about the cell signaling involved. A central role for the hPar₁ gene was established in mammary gland hyperplasia and revealed a novel pathway triggered by PAR₁ signaling for the functional stabilization of β-catenin, a core protein in the canonical Wnt signaling pathway. We have demonstrated that PAR₁ C-tail serves as a scaffold site for the binding of key signaling partners. The hierarchy of binding as also defining the minimal connecting region in PAR₁ C-tail, critical for signal initiation-were established. Mutations inserted into hPar₁-C-tail (successive replacement of seven A residues; 378-387) resulted with a failure to bind Etk/Bmx and abrogated Matrigel invasion and tissue wounding closure. This stands in-contrast to wt hPar1 that binds Etk/Bmx, induces Matrigel invasion and fills-up the gap of tissue wounding. Therefore, this domain has been assigned as a target-site for future therapeutic vehicles in breast cancer. Altogether, essential signaling partners have been allocated, the hierarchy of binding was determined and a platform for therapeutic vehicles is provided via defining the critical PAR₁ associating region in breast cancer signaling niche.