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Background  While  protease-activated-receptor 1  (PAR 1 ) plays a central role in tumor progression, little is known about the cell signaling involved.    Methodology/Principal Findings  We show here the impact of PAR 1  cellular activities using both an orthotopic mouse mammary xenograft and a colorectal-liver metastasis model  in vivo , with biochemical analyses  in vitro . Large and highly vascularized tumors were generated by cells over-expressing  wt hPar1 ,  Y397Z hPar1 , with persistent signaling, or  Y381A hPar1  mutant constructs. In contrast, cells over-expressing the truncated form of  hPar1 , which lacks the cytoplasmic tail, developed small or no tumors, similar to cells expressing empty vector or control untreated cells. Antibody array membranes revealed essential  hPar1  partners including Etk/Bmx and Shc. PAR 1  activation induces Etk/Bmx and Shc binding to the receptor C-tail to form a complex. Y/A mutations in the PAR 1  C-tail did not prevent Shc-PAR 1  association, but enhanced the number of liver metastases compared with the already increased metastases obtained with  wt hPar1 . We found that Etk/Bmx first binds via the PH domain to a region of seven residues, located between C378-S384 in PAR 1  C-tail, enabling subsequent Shc association. Importantly, expression of the  hPar1 -7A mutant form (substituted A, residues 378-384), which is incapable of binding Etk/Bmx, resulted in inhibition of invasion through Matrigel-coated membranes. Similarly, knocking down Etk/Bmx inhibited PAR 1 -induced MDA-MB-435 cell migration. In addition, intact spheroid morphogenesis of MCF10A cells is markedly disrupted by the ectopic expression of  wt hPar1 . In contrast, the forced expression of the  hPar1- 7A mutant results in normal ball-shaped spheroids. Thus, by preventing binding of Etk/Bmx to PAR 1  -C-tail,  hPar1  oncogenic properties are abrogated.    Conclusions/Significance  This is the first demonstration that a cytoplasmic portion of the PAR 1  C-tail functions as a scaffold site. We identify here essential signaling partners, determine the hierarchy of binding and provide a platform for therapeutic vehicles via definition of the critical PAR 1   - associating region in the breast cancer signaling niche.

Etk/Bmx Regulates Proteinase-Activated-Receptor1 (PAR1) in Breast Cancer Invasion: Signaling Partners, Hierarchy and Physiological Significance