Abstract
Protease‐activated receptor1 (PAR~1~) is the first and prototype member of an established PAR family comprising four members. The role of PAR~1~ in tumor biology has been established, and is characterized by a consistent direct correlation between overexpression of its levels and epithelial tumor aggressiveness. We have found that high expression of the human Par~1~ (hPar~1~) gene in epithelial tumors is controlled largely at the transcriptional level. This led us to assign Egr‐1, a transcription activator, as an inducer of hPar~1~, and p53, a tumor suppressor gene, as an inhibitor, both acting to achieve fine tuning of hPar~1~ in prostate carcinoma. High PAR~1~ levels maintain prosurvival signals in tumor cells while silencing or ablation of the gene induce apoptosis. Studies of our hPar~1~ transgenic mice, which overexpress hPar~1~ in the mammary glands, revealed a novel PAR~1~‐induced β‐catenin stabilization function. The components connecting PAR~1~ to β‐catenin stabilization have been determined, assigning at first G~α~~13~ as a selective immediate component. The PAR~1~‐G~α~~13~ axis recruits disheveled (DVL), an upstream signaling partner of the canonical Wnt signaling pathway. Silencing of DVL by siRNA‐DVL potently abrogates PAR~1~‐induced β‐catenin stabilization, demonstrating its critical role in the process. We, thus, propose that transcriptional regulation of hPar~1~ gene over expression in epithelia malignancies initiates a novel signaling pathway, directly connecting to β‐catenin stabilization, a core event in both tumorigenesis and developmental processes. © 2011 IUBMB IUBMB Life, 63(6): 397–402, 2011