PAR1 Plays a Role in Epithelial Malignancies: Transcriptional Regulation and Novel Signaling Pathway

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 beta-catenin stabilization function. The components connecting PAR(1) to beta-catenin stabilization have been determined, assigning at first G(alpha 13) as a selective immediate component. The PAR(1)-G(alpha 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 beta-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 beta-catenin stabilization, a core event in both tumorigenesis and developmental processes. (C) 2011 IUBMB IUBMB Life, 63(6): 397-402, 2011