PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

Abstract

SummaryProtease-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 b-catenin stabilization function. The components connecting PAR 1 to b-catenin stabilization have been determined, assigning at first G a13 as a selective immediate component. The PAR 1 -G a13 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 b-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 b-catenin stabilization, a core event in both tumorigenesis and developmental processes.

Regulation of the Hippo–YAP pathway by protease-activated receptors (PARs)

“…Not surprisingly, expression of some TRAP6-inducible genes, such as CXCL1, did not depend on YAP/TAZ. This is likely due to the ability of PAR to activate other downstream transcription factors parallel to YAP/TAZ (Bar-Shavit et al 2011).…”

“…PAR is known to stimulate cell migration and has been implicated in tumor metastasis (Even-Ram et al 1998;Tellez and Bar-Eli 2003;Bar-Shavit et al 2011). We therefore examined the function of YAP/TAZ in mediat- ing the cellular function of PAR.…”

“…Activation of PAR1 and other GPCRs that couple to G 12/13 and Rho signaling pathways can lead to aberrant cell growth, and ligands for these receptors are increased under pathophysiological conditions. For example, thrombin and PAR1 expression are up-regulated in a tumor microenvironment and malignant or invasive cancer cells (Bar-Shavit et al 2011;Ramachandran et al 2012). On the other hand, thrombin is generated at sites of tissue injury to promote wound healing.…”

“…Several reports have demonstrated that thrombin increases the expression of CTGF and Cyr61 (Chambers et al 2000;Pendurthi et al 2002;Walsh et al 2008). PARs have recently been implicated to play a central role in tumor cell growth, invasion, and cancer metastasis, and up-regulation of receptor expression has been detected in tumor tissues, including melanomas; colon, breast, lung, pancreatic, and prostate cancer; and oral squamous cell carcinoma (Booden et al 2004;Elste and Petersen 2010;Bar-Shavit et al 2011;Ramachandran et al 2012).…”

Mentors And The Butterfly Effect: Triggers For Discovering Signalling by Proteinases via Proteinase-Activated Receptors (PARs) And More

“…It was not at all anticipated that PARs would represent novel keys for understanding proteinase functions in the setting of in ammation. Of note, quite apart from its expected role in vascular disease, PAR1, along with PAR2, has been found to be integrally involved in the process of epithelial tumour cell growth and invasion [80]. Finally, pathogen-derived proteinases like those present in insect allergens can also promote in ammation by activating PARs [81].…”