Protease-activated receptors (PARs) in cancer

Bar-Shavit, Rachel; Maoz, Myriam; Kancharla, Arun; Jaber, Mohammad; Agranovich, Daniel; Grisaru‐Granovsky, Sorina; Uziely, Beatrice

doi:10.1016/bs.mcb.2015.11.006

Cited by 17 publications

(15 citation statements)

References 80 publications

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“…PARs are characterized by a unique activation mechanism involving protein degradation of the lanthanide ligands. Several studies indicated that PARs were associated with vascular regulation, inflammatory response, tissue fibrosis and carcinogenesis [20–22], which made PARs the potential targets for novel therapies development. It has been confirmed that PAR2 was involved in development of HCC and pancreas cancer [20, 23].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies indicated that PARs were associated with vascular regulation, inflammatory response, tissue fibrosis and carcinogenesis [20–22], which made PARs the potential targets for novel therapies development. It has been confirmed that PAR2 was involved in development of HCC and pancreas cancer [20, 23]. PAR2 is the only member of PAR family to be considered a tumor suppressor factor in skin tumor [22].…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of protease-activated receptors 2 indicates poor prognosis in HBV related hepatocellular carcinoma

Chen

Yang

Liu

et al. 2019

Infect Agents Cancer

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ObjectiveTo investigate the potential role of protease-activated receptor 2 (PAR2) in the prognosis of hepatocellular carcinoma (HCC).MethodsA total of 202 HCC patients who underwent liver resections were included. Tissue microarray was established with specimens of both HCC and paired adjacent liver tissues. PAR2 expression was detected by immunohistochemistry (IHC) assays.. A semi-quantification method was used to define the expression level of PAR2. The correlations between PAR2 expression and clinical features of patients with HCC was explored. The association of different PAR2 expressions with both overall survival and disease-free survival was analyzed.ResultsResults showed that the expression of PAR2 in HCC tissues was higher than that in paired para-cancerous liver tissues (4.12 ± 3.55 vs. 2.71 ± 2.56, P < 0.001). Higher expression of PAR2 was associated with poor differentiation (P < 0.001) and advanced tumor-node-metastasis stage (P = 0.015). Kaplan-Meier survival analysis indicated that HCC patients with high PAR2 expression had decreased overall survival (P = 0.033) and disease-free survival (P = 0.043) compared to patients with lower PAR2 expression. Multivariate analysis indicated that PAR2 expression (P = 0.032) was a significant independent prognostic factor for both overall survival and disease-free survival (P = 0.032; P = 0.032, respectively).ConclusionOur data revealed that PAR2 expression was increased in HCC. High PAR2 expression was correlated with both decreased overall survival and disease-free survival in patients with HCC. High PAR2 expression indicated a poor prognosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased expression of protease-activated receptors 2 indicates poor prognosis in HBV related hepatocellular carcinoma

Chen

Yang

Liu

et al. 2019

Infect Agents Cancer

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“…PAR4 can activate multiple signaling pathways through coupling to G␣ q/11 , G␣ 12/13 , and ␤-arrestin (24 -26). In previous work, we and others (26,27) showed that pepducins targeting different intracellular motifs in PAR4 could be employed to differentially inhibit platelet activation by blocking G-protein-coupled or ␤-arrestin-dependent signaling. The ability to selectively activate or inhibit GPCR signaling in a biased manner is of great interest and has been proposed as a strategy for obtaining therapeutically superior drugs for a number of conditions (28 -30).…”

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confidence: 99%

Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4)

Thibeault

LeSarge

Arends

et al. 2020

Journal of Biological Chemistry

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Proteinase-activated receptor (PAR)-4 is a member of the proteolytically-activated PAR family of G-protein–coupled receptors (GPCR) that represents an important target in the development of anti-platelet therapeutics. PARs are activated by proteolytic cleavage of their receptor N terminus by enzymes such as thrombin, trypsin, and cathepsin-G. This reveals the receptor-activating motif, termed the tethered ligand that binds intramolecularly to the receptor and triggers signaling. However, PARs are also activated by exogenous application of synthetic peptides derived from the tethered-ligand sequence. To better understand the molecular basis for PAR4-dependent signaling, we examined PAR4-signaling responses to a peptide library derived from the canonical PAR4-agonist peptide, AYPGKF-NH2, and we monitored activation of the Gαq/11-coupled calcium-signaling pathway, β-arrestin recruitment, and mitogen-activated protein kinase (MAPK) pathway activation. We identified peptides that are poor activators of PAR4-dependent calcium signaling but were fully competent in recruiting β-arrestin-1 and -2. Peptides that were unable to stimulate PAR4-dependent calcium signaling could not trigger MAPK activation. Using in silico docking and site-directed mutagenesis, we identified Asp230 in the extracellular loop-2 as being critical for PAR4 activation by both agonist peptide and the tethered ligand. Probing the consequence of biased signaling on platelet activation, we found that a peptide that cannot activate calcium signaling fails to cause platelet aggregation, whereas a peptide that is able to stimulate calcium signaling and is more potent for β-arrestin recruitment triggered greater levels of platelet aggregation compared with the canonical PAR4 agonist peptide. These findings uncover molecular determinants critical for agonist binding and biased signaling through PAR4.

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“…Thrombin, a serine protease coagulation factor, binds to protease-activated receptor-1 (PAR-1), which is a member of a family of 4 GPCRs (reviewed in [12, 13]). This induces a conformational change in PAR-1 leading to the separation of the Gα and the Gβγ subunits of the G-protein and further downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

“…PARs are ubiquitously expressed throughout mammalian tissue, and the physiological role of particularly PAR-1 includes platelet aggregation, endothelial barrier disruption and smooth muscle cell proliferation [12]. PAR-1 is an emerging therapeutic target in cancer [13]. Trypsin, an alternate serine protease, primarily activates GPCRs through PAR-2 binding [15].…”

Section: Introductionmentioning

confidence: 99%

The TRPM7 kinase limits receptor-induced calcium release by regulating heterotrimeric G-proteins

Suzuki

Lis

Schmitz

et al. 2018

Cell. Mol. Life Sci.

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The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of G, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)β and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply.

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Protease-activated receptors (PARs) in cancer

Cited by 17 publications

References 80 publications

Increased expression of protease-activated receptors 2 indicates poor prognosis in HBV related hepatocellular carcinoma

Increased expression of protease-activated receptors 2 indicates poor prognosis in HBV related hepatocellular carcinoma

Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4)

The TRPM7 kinase limits receptor-induced calcium release by regulating heterotrimeric G-proteins

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