Disease relevance of F2rl3

• Importantly, PAR4-deficient mice had markedly prolonged bleeding times and were protected in a model of arteriolar thrombosis [1].
• Importantly, PAR4 heterozygosity conferred some protection against metastasis in this model [2].
• In a severe combined immunodeficiency (SCID) background, median lung tumor count in Nf-E2(-/-), Par4(-/-), and Fib(-/-) mice was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%, 9%, and 3% of wild type, respectively [2].
• Interestingly, endotoxin-induced thrombocytopenia was not diminished in Par4(-/-) mice [3].
• Par-4-dependent apoptosis by the dietary compound withaferin a in prostate cancer cells [4].

High impact information on F2rl3

• Prostate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis [5].
• Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy [5].
• Par-4 links dopamine signaling and depression [5].
• In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors [6].
• NP formation was concomitant with elevated apoptosis and increased expression of ceramide and prostate apoptosis response 4 (PAR-4) [7].

Chemical compound and disease context of F2rl3

• The recent observation that knock-out of protease-activated receptor-4 (PAR4) ablates thrombin signaling in mouse platelets and protects against ferric chloride-induced thrombosis of mouse mesenteric arterioles suggests that thrombin's actions on platelets can play an important role in thrombosis [8].
• Thus, when judiciously combined with anti-androgens, WA inhibits survival of both androgen-responsive and androgen-refractory prostate cancer cells by a Par-4-dependent mechanism [4].
• Prostate apoptosis response-4 (Par-4), a protein containing a leucine zipper domain within a death domain, is up-regulated in prostate cancer cells and hippocampal neurons induced to undergo apoptosis [9].

Biological context of F2rl3

• Down-regulation of PAR4 expression in microglial cultures by a specific antisense, but not a sense, oligonucleotide reduced PAR4AP-induced TNF-alpha [10].
• We conclude that plasmin induces platelet aggregation primarily through slow cleavage of PAR-4 [11].
• Further, the phenotype of mice reconstituted with Par4-/- marrow was almost as dramatic as that seen in Nf-e2-/- mice, which lack platelets [12].
• However, in addition to its role in platelets, PAR4 contributes to thrombin signaling in cells in the blood vessel wall that might participate in hemostasis and thrombosis, such as endothelial cells [12].
• We show that in tumors formed after engraftment of EBCs into mouse brain, expression of the pluripotency marker Oct-4 colocalized with that of prostate apoptosis response-4 (PAR-4), a protein mediating ceramide-induced apoptosis during neural differentiation of ES cells [13].

Anatomical context of F2rl3

• Wild-type endothelial cells responded to agonists for PAR1, PAR2, and PAR4 [14].
• In the present study, we now report that thrombin action in promoting inflammatory mediators from brain microglia is mediated through another thrombin receptor, PAR4 [10].
• Neither thrombin nor PAR-4-activating peptide was able to affect osteoblast proliferation or alkaline phosphatase activity in cells isolated from PAR-1-null mice [15].
• We also compared the levels of Par-4 in lumbar spinal cord samples from wild-type and transgenic mice expressing the human Cu/Zn-superoxide dismutase gene with a familial ALS mutation [9].
• Collectively, these data suggest a role for Par-4 in models of motor neuron injury relevant to ALS [9].

Associations of F2rl3 with chemical compounds

• Several studies suggest an essential function for the COOH-terminal leucine repeats/death domain of Par-4 in mediating apoptosis [16].
• We now report that Par-4 levels increase dramatically in midbrain dopaminergic neurons of monkeys and mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [17].
• The authors recently identified prostate apoptosis response-4 (Par-4) as a protein that participates in the death of cultured hippocampal neurons induced by trophic factor withdrawal and exposure to glutamate [18].
• Furthermore, immunohistochemistry results revealed that the abnormal upregulation of the apoptotic related factor such as Bax, Caspase-3, and (Par-4) greatly reduced expression after melatonin or 17beta-estradiol supplement action [19].
• However, our results showed almost identical levels of peak calcium between wild-type or PAR-4 null mice when stimulated with either ADP or U46619 [20].

Regulatory relationships of F2rl3

• Despite wild-type levels of alphaIIbbeta3, caspase-12(-/-) platelets exhibit reduced fibrinogen binding to alphaIIbbeta3 following stimulation by adenosine diphosphate (ADP) or protease-activated receptor 4 (PAR4) receptor-activating peptide [21].

Other interactions of F2rl3

• We now report that mice that lacked both PAR4 and fibrinogen exsanguinated at birth like prothrombin-deficient mice [22].

Analytical, diagnostic and therapeutic context of F2rl3

• One of the compounds, withaferin A (WA), a major constituent of the dietary compound Withania somnifera, induced Par-4-dependent apoptosis in androgen-refractory prostate cancer cells and regression of PC-3 xenografts in nude mice [4].
• In sections of day E14.5 mouse brain, the intermediate zone showed intensive staining for complex gangliosides, but only low staining for apoptosis (TUNEL) and PAR-4 [23].
• The current data suggest that early up-regulation of Par-4 plays a pivotal role in ischemic neuronal death in animal models of stroke and cardiac arrest [18].
• After transient focal ischemia in mice, Par-4 levels were increased 6 to 12 hours after reperfusion in the infarcted cortex and the striatum, and activation of caspase-8 occurred with a similar time course [18].
• The expression of prostate apoptotic response-4 (Par-4) was detected by Western blot [24].

References