The traditional view on the role of serine proteases in tumor biology has changed with the recent discovery of a family of protease-activated receptors (PARs). In this study we explored the expression and functional role of the thrombin receptor PAR-1 in human colon cancer cells. Reverse transcripta …
TY - JOUR. T1 - Co-expressing Turnip Crinkle Virus-coat protein with the serine protease α-thrombin precursor (pFIIa) in Nicotiana benthamiana Domin. AU - Laguia-Becher, Melina. AU - Zaldúa, Zurima. AU - Xu, Weijie. AU - Marconi, Patricia Laura. AU - Velander, William. AU - Alvarez, María Alejandra. PY - 2019/2/15. Y1 - 2019/2/15. N2 - The serine protease α-thrombin (FIIa) plays a fundamental role in blood clotting. In the present report, a FIIa precursor (pFIIa) was expressed in Nicotiana benthamiana Domin. The expression construct featured the Kozak consensus sequence and the 2S2 Arabidopsis thaliana (L.) Heynh. signal peptide to direct the protein into the secretory pathway (sec-pFIIa). A version carrying the KDEL endoplasmic reticulum (ER) retention signal (pFIIa-ER) was also constructed. Transient expression of pFIIa in N. benthamiana leaves was achieved by Agrobacterium tumefaciens infiltration. The influence of post-transcriptional gene silencing (PTGS) was analyzed by co-infiltrating ...
Principal Investigator:KATAOKA Kazuo, Project Period (FY):2002 - 2005, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Cerebral neurosurgery
Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 ...
TY - CONF. T1 - Protease-activated receptor-2 expression by oral epithelial cells is required for bone loss associated with periodontal disease. AU - Francis, Nidhish. AU - Ayodele, Babatunde. AU - Pike, Rob. AU - Pagel, Charles. AU - Mackie, Eleanor. PY - 2017/6/18. Y1 - 2017/6/18. M3 - Abstract. ER - ...
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Vorapaxar (brand name Zontivity, formerly known as SCH 530348) is a thrombin receptor (protease-activated receptor, PAR-1) antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co. Vorapaxar is used for persons with a history of myocardial infarction (heart attack) or persons with peripheral arterial disease. Studies have shown that this medication can reduce the rate of combined endpoint cardiovascular death, MI, stroke, and urgent coronary revascularization. Vorapaxar is contraindicated for people with a history of stroke, transient ischemic attack, or intracerebral hemorrhage. In studies of vorapaxar on persons with prior ischemic stroke, there was an increased risk of intracranial hemorrhage without an improvement in major vascular events. Vorapaxar possesses a long half life which is a problem because there is currently no treatment to reverse the antiplatelet effects of vorapaxar. Because of this, it is important that vorapaxar not be ...
Background The Protease-Activated Receptor 1 (PAR1) is activated by the proteolytic release of the N-terminal 41 amino acids. Exogenously administered PAR1(1- 41) peptides protect against myocardial ischemia and reperfusion injury in the rat. In the present study, we determined whether PAR1(1-26), the putative signal peptide of PAR1 contains the functional domain of PAR1(1- 41).. Methods and Results We assessed the protective role of a synthesized PAR1(1-26) peptide in an in vivo rat model of myocardial regional ischemia and reperfusion injury (n=6/group). PAR1(1-26) (0.01-10 μg/kg) treatment immediately before ischemia reduced infarct size from 58±1% to 13±1% area at risk (p,0.01) at an optimal dose of 10 μg/kg. Treatment with PAR1(1-26) after the onset of reperfusion decreased infarct size to 22±1% area at risk (p,0.01). We then explored the survival pathways known to be up-regulated by pharmacologic cardioprotectants. Inhibition of Gi proteins (pertussis toxin), PI3K/Akt (Wortmannin), ...
Buy TFLLR-NH2 (CAS 197794-83-5), a water soluble PAR1 agonist peptide. Join researchers using high quality TFLLR-NH2 from Abcam and achieve your mission…
Par 1 | Protease-activated receptor 1 stimulate phosphoinositide hydrolysis. Specific for platelets and vascular endothelial cells. Alternative names: Coagulation factor II receptor, Thrombin receptor. AS10 1572, P25116
PARs (protease-activated receptors) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.
Als Äquivalent einer Habilitationsschrift werden drei Originalarbeiten zusammengefasst und eingereicht. Die aufgeführten Arbeiten beschreiben wie Gerinnungsproteasen via Protease aktivierbare Rezeptoren auf das Endothel wirken. Die Arbeiten zielen dahin, dass Gerinnungsfaktoren in Zukunft therapeutisch breiter und mit besserem Nutzen eingesetzt werden können. Quellenangabe der vorgestellten Publikationen: 1. Schuepbach RA, Feistritzer C, Brass LF, Riewald M. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood. 2008 Mar 1;111(5):2667-73. 2. Schuepbach RA*, Feistritzer C*, Fernandez JA, Griffin JH and Riewald M. Protection of Vascular Barrier Integrity by Activated Protein C Dependent on Protease-Activated Receptor-1. Thromb Haemost. 2009 Apr;101(4):724-33 3. Schuepbach RA and Riewald M. Clotting Factor Xa Cleaves PAR1 and Mediates Signaling Dependent on Binding to the Endothelial Protein C Receptor. J ...
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the protease-activated receptor (PAR) family which is a subfamily of the seven transmembrane G protein-coupled cell surface receptor family. The encoded protein acts as a cofactor in the thrombin-mediated cleavage and activation of the protease-activated receptor family member PAR4. The encoded protein plays an essential role in hemostasis and thrombosis. Alternate splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Feb 2012 ...
Proteinase-activated receptors (PARs) are a class of G-protein-coupled receptors which are involved in various physiological and pathophysiological processes. The new product monograph PAR-Activating-Peptides gives you an overview of Bachem´s PAR-activating-peptides and analogs useful for studying receptor function ...
History The upregulation of matrix metalloproteinase-1 (MMP-1) continues to be proven correlated with lymph node metastasis of nasopharyngeal carcinoma (NPC) as the activation of protease-activated receptor-1 (PAR-1) mediates proliferation and invasion of NPC cells. in 190 (71.43%) and 182 (68.42%) from the 266 NPC sufferers. Furthermore the mixed MMP-1 and PAR-1 appearance was significantly connected with advanced T-stage (= 0.01) advanced clinical stage (= 0.002) positive recurrence (= 0.01) and metastatic position (= 0.01) of NPC. Furthermore the overall success in NPC sufferers MAP3K8 with MMP-1 and PAR-1 dual overexpression was considerably shorter than in people that have dual low appearance (< 0.001). Furthermore the multivariate analyses indicated the fact that mixed MMP-1 and PAR-1 overexpression was an unbiased prognostic aspect for overall success (= 0.001) in NPC sufferers however the upregulation of MMP-1 and PAR-1 alone is at each case no independent prognostic aspect because of ...
1. van der Merwe, J. Q., Moreau, F., and MacNaughton, W. K. Protease-activated receptor-2 stimulates intestinal SCBN epithelial chloride transport through activation of PLC and selective PKC isoforms. Am J Physiol Gastrointest Liver Physiol, 296: G1258-1266, 2009. 2. van der Merwe, J. Q., Ohland, C. L., Hirota, C. L., and MacNaughton, W. K. Prostaglandin E2 derived from cyclooxygenases 1 and 2 mediates intestinal SCBN epithelial ion transport stimulated by the activation of protease-activated receptor 2. J Pharmacol Exp Ther, 329: 747-752, 2009. 3. Dong, X., Smoll, E. J., Ko, K. H., Lee, J., Chow, J. Y., Kim, H. D., Insel, P. A., and Dong, H. P2Y receptors mediate Ca2+ signaling in duodenocytes and contribute to duodenal mucosal SCBN bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol, 296: G424-432, 2009. 4. Buret, A. and Lin, Y. C. Genotypic characterization of an epithelial cell line SCBN for the study of parasite-epithelial interactions. J Parasitol, 94: 545-548, 2008. 5. Smith, ...
Luo, W., Wang, Y., Hanck, T., Stricker, R. and Reiser, G. (2006) JAB1, A Novel Protease-Activated Receptor-2 (PAR-2) - Interacting Protein Is Involved in PAR-2-Induced Activation of AP-1. J. Biol. Chem. Papers in press. Published on January 12, 2006 as Manuscript M510784200 ...
heart attack or blockages in the arteries to the legs.. Zontivity is the first in a new class of drug, called a protease-activated receptor-1 (PAR-1) antagonist. It is an anti-platelet agent, designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of blood clots, Zontivity decreases the risk of heart attack and stroke.. Like other drugs that inhibit blood clotting, Zontivity increases the risk of bleeding, including life-threatening and fatal bleeding. Bleeding is the most commonly reported adverse reaction in people taking Zontivity. The drugs prescribing information (label) includes a Boxed Warning to alert health care professionals about this risk.. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm396585.htm. ...
The Italian minister of health, Livia Turco, has announced that she will make use of an administrative procedure to change the tough drug law passed through par...
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Title: Discovery of Potent Peptide-Mimetic Antagonists for the Human Thrombin Receptor, Protease-Activated Receptor-1 (PAR-1). VOLUME: 1 ISSUE: 1. Author(s):Bruce E. Maryanoff, Han-Cheng Zhang, Patricia Andrade-Gordon and Claudia K. Derian. Affiliation:Johnson&Johnson Pharmaceutical Research&Development (formerly The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477- 0776, USA. Keywords:thrombin receptor, protease-activated receptor, par, antagonist, indole, indazole, dipeptide urea, trap, sfllrn, tethered ligand. Abstract: Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease α-thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, ...
Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2). The possibility that a tryptase/PAR-2 signaling pathway exists in skeletal muscle cell has never been investigated. The aim of this study was to evaluate whether tryptase can stimulate myoblast proliferation and determine the downstream cascade. Proliferation of L6 rat skeletal myoblasts stimulated with PAR-2 agonists (tryptase, trypsin and SLIGKV) was assessed. The specificity of the tryptase effect was evaluated with a specific inhibitor, APC-366. Western blot analyses were used to evaluate the expression and functionality of PAR-2 receptor and to assess the expression of COX-2. COX-2 activity was evaluated with a commercial activity assay kit and by measurement of PGF2α production. Proliferation assays were also performed in presence of different prostaglandins (PGs). Tryptase increased L6 myoblast proliferation
Tissue factor (TF)-mediated protease-activated receptor (PAR)-2 signaling is associated with a promigratory, invasive and proangiogenic phenotype in experimental models of breast cancer and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings is unknown. Here, we provide the first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA-MB-231 xenografts and in tumors from the MMTV-PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR-2-deficient transgenic mice were negative for pTF, thus linking pTF to PAR-2 signaling. The clinical correlation between TF, pTF, PAR-1, PAR-2 and vascular endothelial growth factor (VEGF)-A was determined by immunohistochemistry on tumors from a cohort of 172 consecutive primary breast cancer patients, with a median follow-up time of 50 months. In 160 evaluable patient tumors, pTF was ...
Protease-activated receptor-2 (PAR2) is activated by proteases, such as trypsin, human mast cell beta-tryptase, human kallikrein isoforms, coagulation factors VIIa and Xa, etc. PAR2 is believed to have an important role under inflammatory pathological conditions, but its role in metabolic syndrome remains uncertain. We have reported that PAR2-activating peptide, 2-furoyl-LIGRLO-amide (2fly) causes NO-mediated vasorelaxation in rat aortas similar to that observed with acetylcholine (ACh), and that 2fly-induced vasorelaxation is maintained in aortas from SHRSP.Z-Leprfa/IzmDmcr (SHRSP.ZF) rats with metabolic syndrome, even though ACh- and sodium nitroprusside (SNP)-induced vasodilation is lower than that in control (Wistar-Kyoto rats, WKY). In this study, we assessed the mechanisms involved in the preservation of PAR2-mediated vasorelaxation in metabolic syndrome.. Aortas were isolated from male WKY and SHRSP.ZF rats between 18-20 weeks of age. ACh- and 2fly-induced vasorelaxations were measured in ...
By using biochemical, immunological and immunohistochemical techniques, we have investigated the expression and functional activity of protease-activated receptor (PARs) 1 and 2 in the rat olfactory system. Western blot analysis of microdissected main olfactory bulb indicated the presence of both PAR1 and PAR2 in olfactory nerve-glomerular cell layer (ON-GL), external plexiform layer (EPL) and granule cell layer (GRL). In functional assays, PAR1 and PAR2 selective peptides stimulated [35S]GTPyS binding and phosphoinositide hydrolysis and inhibited cyclic AMP formation in ON-GL but not in EPL and GRL, whereas they induced RhoA activation in both ON-GL and EPL+GRL. Olfactory bulb deafferentation by lesions of the olfactory mucosa elicited a significant decrease of PAR1 and PAR2 immunoreactivity in ON-GL and a reduced stimulation of [35S]GTPyS binding by PAR selective peptides. In primary cultures of olfactory neurons both PAR1 and PAR2 were detected by immunofluorescence and their activation by ...
G protein-coupled receptors (GPCRs) are well recognized as being able to activate several signaling pathways through the activation of different G proteins as well as other signaling proteins such as beta-arrestins. Therefore, understanding how such multiple GPCR-mediated signaling can be integrated constitute an important aspect. Here, we applied bioluminescence resonance energy transfer (BRET) to shed more light on the G protein coupling profile of trypsin receptor, or protease-activated receptor 2 (PAR2), and its interaction with beta-arrestin1. Using YFP and Rluc fusion constructs expressed in COS-7 cells, BRET data revealed a pre-assembly of PAR2 with both Galphai1 and Galphao and a rapid and transient activation of these G proteins upon receptor activation. In contrast, no preassembly of PAR2 with Galpha12 could be detected and their physical association can be measured with a very slow and sustained kinetics similar to that of beta-arrestin1 recruitment. These data demonstrate the coupling of
Mechanical strain on the artery wall is increased up to 30% in hypertension and is postulated to play a role in vascular injury.2-5 Thrombin is concentrated in vivo at sites of vascular injury, and its effects are mediated chiefly through PAR-1.21 PAR-1 is expressed at very low levels in normal arteries but increases after vascular injury12,18,22 and is increased in the arteries of hypertensive rats.11 Thus, we hypothesized that cyclic strain administered to VSMCs in vitro would increase PAR-1 expression.. Cyclic strain increased PAR-1 mRNA and protein levels (Figures 1 and 2⇑), and after 48 hours of cyclic strain, thrombin also produced a 50% increase in cell number (Figure 3). The significance of these findings is based on the opposite responses of PAR-1 expression to cyclic strain and shear stress. PAR-1 expression increases 2-fold under 20% cyclic strain for 24 hours, whereas it decreases by ≈4-fold under shear stress (25 dyne/cm2) for 24 hours.14 Thus, mechanical forces regulate the ...
Learn how Dr. Scarisbricks Neuroregeneration and Neurorehabilitation Laboratory at Mayo Clinic is identifying the role of PARs in spinal cord repair.
The present study shows that PAR1 acts as a cofactor for thrombin activation of PAR4 on human platelets and other cells and provides a mechanistic basis to understand PAR1-PAR4 synergy. By selectively ablating the PAR1 signal with a potent inhibitor of the PAR1 tethered ligand,23 we determined that PAR4 is activated at surprisingly low concentrations of thrombin on human platelets. By inhibiting the ability of thrombin to associate with PAR1, we show that PAR1 plays a critical helper function in assisting PAR4 activation by thrombin. A cleavage-sensitive PAR4-Ab was used to demonstrate that PAR1 and PAR4 exist as a complex on human platelets. Stable hetero-oligomerization between PAR1 and PAR4 was also observed in recombinant systems and did not require prior cleavage by thrombin.. The present work supports earlier observations with PAR1 and PAR4 pepducin antagonists7 and blocking antibodies8,10,31 that targeting only PAR1 and not PAR4 may have a partial therapeutic effect. Thus, a combination ...
The importance of MCP-1 for mononuclear cell recruitment has been shown in various animal models of disease (9-13). Our results confirm that peritoneal MΦ recruitment after thioglycollate is significantly reduced in MCP-1 KO mice, and we demonstrate for the first time the importance of this chemokine for NK cell and MΦ recruitment during acute humoral rejection. By performing the transplant study in a xenogeneic model, it was possible to differentiate between MCP-1 made by donor tissue from that made by recipient. Only the former was associated with infiltration into rejecting hearts.. Results from complimentary but distinct experimental approaches, using either WT or PAR-1 KO hearts transplanted into defibinogenated rats or CD31-Hir-Tg hearts transplanted into unmanipulated rats, showed that PAR-1 activation on donor cells was necessary to generate sufficient quantities of donor MCP-1 to promote leukocyte infiltration. Similarly, MCP-1 generation and MΦ recruitment into the inflamed ...
The mechanism of PAR1 activation is strikingly irreversible. Cleavage of PAR1 by thrombin is irrevocable, and the tethered ligand generated cannot diffuse away from the receptor. In the absence of the reversible ligation that characterizes most receptor systems, how is PAR1 shut off? The β2-adrenergic receptor has served as a prototype for dissecting the molecular events responsible for G protein-coupled receptor desensitization and resensitization (10-13). Upon activation, β2-adrenergic receptor is rapidly phosphorylated. It then binds arrestin, preventing further interaction with G proteins. Arrestin also mediates internalization of β2-adrenergic receptors via clathrin-coated pits (14, 15). Within an endosomal compartment, receptors dissociate from ligand, are dephosphorylated, and recycle back to the cell surface competent to signal again. Thus trafficking serves to remove activated β2-adrenergic receptors from the cell surface and to return the receptors to the surface in an off state, ...
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Vorapaxar - Get up-to-date information on Vorapaxar side effects, uses, dosage, overdose, pregnancy, alcohol and more. Learn more about Vorapaxar
F2RL3 / PAR-4 antibody (coagulation factor II (thrombin) receptor-like 3) for IHC-P. Anti-F2RL3 / PAR-4 pAb (GTX71163) is tested in Human samples. 100% Ab-Assurance.
Platelets are central to thrombus formation, the leading cause of global mortality. PAR4 (protease-activated receptor 4) is a G-protein coupled receptor. Meanwhile, PAR4 together with PAR1 is responsible for thrombin-mediated…. Read More Read More. ...
NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: Revision Applications to U01 Awards on Detection of Pathogen-Induced Cancer (DPIC) (U01) PAR-13-173. NCI
NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: Gut Microbiota-Derived Factors in the Integrated Physiology and Pathophysiology of Diseases within NIDDKs Mission (R01) PAR-13-293. NIDDK
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个人简历. 2004年获博士学位,现为遗传与细胞研究所教授、博士生导师。2008-2010年在美国德克萨斯大学医学分校进行博士后研究。2012-2013年在美国德克萨斯大学医学分校进行国际合作研究。多年来从事炎症的信号转导及基因表达调控机制研究。包括两个主要研究方向:1)DNA氧化损伤修复过程偶联基因转录及天然免疫病理发展的分子机制;2)蛋白质的多聚ADP核糖化(PAR化)对基因表达调控的影响、参与炎性疾病病理发展的机制。共发表SCI论文40余篇。主持在研自然科学基金面上项目课题1项,吉林省科技厅自然科学基金1项,及国际合作基金1项。主持完成自然科学基金面上项目课题1项,参加完成自然科学基金面上项目课题1项,参加国家重点基础研究发展规划项目(973)项目2项。学习经历: 1986年--1990年:东北师范大学 生命科学学院 生物学专业 学士 ...
TY - JOUR. T1 - Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. AU - Iwasaki, Hiroko. AU - Arai, Fumio. AU - Kubota, Yoshiaki. AU - Dahl, Maria. AU - Suda, Toshio. PY - 2010/7/29. Y1 - 2010/7/29. N2 - Hematopoietic stem cells (HSCs) are maintained in specialized niches in adult bone marrow. However, niche and HSC maintenance mechanism in fetal liver (FL) still remains unclear. Here, we investigated the niche and the molecular mechanism of HSC maintenance in mouse FL using HSCs expressing endothelial protein C receptor (EPCR). The antiapoptotic effect of activated protein C (APC) on EPCR+ HSCs and the expression of protease-activated receptor 1 (Par-1) mRNA in these cells suggested the involvement of the cytoprotective APC/ EPCR/Par-1 pathway in HSC maintenance. Immunohistochemistry revealed that EPCR+ cells were localized adjacent to, or integrated in, the Lyve-1+ sinusoidal network, whereAPC and extracellular matrix (ECM) are ...
Author(s): Min, Jungah | Advisor(s): DeFea, Kathryn A | Abstract: β-arrestins, originally discovered in the context of G protein-coupled receptor (GPCR) desensitization and internalization, also function in signaling of these receptors independently of G protein coupling. These novel functions involve the roles for β-arrestins as scaffolds. It has been reported that β-arrestins interact with a number of binding partners including trafficking proteins, cytosolic kinases, cytoskeletal proteins, and non-receptor tyrosine kinase. Downstream of protease-activated receptor-2 (PAR-2), β-arrestin scaffolds the components of the ERK cascade, Raf-1, MEK1, and ERK1/2 with the receptor at the plasma membrane, leading to activation of cytoplasmic/membrane ERK1/2 signaling independent of G-protein coupling. Furthermore, we previously demonstrated that stimulation of PAR-2 resulted in prolonged activation of ERK1/2 in pseudopodia in a β-arrestin-dependent manner and β-arrestins were required in PAR-2 mediated