In addition to the key role of thrombin in blood coagulation, this multifunctional serine protease activates platelets and regulates the behavior of other cells through G-protein coupled protease activated receptors (PARs). PAR-1 is the principal thrombin-activated receptor involved in platelet aggregation and in endothelial and tumor cell proliferation. PAR-1 is overexpressed in invasive and metastatic tumors and the expression levels directly correlate with the degree of invasiveness of the cancer. In an attempt to give some insight into the perspectives of targeting PAR-1 in cancer and angiogenesis, this review provides an overview on the thrombin/PAR-1 interaction, receptor activation, signaling, desensitization and dysregulation mechanisms in relation to these diseases. A central aspect of this review is that directed to summarize the approaches that have been followed to the search of PAR-1 antagonists, illustrating with some significant examples. Attention is called to the scarce data concerning the effects of these antagonists on anticancer assay models.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.2174/092986710790112639 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
An αIIbβ3 monoclonal antibody traps a semiextended conformation and allosterically inhibits large ligand binding.
Blood Adv
August 2024
Laboratory of Blood and Vascular Biology, The Rockefeller University, New York, NY.
Article Synopsis
- - Monoclonal antibodies (mAbs) have been used to study the platelet αIIbβ3 protein, and a new mAb called R21D10 was identified that interferes with protein disulfide isomerase (PDI) binding to activated platelets.
- - R21D10 not only inhibits PDI binding but also affects fibrinogen and PAC-1 binding, as well as platelet aggregation induced by specific peptides, without impacting the binding of other known mAbs against αIIbβ3.
- - Structural analysis using cryogenic electron microscopy showed that R21D10 binds to a specific domain on β3 integrin and induces conformational changes in αIIbβ3, suggesting a
Recombinant hirudin suppresses angiogenesis of diffuse large B-cell lymphoma through regulation of the PAR-1-VEGF.
Chem Biol Drug Des
May 2024
Department of Hematology, The First People's Hospital of Yunnan Province, Kunming, China.
Hirudin is one of the specific inhibitors of thrombin, which has been confirmed to have strong bioactivities, including inhibiting tumors. However, the function and mechanism of hirudin and protease-activated receptor 1 (PAR-1) in diffuse large B-cell lymphoma (DLBCL) have not been clear. Detecting the expression PAR-1 in DLBCL tissues and cells by RT-qPCR and IHC.
View Article and Find Full Text PDFThrombin-Induced COX-2 Expression and PGE Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation.
Int J Mol Sci
October 2023
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan.
In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs).
View Article and Find Full Text PDFAn siRNA library screen identifies CYLD and USP34 as deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses.
J Biol Chem
December 2023
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California, USA. Electronic address:
G protein-coupled receptors (GPCRs) are highly druggable and implicated in numerous diseases, including vascular inflammation. GPCR signals are transduced from the plasma membrane as well as from endosomes and controlled by posttranslational modifications. The thrombin-activated GPCR protease-activated receptor-1 is modified by ubiquitin.
View Article and Find Full Text PDFThrombin-Induced Microglia Activation Modulated through Aryl Hydrocarbon Receptors.
Int J Mol Sci
July 2023
Department of Medical Research, Taichung Veterans General Hospital, Taichung 40210, Taiwan.
Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!