Cell painting with an engineered EPCR to augment the protein C system

Bouwens, Eveline A.; Stavenuiter, Fabian; Mosnier, Laurent O.

doi:10.1160/th15-01-0079

Cited by 10 publications

(15 citation statements)

References 60 publications

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“…This raises the question whether the interaction with EPCR provokes all the various pathological processes initiated by parasite sequestration. EPCR activation of protein C plays an essential role in the regulation of coagulation, vascular inflammation and endothelial permeability (Bouwens et al , ). PfEMP1 binding to EPCR inhibits protein C conversion (Gillrie et al , ; Petersen et al , ; Sampath et al , ), and thus, parasite sequestration through EPCR engagement could directly influence pathogenic processes leading to unfavourable inflammation and coagulation events (Moxon et al , ) as well as leakage through the blood–brain barrier and brain swelling (Seydel et al , ).…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

et al. 2016

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Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR‐binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full‐length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1‐EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction.

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

et al. 2016

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“…Notably, colocalization of EPCR and PAR-1 in lipid rafts/caveolae is reportedly required for APC to cleave PAR-1 and elicit protective cellular responses in endothelial cells (39). EPCR promotes PAR-1 and PAR-3 cleavage via APC (40). Cell membranes display a complex network of lipids and proteins designed to perform essential cell functions (41).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of EPCR inhibits the proliferation and migration of human gastric cancer cells via the ERK1/2 pathway in a PAR-1-dependent manner

et al. 2018

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Endothelial protein C receptor (EPCR) has been implicated in the carcinogenesis of diverse tumor types. This tumor-promoting effect of EPCR is associated with the upregulation of activated protein C and the activation of protease-activated receptor 1 (PAR-1). However, the exact role of EPCR in gastric cancer (GC) and the mechanisms underlying the regulation of EPCR remain elusive. In the present study, we investigated the effects of EPCR on human GC cells, as well as the underlying mechanisms. An siRNA inference system was used to knock down the expression of EPCR in GC cells, and CCK-8, colony formation and Transwell assays were performed to determine the effects of EPCR knockdown on the proliferation and migration of the tumor cells. Additionally, cell cycle distribution and apoptosis were assessed by flow cytometry, and activated PAR-1 levels were determined by cell ELISA. The results indicated that the proliferation, clonogenicity and migration were significantly reduced and that the cell cycle was arrested in the Gap 1 phase by EPCR knockdown in SGC7901 and AGS cells. Meanwhile, apoptosis was promoted by EPCR knockdown in the two cell lines. The activation of PAR-1 on the cell surface of SGC7901 and AGS cells was significantly reduced after the knockdown of EPCR. By contrast, blockade of PAR-1 reduced the proliferation and migration of gastric cells in vitro. Additionally, after the knockdown of EPCR or treatment with PAR-1 antibody, the expression of pERK1/2 was significantly downregulated in the SGC7901 and AGS cells, while the expression levels of p-AKT (S473) and p-AKT (T308) were unchanged. The findings of the present study demonstrated that EPCR exerts pro-carcinogenic effects in GC cells in a PAR-1-dependent manner via the ERK1/2-MAPK pathway. Thus, EPCR may be a potential molecular diagnostic or therapeutic target for GC.

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“…From this perspective, the protective effects of thrombin are attractive in the development of therapeutic approaches. EPCR is thought to be a key molecule in mediating the protective effects of thrombin, and therapeutic methods employing recombinant EPCRs are being developed [44,63,64]. However, the mechanisms leading to switching between the protective and deleterious signaling via thrombin remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional Pathologic Effects of Thrombin

Hidai¹

2018

Anat Physiol

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Hemostasis is an essential reaction in organisms with circulatory systems. To stop bleeding as soon as possible, reactions of the coagulation system proceed rapidly and are regulated by positive feedback loops. However, coagulation can be harmful when induced at inappropriate sites, potentially resulting in local thromboembolisms in vital organs such as the heart and brain and systemic microthrombi in conditions such as disseminated intravascular coagulopathy. Increasingly, reports indicate that coagulation-related factors can cause serious diseases without obvious thromboembolism-associated ischemia, for example, atherosclerosis and Alzheimer disease. Thrombin is an essential coagulation factor that can also cause tissue injury, particular to endothelial cells. However, thrombin can also function as a tissue-protective factor depending on conditions. Endothelial protein C receptor (EPCR) and protease-activated receptors (PARs) regulate thrombin activity, but many details regarding the mechanisms remain unknown. This short review summarizes the bidirectional effects of thrombin signaling via EPCR and PAR1 and discusses points relevant to translating the tissue-protective effects of thrombin into clinical benefits.

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Cell painting with an engineered EPCR to augment the protein C system

Cited by 10 publications

References 60 publications

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

Knockdown of EPCR inhibits the proliferation and migration of human gastric cancer cells via the ERK1/2 pathway in a PAR-1-dependent manner

Bidirectional Pathologic Effects of Thrombin

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