PARticipation in inflammation

Coughlin, Shaun R.; Camerer, Eric

doi:10.1172/jci17564

Cited by 219 publications

(170 citation statements)

References 21 publications

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“…Genetic evidence established an essential in vivo role of PAR signaling for platelet activation and the hemostatic response (2,3). However, PAR signaling also has important nonhemostatic functions in development (4), inflammation (5), and tumor biology (6). All PARs, except for PAR2, are directly activated by thrombin, and PAR signaling is typically attributed to the action of thrombin in vivo.…”

Section: From the Scripps Research Institute La Jolla California 92037mentioning

confidence: 99%

Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain

Ahamed

Ruf

2004

Journal of Biological Chemistry

124

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Tissue factor (TF) is the physiological activator of the coagulation cascade that plays pathophysiological roles in metastasis, angiogenesis, and inflammation. Downstream in coagulation, thrombin is the central protease that signals through G protein-coupled, protease-activated receptors (PARs). However, the TF-VIIa-Xa complex upstream in coagulation also activates PAR1 and 2. Here, we address the question of whether signaling of the TF initiation complex is a relevant pathway that leads to TF cytoplasmic domain phosphorylation. In heterologous expression systems and primary endothelial cells, we demonstrate that the ternary TF-VIIa-Xa complex induces TF phosphorylation specifically by activating PAR2 but not through PAR1 signaling. In addition, TF cytoplasmic domain phosphorylation is induced only by TF-dependent signaling but not by other coagulation factors in endothelial cells. Phosphorylation of the Prodirected kinase target site Ser 258 is dependent on prior phosphorylation of Ser 253 by protein kinase C (PKC) ␣. TF phosphorylation is somewhat delayed and coincides with sustained PKC␣ activation downstream of PAR2 but not PAR1 signaling. Phosphatidylcholine-dependent phospholipase C is the major pathway that leads to prolonged PKC␣ recruitment downstream of PAR2. Thus, PAR2 signaling specifically phosphorylates TF in a receptor cross-talk that distinguishes upstream from downstream coagulation protease signaling.

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Section: From the Scripps Research Institute La Jolla California 92037mentioning

confidence: 99%

Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain

Ahamed

Ruf

2004

Journal of Biological Chemistry

124

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“…Thrombin activation of platelets through PARs is central to their haemostatic and prothrombotic functions 6,7 and leads to the generation and release of a broad range of proinflammatory molecules 8,9 . Thrombin activation of endothelial and immune effector cells induces the production of several growth factors, chemokines and cytokines 4,10,11 and also alters their adhesive phenotype 12,13 . Thrombin stimulation of endothelial cells via PAR1 induces signalling predominantly via the NF-kB pathway, resulting in the expression of a broad range of chemokines including interleukin (IL)-6 (ref.…”

mentioning

confidence: 99%

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

et al. 2015

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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIba and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIba, as seen in mice with abrogated thrombin-platelet GPIba binding (hGPIba D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIba and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

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“…Four members of this receptor family have been cloned thus far (19). PAR signaling in human platelets is thought to be carried out primarily via PAR-1 and PAR-4, whereas PAR-1 and the trypsin-sensitive PAR-2 (19) are the predominant isoforms expressed in the endothelium (20,21). Coupling to members of the G i/o , G q , and G 12/13 families (22)(23)(24)(25), activation of PAR-1 can lead to modulation of various signaling pathways, which in turn control cell shape and mobility, secretion, integrin activation, and metabolic and transcriptional responses.…”

mentioning

confidence: 99%

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

McLaughlin¹,

Mazzoni

Cleator

et al. 2005

Journal of Biological Chemistry

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PARticipation in inflammation

Cited by 219 publications

References 21 publications

Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain

Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain

Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

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