Cellular consequences of thrombin-receptor activation

Grand, Roger J. A.; Turnell, Andrew; Grabham, Peter

doi:10.1042/bj3130353

Cited by 346 publications

(296 citation statements)

References 239 publications

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“…It has recently been reported that intracellular S1P is involved in thrombin-stimulated histamine release from mast cells (Gordon et al 2000). The mechanisms governing PAR signaling may vary, depending upon the system studied (Grand et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

Garrido

Segura

Zhang³

et al. 2002

Journal of Neurochemistry

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Section: Discussionmentioning

confidence: 99%

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

Garrido

Segura

Zhang³

et al. 2002

Journal of Neurochemistry

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“…The thrombin receptor is activated when the N-terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor, thus leading to downstream cell signaling events that evoke a variety of cellular responses (Vu et al, 1991;Grand et al, 1996). The pathway of cellular activation and induction of mitogenesis by thrombin is well characterized for fibroblasts and other cell types.…”

Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 99%

“…It involves increases in Ca 2+ and activation of protein kinase C via second messengers, inositol 1,4,5-triphosphate and diacylglycerol (Vouret-Craviari et al, 1992). Furthermore, activation of the thrombin receptor induces intracellular signaling molecules such as Ras, PAR-1 regulation by AP-2 in human melanoma C Tellez and M Bar-Eli phosphoinositide 3-kinase (PI3 K), and mitogen-activated protein kinase (MAPK), which have been shown to be involved in cell growth, tumor promotion, and carcinogenesis (Grand et al, 1996;Macfarlane et al, 2001).…”

Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 99%

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

2003

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To determine treatment strategies and predict the clinical outcome of patients with melanoma it is important to understand the etiology of this disease. Recently, there has been some insight into molecular basis of melanoma including identification of a few of the regulatory factors and genes involved in this disease. For instance, the transcription factor AP-2 plays a tumor suppressor-like role in melanoma progression by regulating genes involved in tumor growth and metastasis. Previously, we have shown that the progression of human melanoma to the metastatic phenotype is associated with loss of AP-2 expression and deregulation of target genes such as MUC18/MCAM, c-KIT, and MMP-2. Increasing evidence demonstrates that the thrombin receptor (proteaseactivated receptor-1, PAR-1) plays a major role in tumor invasion and contributes to the metastatic phenotype of human melanoma. This review focuses on the role of the thrombin receptor in melanoma and its regulation by AP-2. We show that loss of AP-2 expression in metastatic melanoma cells correlates with overexpression of the thrombin receptor. Our analysis of AP-2/Sp1 complexes within the regulatory region of the thrombin receptor demonstrates that AP-2 binds the proximal 3 0 region of the promoter and diminishes PAR-1 expression. Levels of AP-2 and Sp1 proteins in a panel of melanoma cell lines demonstrated a marked decrease in the ratio of AP-2/ Sp1, a decrease that correlated with overexpression of PAR-1 in metastatic melanoma cells. We propose that loss of AP-2 results in increased expression of the thrombin receptor, which subsequently contributes to the metastatic phenotype of melanoma by upregulating the expression of adhesion molecules, proteases, and angiogenic molecules.

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“…In its hemostatic roles, it converts fibrinogen to fibrin, and activates platelet adhesion, aggregation, and secretion. 9 Thrombin also elicits mitogenic responses in retinal pigment epithelial cells, retinal glial cells, vascular endothelial cells, vascular smooth muscle cells, and fibroblasts. 7,10,11 Thrombin has been tried as a therapeutic agent during intra-ocular surgery for diabetic retinopathy and ocular trauma to control bleeding and for macular holes as a mitogen of retinal cells, frequently resulting in severe ocular inflammation.…”

mentioning

confidence: 99%