A 14 amino acid peptide derived from the amino terminus of the cleaved thrombin receptor elevates intracellular calcium and stimulates prostacyclin production in human endothelial cells

Ngaiza, Justinian R.; Jaffe, Eric

doi:10.1016/0006-291x(91)91765-5

Cited by 91 publications

(39 citation statements)

References 9 publications

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“…Moreover, when measured by phosphoinositide hydrolysis, thrombin signaling in HUVECs was not diminished by pretreatment with PMA (not shown). Thrombin responses in HUVECs are PAR1-dependent (16,33,34); thus, at face value, the level of shedding achieved under the conditions employed in our studies is insufficient to attenuate cellular responses to thrombin, at least as measured by intracellular calcium flux and phosphoinositide hydrolysis.…”

Section: Resultsmentioning

confidence: 81%

“…Physiologically reasonable concentrations of thrombin (1-10 nM) cleave and activate the majority of PAR1 molecules on a cell surface within a few minutes, consistent with the rapid tempo of many biologically important responses to thrombin. Signaling by individual PAR1 molecules is also terminated within minutes by a mechanism that depends upon receptor phosphorylation (29), and desensitization of cells to thrombin occurs over the same time frame (16,25,33). By contrast, induced shedding of the PAR1 N-terminal exodomain by either PMA or by PAR1/PAR2 activation took ϳ30 min to reach half-maximal levels, and at 1 h only 60 -70% of receptor N-terminal exodomains were shed.…”

Section: Discussionmentioning

confidence: 99%

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Regulated Shedding of PAR1 N-terminal Exodomain from Endothelial Cells

Ludeman

Zheng

Ishii

et al. 2004

Journal of Biological Chemistry

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G protein-coupled receptors can trigger metalloproteinase-dependent shedding of proteins from the cell surface. We now report that G protein-coupled receptors can themselves undergo regulated metalloproteinasedependent shedding. The N-terminal exodomain of protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, displayed regulated shedding in endothelial cells, which normally express this receptor. Cleavage occurred at a site predicted to render the receptor unresponsive to thrombin. A chimeric protein in which the N-terminal exodomain of PAR1 was fused to an unrelated transmembrane segment was shed as efficiently as PAR1, shedding of both proteins was stimulated by phorbol ester and by a PAR1 agonist. TNF␣ protease inhibitor-2 (TAPI-2), phenanthroline, and tissue inhibitor of metalloproteinase-3 (TIMP-3) but not TIMP-1 or -2 inhibited such shedding. These and other data suggest that the information that specifies PAR1 shedding resides within its N-terminal exodomain rather than its heptahelical segment, that activation of protein kinase C or of PAR1 itself can stimulate PAR1 shedding in trans, and that ADAM17/TACE or a metalloproteinase with similar properties mediates PAR1 shedding. Regulated shedding reduced the amount of cell surface PAR1 available for productive cleavage by thrombin by half or more, but thus far we have been unable to demonstrate an effect of PAR1 shedding on cellular responsiveness to thrombin. Nonetheless, regulated shedding of G protein-coupled receptors represents a new mechanism by which signaling by this important class of receptors might be modulated.

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Section: Resultsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Regulated Shedding of PAR1 N-terminal Exodomain from Endothelial Cells

Ludeman

Zheng

Ishii

et al. 2004

Journal of Biological Chemistry

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“…Thrombin receptors have been identified on platelets (10), endothelial cells (10,12), fibroblasts (13,14), vascular smooth muscle cells (9,15), and other cell types. The thrombin receptor contains seven hydrophobic (membrane-spanning) domains and belongs to the family of G protein-coupled receptors (10).…”

Section: Introductionmentioning

confidence: 99%

Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist.

Molloy¹,

Pawlowski²,

Taylor³

et al. 1996

J. Clin. Invest.

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“…The receptor encoded by this clone appears to mediate thrombin-induced platelet activation (20)(21)(22)(23) and can mediate a variety of thrombin responses in cultured fibroblasts and endothelial cells (24)(25)(26). As a first step toward defining the role ofthe thrombin receptor in vivo, we have examined thrombin receptor expression in normal and diseased human blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Thrombin receptor expression in normal and atherosclerotic human arteries.

Nelken

Soifer²,

O'Keefe³

et al. 1992

J. Clin. Invest.

321

185

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Thrombin is a multifunctional serine protease generated at sites of vascular injury. A host of thrombin actions on vascular endothelial cells, smooth muscle cells, and macrophages has been defined in cell culture systems, but the in vivo significance of these activities is unknown. We have defined the expression of the recently identified receptor for thrombin in human arteries by both in situ hybridization and immunohistochemistry. In normal-appearing arteries, thrombin receptor was expressed almost exclusively in the endothelial layer. By contrast, in human atheroma, the receptor was widely expressed, both in regions rich in macrophages and in regions rich in vascular

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A 14 amino acid peptide derived from the amino terminus of the cleaved thrombin receptor elevates intracellular calcium and stimulates prostacyclin production in human endothelial cells

Cited by 91 publications

References 9 publications

Regulated Shedding of PAR1 N-terminal Exodomain from Endothelial Cells

Regulated Shedding of PAR1 N-terminal Exodomain from Endothelial Cells

Thrombin receptor expression in normal and atherosclerotic human arteries.

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