Thrombin-mediated activation of Proteinase-activated receptors

Stable Identifier
R-HSA-114697
Type
Reaction [transition]
Species
Homo sapiens
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Thrombin signaling is mediated at least in part by a small family of G protein-coupled Proteinase Activated Receptors (PARs). Human platelet activation by thrombin is mediated predominantly by PAR1; PAR4-induced platelet responses are less pronounced. PAR2 is not present in human platelets. PARs 1, 3 and 4 are activated when thrombin cleaves an N-terminal exodomain. This cleavage event unmasks a new N-terminus that serves as a tethered ligand that binds intramolecularly to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but, not surprisingly, appears to be less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. In addition to providing evidence for the tethered ligand mechanism, such tethered ligand-mimicking peptides have provided a convenient pharmacological tool for probing the effects of PAR activation in cells and tissues.

Literature References
PubMed ID Title Journal Year
9618465 Cloning and characterization of human protease-activated receptor 4

Xu, WF, Andersen, H, Whitmore, TE, Presnell, SR, Yee, DP, Ching, A, Gilbert, T, Davie, EW, Foster, DC

Proc Natl Acad Sci U S A 1998
9087410 Protease-activated receptor 3 is a second thrombin receptor in humans

Ishihara, H, Connolly, AJ, Zeng, D, Kahn, ML, Zheng, YW, Timmons, C, Tram, T, Coughlin, SR

Nature 1997
1672265 Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation

Vu, TK, Hung, DT, Wheaton, VI, Coughlin, SR

Cell 1991
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Catalyst Activity
Title
serine-type endopeptidase activity of activated thrombin (factor IIa) [extracellular region]
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Activity
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Created