Thrombin signalling through proteinase activated receptors (PARs) (Homo sapiens)

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92225672223, 8, 121, 2611cytosolGNA15 p-T185,Y187-MAPK1 SRC-1 F2R F2R ActivatedPAR1:Beta-arrestin-1:Src:ERKSRC-1GDP GNA13 MAPKsARRB1 F2R Thrombin activatedPAR:G12/13(inactive)G-protein alpha(12/13):GTPGNA14 F2RL3 SRC-1 Activated SRC-1 F2RGNA11 MAPK3 F2R GNA11 F2R G-protein alpha(q/11): GTPGNA12 ARRB1 G-protein G12/G13(inactive)G-protein G12/G13(active)GNA12 GDPMAPK3 GDP GNA14 MAPK3 F2RL3 ARRB2 GNAQ GNA12 PAR N-teminalfragmentsF2RL2 F2R Thrombin-activatedPAR:Gq (active)ARRB1GNA14 ARRB2MAPK1 GTP GDP Thrombin-activatedPARPAR1, 3, 4GNA13 F2R MAPK1 GNAQ ActivatedPAR1:Beta-arrestin-2:Src:ERKThrombin-activatedPAR:Gq (inactive)MAPK1 G-protein beta-gammacomplexGNA15 ActivatedPAR1:Beta-arrestin-1:Activated Src:Activated ERKGTP GNA15 GDP F2RL2 GNA13 Ca2+ ActivatedPAR1:Beta-arrestin-2HeterotrimericG-protein Gq/11(inactive)thrombin light chainF2RL2 ActivatedPAR1:Beta-arrestin-1:Activated Src:ERKactivated thrombin(factor IIa)GNA12 ActivatedPAR1:Beta-arrestin-1F2R Thrombin activatedPAR:G12/13 (active)GNA11 ARRB1 F2R GTPF2R Activated SRC-1 F2RL3 GNAQ GTP p-T202,Y204-MAPK3 thrombin heavy chainARRB2 F2RL2 GNA12 ARRB1 GTP GNA14 GNA11 GTP F2RL3 GNA13 GNAQ GNA15 GNA13 4, 104, 10


Description

Thrombin activates proteinase activated receptors (PARs) that signal through heterotrimeric G proteins of the G12/13 and Gq families, thereby connecting to a host of intracellular signaling pathways. Thrombin activates PARs by cleaving an N-terminal peptide that then binds to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but is 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. PARs are key to platelet activation. Four PARs have been identified, of which PARs 1 ,3 and 4 are substrates for thrombin. In humans PAR 1 is the predominant thrombin receptor followed by PAR4 which is less responsive to thrombin. PAR 3 is not considered important for human platelet responses as it is minimally expressed, though this is not the case for mouse. PAR2 is not expressed in platelets. In mouse platelets, Gq is necessary for platelet secretion and aggregation in response to thrombin but is not necessary for thrombin-triggered shape change. G13 appears to contribute to platelet aggregation as well as shape change in response to low concentrations of thrombin but to be unnecessary at higher agonist concentrations; G12 appears to be dispensable for thrombin signaling in platelets. G alpha (q) activates phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gbeta:gamma subunits can activate phosphoinositide-3 kinase and other lipid modifying enzymes, protein kinases, and channels. PAR1 activation indirectly leads to activation of cell surface 'sheddases' that liberate ligands for receptor tyrosine kinases, providing a link between thrombin and receptor tyrosine kinases involved in cell growth and differentiation. The pleiotrophic effects of PAR activation are consistent with many of thrombin's diverse actions on cells. Source:Reactome.

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Bibliography

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  1. Ogino Y, Tanaka K, Shimizu N.; ''Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells.''; PubMed Europe PMC
  2. Offermanns S, Laugwitz KL, Spicher K, Schultz G.; ''G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets.''; PubMed Europe PMC
  3. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ.; ''Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.''; PubMed Europe PMC
  4. Coughlin SR.; ''Thrombin signalling and protease-activated receptors.''; PubMed Europe PMC
  5. Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR.; ''Protease-activated receptor 3 is a second thrombin receptor in humans.''; PubMed Europe PMC
  6. Kuo FT, Lu TL, Fu HW.; ''Opposing effects of beta-arrestin1 and beta-arrestin2 on activation and degradation of Src induced by protease-activated receptor 1.''; PubMed Europe PMC
  7. Vu TK, Hung DT, Wheaton VI, Coughlin SR.; ''Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.''; PubMed Europe PMC
  8. Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC.; ''Cloning and characterization of human protease-activated receptor 4.''; PubMed Europe PMC
  9. Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC
  10. Coughlin SR.; ''Protease-activated receptors in hemostasis, thrombosis and vascular biology.''; PubMed Europe PMC
  11. Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC
  12. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101361view11:25, 1 November 2018ReactomeTeamreactome version 66
100899view20:59, 31 October 2018ReactomeTeamreactome version 65
100440view19:34, 31 October 2018ReactomeTeamreactome version 64
99989view16:18, 31 October 2018ReactomeTeamreactome version 63
99543view14:52, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99177view12:42, 31 October 2018ReactomeTeamreactome version 62
93866view13:41, 16 August 2017ReactomeTeamreactome version 61
93431view11:23, 9 August 2017ReactomeTeamreactome version 61
86523view09:20, 11 July 2016ReactomeTeamreactome version 56
83369view11:01, 18 November 2015ReactomeTeamVersion54
81531view13:04, 21 August 2015ReactomeTeamVersion53
77002view08:29, 17 July 2014ReactomeTeamFixed remaining interactions
76707view12:07, 16 July 2014ReactomeTeamFixed remaining interactions
76033view10:09, 11 June 2014ReactomeTeamRe-fixing comment source
75742view11:22, 10 June 2014ReactomeTeamReactome 48 Update
75092view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74739view08:49, 30 April 2014ReactomeTeamReactome46
68952view17:37, 8 July 2013MaintBotUpdated to 2013 gpml schema
45083view20:47, 6 October 2011KhanspersOntology Term : 'G protein mediated signaling pathway' added !
42144view22:00, 4 March 2011MaintBotAutomatic update
39955view05:58, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ARRB1 ProteinP49407 (Uniprot-TrEMBL)
ARRB1ProteinP49407 (Uniprot-TrEMBL)
ARRB2 ProteinP32121 (Uniprot-TrEMBL)
ARRB2ProteinP32121 (Uniprot-TrEMBL)
Activated PAR1:Beta-arrestin-1:Activated Src:Activated ERKComplexR-HSA-418210 (Reactome)
Activated PAR1:Beta-arrestin-1:Activated Src:ERKComplexR-HSA-418144 (Reactome)
Activated PAR1:Beta-arrestin-1:Src:ERKComplexR-HSA-418103 (Reactome)
Activated PAR1:Beta-arrestin-1ComplexR-HSA-418080 (Reactome)
Activated PAR1:Beta-arrestin-2:Src:ERKComplexR-HSA-418179 (Reactome)
Activated PAR1:Beta-arrestin-2ComplexR-HSA-418167 (Reactome) Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling.
Activated SRC-1 ProteinP12931-1 (Uniprot-TrEMBL) This entity represents Src activated by an uncharacterised mechanism and phosphorylation state.
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
F2R ProteinP25116 (Uniprot-TrEMBL)
F2RL2 ProteinO00254 (Uniprot-TrEMBL)
F2RL3 ProteinQ96RI0 (Uniprot-TrEMBL)
F2RProteinP25116 (Uniprot-TrEMBL)
G-protein G12/G13 (active)ComplexR-HSA-398080 (Reactome)
G-protein G12/G13 (inactive)ComplexR-HSA-398082 (Reactome)
G-protein alpha (12/13):GTPComplexR-HSA-418572 (Reactome)
G-protein alpha (q/11): GTPComplexR-HSA-114534 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNA11 ProteinP29992 (Uniprot-TrEMBL)
GNA12 ProteinQ03113 (Uniprot-TrEMBL)
GNA13 ProteinQ14344 (Uniprot-TrEMBL)
GNA14 ProteinO95837 (Uniprot-TrEMBL)
GNA15 ProteinP30679 (Uniprot-TrEMBL)
GNAQ ProteinP50148 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Heterotrimeric

G-protein Gq/11

(inactive)
ComplexR-HSA-114557 (Reactome)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPKsProteinR-HSA-169291 (Reactome)
PAR N-teminal fragmentsProteinR-HSA-453303 (Reactome)
PAR1, 3, 4ProteinR-HSA-453302 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
Thrombin activated

PAR:G12/13

(inactive)
ComplexR-HSA-397883 (Reactome)
Thrombin activated PAR:G12/13 (active)ComplexR-HSA-397884 (Reactome)
Thrombin-activated PAR:Gq (active)ComplexR-HSA-397802 (Reactome)
Thrombin-activated PAR:Gq (inactive)ComplexR-HSA-397803 (Reactome)
Thrombin-activated PARProteinR-HSA-114530 (Reactome)
activated thrombin (factor IIa)ComplexR-HSA-156786 (Reactome)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ARRB1R-HSA-418091 (Reactome)
ARRB2R-HSA-418172 (Reactome)
Activated PAR1:Beta-arrestin-1:Activated Src:Activated ERKArrowR-HSA-418163 (Reactome)
Activated PAR1:Beta-arrestin-1:Activated Src:ERKArrowR-HSA-418158 (Reactome)
Activated PAR1:Beta-arrestin-1:Activated Src:ERKR-HSA-418163 (Reactome)
Activated PAR1:Beta-arrestin-1:Activated Src:ERKmim-catalysisR-HSA-418163 (Reactome)
Activated PAR1:Beta-arrestin-1:Src:ERKArrowR-HSA-418170 (Reactome)
Activated PAR1:Beta-arrestin-1:Src:ERKR-HSA-418158 (Reactome)
Activated PAR1:Beta-arrestin-1ArrowR-HSA-418091 (Reactome)
Activated PAR1:Beta-arrestin-1R-HSA-418170 (Reactome)
Activated PAR1:Beta-arrestin-2:Src:ERKArrowR-HSA-418176 (Reactome)
Activated PAR1:Beta-arrestin-2:Src:ERKArrowR-HSA-418200 (Reactome)
Activated PAR1:Beta-arrestin-2:Src:ERKR-HSA-418200 (Reactome)
Activated PAR1:Beta-arrestin-2ArrowR-HSA-418172 (Reactome)
Activated PAR1:Beta-arrestin-2R-HSA-418176 (Reactome)
F2RR-HSA-418091 (Reactome)
F2RR-HSA-418172 (Reactome)
G-protein G12/G13 (inactive)R-HSA-396941 (Reactome)
G-protein alpha (12/13):GTPArrowR-HSA-397891 (Reactome)
G-protein alpha (q/11): GTPArrowR-HSA-397835 (Reactome)
G-protein beta-gamma complexArrowR-HSA-397835 (Reactome)
G-protein beta-gamma complexArrowR-HSA-397891 (Reactome)
GDPArrowR-HSA-114552 (Reactome)
GDPArrowR-HSA-114558 (Reactome)
GTPR-HSA-114552 (Reactome)
GTPR-HSA-114558 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)
R-HSA-396996 (Reactome)
MAPKsR-HSA-418170 (Reactome)
MAPKsR-HSA-418176 (Reactome)
PAR N-teminal fragmentsArrowR-HSA-114697 (Reactome)
PAR1, 3, 4R-HSA-114697 (Reactome)
R-HSA-114552 (Reactome) PAR1, 3 and 4 have been shown to directly couple with G12/13 (Offermanns et al. 1994). G12 and G13 have overlapping but distinct signalling roles (Suzuki et al. 2009). Evidence from conditional knockout mice (KOs) suggests that G13 is the subtype responsible for platelet shape change and aggregation responses in response to low and intermediate concentrations of thrombin, thromboxane and collagen. Platelets from G12 KOs were indistinguishable from wild-type, while those from mice with disrupted G13 had impaired shape change and aggregation responses, failed to form stable thrombi ex vivo, and exhibited a large increase in tailbleeding times (Moers et al. 2003). Both subtypes of G12/13 are unnecessary for platelet shape change and aggregation at higher agonist concentrations. The alpha-subunits of G12 and 13 bind RhoGEFs (guanine nucleotide exchange factors, which activate small G proteins) providing a path to Rho-mediated cytoskeletal responses that are involved in shape change in platelets and permeability and migration in endothelial cells.

R-HSA-114558 (Reactome) Activated PAR stimulates the G alpha (q) subunit to release GDP and bind GTP (which is present in much greater concentrations physiologically). This activation is required for Gq to participate in downstream signalling events.
R-HSA-114697 (Reactome) 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.
R-HSA-396941 (Reactome) Thrombin receptors activate G-proteins in the G12/13 family. Gq knockout mice exhibit defective platelet activation, but retain shape change responses to thrombin, mediated by G12/13.
R-HSA-396996 (Reactome) Thrombin signalling through PARs is mediated in part through the Gq family of G-proteins. Gq knockout mice have defective platelet responses to thrombin (as well as to ADP and thromboxane).
R-HSA-397835 (Reactome) The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
R-HSA-397891 (Reactome) The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
R-HSA-418091 (Reactome) Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling.
R-HSA-418158 (Reactome) The activity of Src-kinase is increased when bound to Beta-arrestin-1. The mechanism for this activation is not clear. Src bound to beta -arrestin 1 is substantially dephosphorylated at Tyr530 and this is often associated with Src activation. Binding results with Y530F mutants of Src suggest that binding of Src to arrestin causes a conformational activation of the kinase, rather than a change in phosphorylation. However, increased phosphorylation of Src Tyr419 in cells overexpressing beta-arrestin-1 has been reported to correlate with PAR1 activation, beta-arrestin signalling complex formation, and increased ERK activation.
R-HSA-418163 (Reactome) Within the beta-arrestin-1:Src:ERK complex, activated Src phosphorylates and activates ERK. ERK activation requires dual Thr and Tyr phosphorylations, at Thr202/Tyr204 for human ERK1 and Thr185/Tyr187 for human ERK2. Significant ERK activation requires phosphorylation at both sites, with Tyr phosphorylation preceding that of Thr. This reaction is given as a black-box event because the phosphorylation state of ERK on binding to beta-arrestin-1 is unknown.
R-HSA-418170 (Reactome) Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling
R-HSA-418172 (Reactome) Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling.
R-HSA-418176 (Reactome) Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling
R-HSA-418200 (Reactome) Activated PAR1 can induce the formation of signalling complexes with a beta-arrestin scaffold. When beta-arrestin-1 is incorporated this leads to Src and subsequent ERK activation. In contrast, complexes containing beta-arrestin-2 do not lead to Src and ERK activation.
SRC-1R-HSA-418170 (Reactome)
SRC-1R-HSA-418176 (Reactome)
Thrombin activated

PAR:G12/13

(inactive)
ArrowR-HSA-396941 (Reactome)
Thrombin activated

PAR:G12/13

(inactive)
R-HSA-114552 (Reactome)
Thrombin activated PAR:G12/13 (active)ArrowR-HSA-114552 (Reactome)
Thrombin activated PAR:G12/13 (active)R-HSA-397891 (Reactome)
Thrombin-activated PAR:Gq (active)ArrowR-HSA-114558 (Reactome)
Thrombin-activated PAR:Gq (active)R-HSA-397835 (Reactome)
Thrombin-activated PAR:Gq (inactive)ArrowR-HSA-396996 (Reactome)
Thrombin-activated PAR:Gq (inactive)R-HSA-114558 (Reactome)
Thrombin-activated PARArrowR-HSA-114697 (Reactome)
Thrombin-activated PARArrowR-HSA-397835 (Reactome)
Thrombin-activated PARArrowR-HSA-397891 (Reactome)
Thrombin-activated PARR-HSA-396941 (Reactome)
Thrombin-activated PARR-HSA-396996 (Reactome)
Thrombin-activated PARmim-catalysisR-HSA-114552 (Reactome)
Thrombin-activated PARmim-catalysisR-HSA-114558 (Reactome)
activated thrombin (factor IIa)mim-catalysisR-HSA-114697 (Reactome)
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