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

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10722231, 11, 12262822, 48G-protein alpha Thrombin-activated PARGq Heterotrimeric G-protein Gq G-protein alpha Heterotrimeric G-protein Gq/11 Thrombin-activated PAR Activated PAR1Beta-arrestin-1 G-protein alpha G-protein beta-gamma complex Heterotrimeric G-protein G12 Thrombin-activated PAR Activated PAR1Beta-arrestin-1Activated SrcActivated ERK Thrombin-activated PARGq G-protein G12/G13 G-protein alpha ERK G-protein G12/G13 G-protein alpha G-protein beta-gamma complex G-protein alpha Thrombin activated PARG12/13 G-protein alpha Activated PAR1Beta-arrestin-1 cytosolG-protein alpha G-protein alpha Activated PAR1Beta-arrestin-2 Activated PAR1Beta-arrestin-1 G-protein alpha G-protein beta-gamma complex Heterotrimeric G-protein G13 G-protein beta-gamma complex G-protein alpha Phospho-ERK G-protein beta-gamma complex ERK Activated PAR1Beta-arrestin-1SrcERK Heterotrimeric G-protein G13 Heterotrimeric G-protein G12 Activated PAR1Beta-arrestin-2SrcERK Thrombin activated PARG12/13 Activated PAR1Beta-arrestin-1Activated SrcERK Activated PAR1Beta-arrestin-2 G-protein alpha Heterotrimeric G-protein Gq/11 G-protein alpha Heterotrimeric G-protein G12 G-protein beta-gamma complex G-protein G12/G13 Activated PAR1Beta-arrestin-1 G-protein G12/G13 Heterotrimeric G-protein G13 Thrombin-activated PAR G-protein beta-gamma complex G-protein alpha Heterotrimeric G-protein G12 G-protein beta-gamma complex G-protein alpha G-protein alpha G-protein alpha G-protein alpha Heterotrimeric G-protein G13 ERK Activated thrombin Thrombin-activated PAR G-protein alpha ERKGTPGTP GNA14 GNAQ F2R Activated PAR1Beta-arrestin-1Activated SrcERKGNA11 Thrombin-activated PARCa2+ GNA12F2RF2R F2R Activated thrombin F2RL2 PAR1, 3, 4G-protein alpha F2R p-T202,Y204-MAPK3 GNA15 GNA12GTP GDP ARRB1 G-protein G12/G13 F2RL3 Activated PAR1Beta-arrestin-1Activated SrcActivated ERKARRB1 F2R F2RL3 GNA15 GNA11 GNA13 GDP Activated PAR1Beta-arrestin-1SrcERKF2R GDP ARRB1 PAR N-teminal fragmentsActivated PAR1Beta-arrestin-1GTP MAPK1 Thrombin-activated PARGq G-protein beta-gamma complexSRC-1 ARRB1thrombin heavy chain GNA15 ARRB2 p-T185,Y187-MAPK1 GNA11 MAPK3 GNA12ARRB2 MAPK3 GNA14 ARRB2F2R F2RL3 GNAQ GNAQ GNA13 F2RL2 GTP ARRB1 GNAQ GNA11 GTP GNA14 G-protein alpha GNA14 GDPActivated SRC-1 Heterotrimeric G-protein Gq/11 GNA12Activated PAR1Beta-arrestin-2GNA15 F2RL2 GDP F2RL3 Activated PAR1Beta-arrestin-2SrcERKF2R F2R G-protein G12/G13 MAPK1 GNA12Activated SRC-1 MAPK1 F2RL2 SRC-1 thrombin light chain SRC-1GNA13 F2R Thrombin activated PARG12/13 GNA13 Thrombin-activated PARGq MAPK3 Thrombin activated PARG12/13 GNA13 5, 95, 9


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=456926

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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 Scholia
  2. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC Scholia
  3. 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 Scholia
  4. Coughlin SR.; ''Protease-activated receptors in hemostasis, thrombosis and vascular biology.''; PubMed Europe PMC Scholia
  5. 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 Scholia
  6. 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 Scholia
  7. Coughlin SR.; ''Thrombin signalling and protease-activated receptors.''; PubMed Europe PMC Scholia
  8. 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 Scholia
  9. 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 Scholia
  10. 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 Scholia
  11. Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC Scholia
  12. Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
116436view09:42, 7 May 2021EweitzModified title
114789view16:28, 25 January 2021ReactomeTeamReactome version 75
113233view11:30, 2 November 2020ReactomeTeamReactome version 74
112454view15:40, 9 October 2020ReactomeTeamReactome version 73
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 ERK		ComplexREACT_24392 (Reactome)
Activated PAR1

Beta-arrestin-1 Activated Src

ERK		ComplexREACT_24357 (Reactome)
Activated PAR1

Beta-arrestin-1 Src

ERK		ComplexREACT_24135 (Reactome)
Activated PAR1 Beta-arrestin-1ComplexREACT_24414 (Reactome)
Activated PAR1

Beta-arrestin-2 Src

ERK		ComplexREACT_24842 (Reactome)
Activated PAR1 Beta-arrestin-2ComplexREACT_24025 (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.
Activated thrombin ComplexREACT_3298 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
ERKProteinREACT_24485 (Reactome)
F2R ProteinP25116 (Uniprot-TrEMBL)
F2RL2 ProteinO00254 (Uniprot-TrEMBL)
F2RL3 ProteinQ96RI0 (Uniprot-TrEMBL)
F2RProteinP25116 (Uniprot-TrEMBL)
G-protein G12/G13 ComplexREACT_17117 (Reactome)
G-protein G12/G13 ComplexREACT_17446 (Reactome)
G-protein alpha ComplexREACT_20092 (Reactome)
G-protein alpha ComplexREACT_5863 (Reactome)
G-protein beta-gamma complexComplexREACT_15674 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNA11 ProteinP29992 (Uniprot-TrEMBL)
GNA12ProteinQ03113 (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 ComplexREACT_5130 (Reactome)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
PAR N-teminal fragmentsProteinREACT_21736 (Reactome)
PAR1, 3, 4ProteinREACT_21743 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
Thrombin activated PAR G12/13 ComplexREACT_17549 (Reactome)
Thrombin activated PAR G12/13 ComplexREACT_18059 (Reactome)
Thrombin-activated PAR Gq ComplexREACT_17562 (Reactome)
Thrombin-activated PAR Gq ComplexREACT_17676 (Reactome)
Thrombin-activated PARProteinREACT_5629 (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
ARRB1REACT_23835 (Reactome)
ARRB2REACT_23805 (Reactome)
Activated PAR1

Beta-arrestin-1 Activated Src

ERK		mim-catalysisREACT_23900 (Reactome)
Activated PAR1 Beta-arrestin-1REACT_23781 (Reactome)
Activated PAR1 Beta-arrestin-2REACT_23960 (Reactome)
Activated thrombin mim-catalysisREACT_72 (Reactome)
ERKREACT_23781 (Reactome)
ERKREACT_23960 (Reactome)
F2RREACT_23805 (Reactome)
F2RREACT_23835 (Reactome)
G-protein G12/G13 REACT_23839 (Reactome)
G-protein alpha ArrowREACT_23796 (Reactome)
G-protein alpha ArrowREACT_23818 (Reactome)
G-protein beta-gamma complexArrowREACT_23796 (Reactome)
G-protein beta-gamma complexArrowREACT_23818 (Reactome)
GDPArrowREACT_1430 (Reactome)
GDPArrowREACT_637 (Reactome)
GTPREACT_1430 (Reactome)
GTPREACT_637 (Reactome)
Heterotrimeric G-protein Gq/11 REACT_23902 (Reactome)
PAR N-teminal fragmentsArrowREACT_72 (Reactome)
REACT_1430 (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.
REACT_23781 (Reactome) Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling
REACT_23796 (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).
REACT_23805 (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.
REACT_23818 (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).
REACT_23835 (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.
REACT_23839 (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.
REACT_23899 (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.
REACT_23900 (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.
REACT_23902 (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).
REACT_23958 (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.
REACT_23960 (Reactome) Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling
REACT_637 (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.

REACT_72 (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.
SRC-1REACT_23781 (Reactome)
SRC-1REACT_23960 (Reactome)
Thrombin activated PAR G12/13 ArrowREACT_637 (Reactome)
Thrombin activated PAR G12/13 REACT_637 (Reactome)
Thrombin-activated PAR Gq ArrowREACT_1430 (Reactome)
Thrombin-activated PAR Gq REACT_1430 (Reactome)
Thrombin-activated PARArrowREACT_23796 (Reactome)
Thrombin-activated PARArrowREACT_23818 (Reactome)
Thrombin-activated PARArrowREACT_72 (Reactome)
Thrombin-activated PARREACT_23839 (Reactome)
Thrombin-activated PARREACT_23902 (Reactome)
Thrombin-activated PARmim-catalysisREACT_1430 (Reactome)
Thrombin-activated PARmim-catalysisREACT_637 (Reactome)
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