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

From WikiPathways

Revision as of 16:28, 25 January 2021 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
85, 7, 11912412121243, 12112122cytosolGNG10 G-protein alpha(q/11): GTPF2RL3 ARRB2GNB1 GNG2 GNB1 GNG12 GNAQ GNB1 GNGT2 GNG7 GNG4 F2RL3 GNG7 MAPK3 GNG3 GTP F2RL2 MAPK3 F2R ActivatedPAR1:Beta-arrestin-1:Src:ERKGNGT1 F2RL2(22-38) ARRB1 GNG11 GNB4 GNB4 GNG11 Ca2+ Thrombin-activatedPARF2R(27-41) GNG13 ARRB1GNB4 GNG3 GNG3 GNB3 GNG8 F2R PAR N-teminalfragmentsF2RL2 GNG5 F2RL3 MAPK1 GNG2 GNGT2 GNG4 GNGT2 GNGT2 GNA12 F2R GNB1 GNB5 GNG8 p-T185,Y187-MAPK1 GNG4 GNG5 GNB4 GNG12 ActivatedPAR1:Beta-arrestin-1:Activated Src:ERKGNB3 GNB3 GDP MAPK1 Thrombin-activatedPAR:Gq (inactive)GNG8 G-protein beta-gammacomplexGNG13 GNG7 thrombin light chain GNGT2 Thrombin activatedPAR:G12/13 (active)F2R GNB2 MAPK1 GNB2 SRC-1GNG11 GNG12 GNG2 GNA12 GNG12 GNG5 GNA13 GNG10 SRC-1 GDP GNG2 F2RG-protein G12/G13(inactive)MAPKsGNB4 GNB2 HeterotrimericG-protein Gq/11(inactive)GNG12 Thrombin-activatedPAR:Gq (active)Thrombin activatedPAR:G12/13(inactive)activated thrombin(factor IIa)GNG4 SRC-1 GTP GNB1 ARRB1 GNA15 GNG13 ActivatedPAR1:Beta-arrestin-2F2R(27-425) GTPGNA15 GNA11 GNG2 GNA13 F2RL2(22-374) GNA11 GNA14 GNB3 F2R MAPK3 GNB4 GNB2 GNB2 ARRB1 GNG8 F2R F2R F2R GNA11 GNG13 GNA12 GNA11 GNB5 GNG10 GNG10 GNG3 GNG5 GNB4 GNG13 GNGT1 GNG4 GNG10 GNG7 ARRB2 GNA13 GNG4 GDP GNG3 GNG7 G-protein alpha(12/13):GTPARRB1 GNAQ GNA14 GNGT1 F2RL2 GNG8 ARRB2 GNG11 GNG8 GNA14 GNA12 Activated SRC-1 GNG13 GNG5 GNG12 GNB2 GNG10 thrombin heavy chain GNG8 GTP F2RL3 GNB3 GNB2 GNB5 GNAQ GNB3 GNGT1 GNB5 GNG11 Activated SRC-1 GNA15 GNGT2 GNA14 GNG7 F2RL2 p-T202,Y204-MAPK3 GNG4 GNG12 GNG11 ActivatedPAR1:Beta-arrestin-1GNG7 GNG5 GNB5 F2R GNA13 GNG2 F2RL3(18-47) GNB1 GNG2 GNG5 F2R F2RL3(18-385) GNB3 GDPPAR1, 3, 4GNG3 GDP F2RL2 ActivatedPAR1:Beta-arrestin-1:Activated Src:Activated ERKGNAQ GNGT1 GNGT1 GNGT1 GNB5 GNB1 F2RL3 GNB5 GTP MAPK1 GNG11 GNG3 ActivatedPAR1:Beta-arrestin-2:Src:ERKF2R GNA15 GNG10 GNGT2 GNG13 MAPK3 6, 106, 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. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 456926
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: Akkerman, Jan Willem N

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  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

View all...
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

View all...
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)
F2R(27-41) ProteinP25116 (Uniprot-TrEMBL) Thrombin recognizes the N-terminal exodomain of PAR1 by interacting with sites both amino and carboxyl terminal to the thrombin cleavage site. Thrombin cleaves the peptide bond between receptor residues Arg41 and Ser42. This serves to unmask a new amino terminus beginning with the sequence SFLLRN that functions as a tethered ligand, docking intramolecularly with the body of the receptor to effect transmembrane signaling. A synthetic peptide of sequence SFLLRN, which mimics the tethered ligand sequence, will function as an agonist for PAR1 independent of receptor cleavage. Thus PAR1 is, in essence, a peptide receptor that carries its own ligand, the latter being active only after receptor cleavage.
F2R(27-425) ProteinP25116 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL2 ProteinO00254 (Uniprot-TrEMBL)
F2RL2(22-374) ProteinO00254 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL2(22-38) ProteinO00254 (Uniprot-TrEMBL)
F2RL3 ProteinQ96RI0 (Uniprot-TrEMBL)
F2RL3(18-385) ProteinQ96RI0 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL3(18-47) ProteinQ96RI0 (Uniprot-TrEMBL)
F2RProteinP25116 (Uniprot-TrEMBL)
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)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (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)
MAPKsComplexR-HSA-169291 (Reactome)
PAR N-teminal fragmentsComplexR-HSA-453303 (Reactome)
PAR1, 3, 4ComplexR-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 PARComplexR-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

View all...
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)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1929"
Personal tools