Signal amplification (Homo sapiens)

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9117143123, 527, 151473, 131461411, 8104cytosolendoplasmic reticulum lumenGNA15 GDP TPreceptor:Thromboxane A2:G-protein G13 (active)ADP GNA14 GNAQ GNA11 P2RY12 GTP G-protein alpha(q/11): GTPGNA14 TXA2 GDP GNA15 GNA13 GTP TXA2 ADPGNA14 GDP ADP P2RY12 G-protein alpha(13):GTPTXA2 GNA15 ADP:P2Y purinoceptor12P2RY12GNA13 ADP:P2Y purinoceptor1:G-protein Gq(inactive)GTPPLA2G4AGDPGNA14 p-T180,Y182-MAPK14GTP GTP HeterotrimericG-protein Gq/11(inactive)GDPADPMAPK14GNAI1 ADP GNA15 GNAQ P2RY1ADP:P2Y purinoceptor1:G-protein Gq(active)TBXA2R TXA2 GDP GNA11 GNAQ TPreceptor:Thromboxane A2:G-protein Gq (inactive)ADP GNAI1 GNAI2 GDPGNAQ TXA2 GNA11 GNAI2 GNAI3 GDP GNA14 p-S505,S727-PLA2G4ATBXA2R GTP GNA11 GNAQ ADPADPGNA13 HeterotrimericG-protein Gi(inactive)GNA13 P2RY1 TBXA2R GNAI3 TPreceptor:Thromboxane A2:G-protein G13 (inactive)GDP GTP GTPTXA2ADP:P2Y purinoceptor1GTP GNAI1 HeterotrimericG-protein G13(inactive)G-protein alpha (i):GTPP2RY12 G-protein beta-gammacomplexGNA11 GNAI1 GNA14 P2RY1 p-Y419-SRCADP:P2Y purinoceptor12:G-protein Gi(active)GNAI2 TBXA2RGDPGNAI3 ATPADP GTPP2RY1 GNA11 GNA15 TPreceptor:Thromboxane A2GTPGNAQ ADP:P2Y purinoceptor12:G-protein Gi(inactive)GNAT3 GDP GNAI2 GNAT3 TBXA2R TPreceptor:Thromboxane A2:G-protein Gq (active)GNAT3 ADP SRC-1ATPGNA15 TBXA2R GNAI3 GNAT3


Description

In the initial response to injury, platelets adhere to damaged blood vessels, responding to the exposure of collagen from the vascular epithelium. Once adhered they degranulate, releasing stored secondary agents such as ADP and ATP, and synthesized thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides secreted following platelet activation signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12 while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation and thrombus formation (Kahner et al. 2006). ADP stimulation of P2Y1 and P2Y12 involves signaling via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006). Source:Reactome.

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Bibliography

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  1. Hardy AR, Jones ML, Mundell SJ, Poole AW.; ''Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets.''; PubMed Europe PMC Scholia
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  3. Schachter JB, Li Q, Boyer JL, Nicholas RA, Harden TK.; ''Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor.''; PubMed Europe PMC Scholia
  4. Kramer RM, Roberts EF, Um SL, Börsch-Haubold AG, Watson SP, Fisher MJ, Jakubowski JA.; ''p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2.''; PubMed Europe PMC Scholia
  5. Chou KC.; ''Coupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding protein.''; PubMed Europe PMC Scholia
  6. Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC Scholia
  7. Davì G, Patrono C.; ''Platelet activation and atherothrombosis.''; PubMed Europe PMC Scholia
  8. Kinsella BT, O'Mahony DJ, Fitzgerald GA.; ''The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha.''; PubMed Europe PMC Scholia
  9. Dangelmaier C, Jin J, Daniel JL, Smith JB, Kunapuli SP.; ''The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets.''; PubMed Europe PMC Scholia
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  11. Shenker A, Goldsmith P, Unson CG, Spiegel AM.; ''The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family.''; PubMed Europe PMC Scholia
  12. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB.; ''Identification of the platelet ADP receptor targeted by antithrombotic drugs.''; PubMed Europe PMC Scholia
  13. Bodor ET, Waldo GL, Hooks SB, Corbitt J, Boyer JL, Harden TK.; ''Purification and functional reconstitution of the human P2Y12 receptor.''; PubMed Europe PMC Scholia
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  15. Schachter JB, Sromek SM, Nicholas RA, Harden TK.; ''HEK293 human embryonic kidney cells endogenously express the P2Y1 and P2Y2 receptors.''; PubMed Europe PMC Scholia
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  17. Reid HM, Wikström K, Kavanagh DJ, Mulvaney EP, Kinsella BT.; ''Interaction of angio-associated migratory cell protein with the TPα and TPβ isoforms of the human thromboxane A₂ receptor.''; PubMed Europe PMC Scholia
  18. Waldo GL, Harden TK.; ''Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptor.''; PubMed Europe PMC Scholia
  19. Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP.; ''Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114772view16:26, 25 January 2021ReactomeTeamReactome version 75
113216view11:28, 2 November 2020ReactomeTeamReactome version 74
112440view15:38, 9 October 2020ReactomeTeamReactome version 73
101345view11:23, 1 November 2018ReactomeTeamreactome version 66
100883view20:57, 31 October 2018ReactomeTeamreactome version 65
100424view19:31, 31 October 2018ReactomeTeamreactome version 64
99973view16:15, 31 October 2018ReactomeTeamreactome version 63
99528view14:51, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99167view12:42, 31 October 2018ReactomeTeamreactome version 62
93937view13:46, 16 August 2017ReactomeTeamreactome version 61
93526view11:26, 9 August 2017ReactomeTeamreactome version 61
86625view09:22, 11 July 2016ReactomeTeamreactome version 56
83050view09:47, 18 November 2015ReactomeTeamVersion54
81353view12:52, 21 August 2015ReactomeTeamVersion53
76822view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76526view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75859view09:51, 11 June 2014ReactomeTeamRe-fixing comment source
75559view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74914view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74558view08:35, 30 April 2014ReactomeTeamReactome46
45229view17:42, 7 October 2011KhanspersOntology Term : 'G protein mediated signaling pathway' added !
45228view17:41, 7 October 2011KhanspersOntology Term : 'platelet aggregation pathway' added !
45227view17:40, 7 October 2011KhanspersOntology Term : 'platelet' added !
42124view21:58, 4 March 2011MaintBotAutomatic update
39934view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADP MetaboliteCHEBI:16761 (ChEBI)
ADP:P2Y purinoceptor

12:G-protein Gi

(active)		ComplexR-HSA-392194 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi

(inactive)		ComplexR-HSA-392184 (Reactome)
ADP:P2Y purinoceptor 12ComplexR-HSA-392179 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(active)		ComplexR-HSA-418575 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(inactive)		ComplexR-HSA-418578 (Reactome)
ADP:P2Y purinoceptor 1ComplexR-HSA-418583 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
G-protein alpha (13):GTPComplexR-HSA-398056 (Reactome)
G-protein alpha (q/11): GTPComplexR-HSA-114534 (Reactome)
G-protein alpha (i): GTPComplexR-HSA-392161 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNA11 ProteinP29992 (Uniprot-TrEMBL)
GNA13 ProteinQ14344 (Uniprot-TrEMBL)
GNA14 ProteinO95837 (Uniprot-TrEMBL)
GNA15 ProteinP30679 (Uniprot-TrEMBL)
GNAI1 ProteinP63096 (Uniprot-TrEMBL)
GNAI2 ProteinP04899 (Uniprot-TrEMBL)
GNAI3 ProteinP08754 (Uniprot-TrEMBL)
GNAQ ProteinP50148 (Uniprot-TrEMBL)
GNAT3 ProteinA8MTJ3 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Heterotrimeric

G-protein G13

(inactive)		ComplexR-HSA-398072 (Reactome)
Heterotrimeric

G-protein Gi

(inactive)		ComplexR-HSA-392165 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)		ComplexR-HSA-114557 (Reactome)
MAPK14ProteinQ16539 (Uniprot-TrEMBL)
P2RY1 ProteinP47900 (Uniprot-TrEMBL)
P2RY12 ProteinQ9H244 (Uniprot-TrEMBL)
P2RY12ProteinQ9H244 (Uniprot-TrEMBL)
P2RY1ProteinP47900 (Uniprot-TrEMBL)
PLA2G4AProteinP47712 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
TBXA2R ProteinP21731 (Uniprot-TrEMBL)
TBXA2RProteinP21731 (Uniprot-TrEMBL)
TP receptor:Thromboxane A2:G-protein G13 (active)ComplexR-HSA-428907 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (inactive)ComplexR-HSA-428905 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (active)ComplexR-HSA-428904 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (inactive)ComplexR-HSA-428764 (Reactome)
TP receptor:Thromboxane A2ComplexR-HSA-391925 (Reactome)
TXA2 MetaboliteCHEBI:15627 (ChEBI)
TXA2MetaboliteCHEBI:15627 (ChEBI)
p-S505,S727-PLA2G4AProteinP47712 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14ProteinQ16539 (Uniprot-TrEMBL)
p-Y419-SRCProteinP12931-1 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADP:P2Y purinoceptor

12:G-protein Gi

(active)		ArrowR-HSA-392195 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi

(active)		R-HSA-392202 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi

(inactive)		ArrowR-HSA-392187 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi

(inactive)		R-HSA-392195 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi

(inactive)		mim-catalysisR-HSA-392195 (Reactome)
ADP:P2Y purinoceptor 12ArrowR-HSA-392180 (Reactome)
ADP:P2Y purinoceptor 12R-HSA-392187 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(active)		ArrowR-HSA-418579 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(active)		R-HSA-418576 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(inactive)		ArrowR-HSA-418581 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(inactive)		R-HSA-418579 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq

(inactive)		mim-catalysisR-HSA-418579 (Reactome)
ADP:P2Y purinoceptor 1ArrowR-HSA-418580 (Reactome)
ADP:P2Y purinoceptor 1R-HSA-418581 (Reactome)
ADPArrowR-HSA-392202 (Reactome)
ADPArrowR-HSA-418576 (Reactome)
ADPArrowR-HSA-428941 (Reactome)
ADPArrowR-HSA-428961 (Reactome)
ADPR-HSA-392180 (Reactome)
ADPR-HSA-418580 (Reactome)
ATPR-HSA-428941 (Reactome)
ATPR-HSA-428961 (Reactome)
G-protein alpha (13):GTPArrowR-HSA-428918 (Reactome)
G-protein alpha (q/11): GTPArrowR-HSA-418576 (Reactome)
G-protein alpha (q/11): GTPArrowR-HSA-428752 (Reactome)
G-protein alpha (q/11): GTPmim-catalysisR-HSA-428941 (Reactome)
G-protein alpha (i): GTPArrowR-HSA-392202 (Reactome)
G-protein beta-gamma complexArrowR-HSA-392202 (Reactome)
G-protein beta-gamma complexArrowR-HSA-418576 (Reactome)
G-protein beta-gamma complexArrowR-HSA-428752 (Reactome)
G-protein beta-gamma complexArrowR-HSA-428918 (Reactome)
GDPArrowR-HSA-392195 (Reactome)
GDPArrowR-HSA-418579 (Reactome)
GDPArrowR-HSA-428750 (Reactome)
GDPArrowR-HSA-428917 (Reactome)
GTPR-HSA-392195 (Reactome)
GTPR-HSA-418579 (Reactome)
GTPR-HSA-428750 (Reactome)
GTPR-HSA-428917 (Reactome)
Heterotrimeric

G-protein G13

(inactive)		R-HSA-428909 (Reactome)
Heterotrimeric

G-protein Gi

(inactive)		R-HSA-392187 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)		R-HSA-418581 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)		R-HSA-428749 (Reactome)
MAPK14R-HSA-428941 (Reactome)
P2RY12ArrowR-HSA-392202 (Reactome)
P2RY12R-HSA-392180 (Reactome)
P2RY1ArrowR-HSA-418576 (Reactome)
P2RY1R-HSA-418580 (Reactome)
PLA2G4AR-HSA-428961 (Reactome)
R-HSA-391939 (Reactome) Thromboxane (TBXA2) is a potent stimulator for platelet aggregation and clot formation and also plays a role in vascular tone. The thromboxane receptor TP (Hirata et al. 1991) is found on the surface of vascular endothelium, platelets and in the placenta. Once bound to its ligand, TP's effects are mediated via coupling to G q/11 activation of a phosphatidylinositol-calcium second messenger system (Kinsella BT et al, 1997). TP signaling also involves G12/13 signaling; selective activation of G12/13 results in dense granule release in a mechanism that is independent of Gq/phospholipase C. The downstream mechanism for this is thought to be RhoA mediated activation of PKCdelta, as PAR-mediated dense granule release is inhibited if RhoA is blocked, and RhoA regulates PKCdelta T505 phosphorylation (Jin et al. 2009).
R-HSA-392180 (Reactome) P2RY12 is one of two ADP receptors expressed in platelets. P2Y12 activation leads to irreversible platelet aggregation. Defects in this receptor are associated with bleeding disorders.
R-HSA-392187 (Reactome) The activated receptor binds the inactive, GDP-bound form of the heterotrimeric G-protein Gi.
R-HSA-392195 (Reactome) The G-protein alpha subunit exchanges GDP for GTP
R-HSA-392202 (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-418576 (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-418579 (Reactome) The G-protein alpha subunit exchanges GDP for GTP
R-HSA-418580 (Reactome) Two platelet ADP receptors, P2Y1 and P2Y12, initiate platelet activation when stimulated in concert. Both are heterotrimeric G-protein-coupled receptors; P2Y1 signals through Gq while P2Y12 signals through Gi. Stimulation of P2Y1 leads to intracellular calcium mobilization and platelet shape change.
R-HSA-418581 (Reactome) P2Y1 is coupled to the Gq family of G protein alpha subunits, causing increases in intracellular calcium concentration through stimulation of PLC.
R-HSA-418662 (Reactome) Activation of Src lies selectively downstream of P2Y1, but not P2Y12. The precise mechanism is not known, but Src regulation of the PI3K component of the intracellular calcium response downstream of P2Y12 represents a point of reciprocal cross-talk between P2Y1 and P2Y12 receptors.
R-HSA-428749 (Reactome) The TP receptor can activate Gq leading to stimulation of Phospholipase C and consequent increase in intracellular calcium.
R-HSA-428750 (Reactome) The G-protein alpha subunit exchanges GDP for GTP
R-HSA-428752 (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-428909 (Reactome) The thromboxane receptor (TP) can activate G12 and G13.
R-HSA-428917 (Reactome) The G-protein alpha subunit exchanges GDP for GTP
R-HSA-428918 (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-428941 (Reactome) ADP activates human platelets and induces endothelial cell migration. These effects are partly mediated by the P2Y1 purinocetor, inducing p38 MAP kinase activation via an uncharacterised factor. Possible mechanisms include flotillin-mediated stimulation of SRC family kinases in lipid rafts (Sugawara et al. 2007).
R-HSA-428961 (Reactome) MAPK p38 alpha activates cPLA2 by phosphorylation of two serine residues.
cPLA2 can be phosphorylated and activated by ERK2 (Lin et al. 1993), and were believed to be responsible for the phosphorylation of cPLA2. However, phosphorylation of cPLA2 occurred in the absence of ERK activation in human platelets stimulated with the thrombin receptor agonist peptide SFLLRN (Kramer et al. 1995), and cPLA2 phosphorylation induced by thrombin or collagen was unaffected by PKC inhibitors that prevent ERK activation (Börsch-Haubold et al. 1995). In addition, a specific inhibitor of ERKs did not block thrombin-induced cPLA2 phosphorylation (Börsch-Haubold et al. 1996).
SRC-1R-HSA-418662 (Reactome)
TBXA2RArrowR-HSA-428752 (Reactome)
TBXA2RArrowR-HSA-428918 (Reactome)
TBXA2RR-HSA-391939 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (active)ArrowR-HSA-428917 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (active)R-HSA-428918 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (inactive)ArrowR-HSA-428909 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (inactive)R-HSA-428917 (Reactome)
TP receptor:Thromboxane A2:G-protein G13 (inactive)mim-catalysisR-HSA-428917 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (active)ArrowR-HSA-428750 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (active)R-HSA-428752 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (inactive)ArrowR-HSA-428749 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (inactive)R-HSA-428750 (Reactome)
TP receptor:Thromboxane A2:G-protein Gq (inactive)mim-catalysisR-HSA-428750 (Reactome)
TP receptor:Thromboxane A2ArrowR-HSA-391939 (Reactome)
TP receptor:Thromboxane A2R-HSA-428749 (Reactome)
TP receptor:Thromboxane A2R-HSA-428909 (Reactome)
TXA2ArrowR-HSA-428752 (Reactome)
TXA2ArrowR-HSA-428918 (Reactome)
TXA2R-HSA-391939 (Reactome)
p-S505,S727-PLA2G4AArrowR-HSA-428961 (Reactome)
p-T180,Y182-MAPK14ArrowR-HSA-428941 (Reactome)
p-T180,Y182-MAPK14mim-catalysisR-HSA-428961 (Reactome)
p-Y419-SRCArrowR-HSA-418662 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1908"
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