Signal amplification (Homo sapiens)
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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).
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- 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
- Léon C, Vial C, Cazenave JP, Gachet C.; ''Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor.''; PubMed Europe PMC Scholia
- 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
- 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
- Chou KC.; ''Coupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding protein.''; PubMed Europe PMC Scholia
- Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC Scholia
- Davì G, Patrono C.; ''Platelet activation and atherothrombosis.''; PubMed Europe PMC Scholia
- 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
- 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
- Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Nakanishi S, Narumiya S.; ''Cloning and expression of cDNA for a human thromboxane A2 receptor.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- Ohlmann P, Laugwitz KL, Nürnberg B, Spicher K, Schultz G, Cazenave JP, Gachet C.; ''The human platelet ADP receptor activates Gi2 proteins.''; PubMed Europe PMC Scholia
- Schachter JB, Sromek SM, Nicholas RA, Harden TK.; ''HEK293 human embryonic kidney cells endogenously express the P2Y1 and P2Y2 receptors.''; PubMed Europe PMC Scholia
- Zhang L, DiLizio C, Kim D, Smyth EM, Manning DR.; ''The G12 family of G proteins as a reporter of thromboxane A2 receptor activity.''; PubMed Europe PMC Scholia
- 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
- Waldo GL, Harden TK.; ''Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptor.''; PubMed Europe PMC Scholia
- 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
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DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP:P2RY12:G-protein Gi (active) | Arrow | R-HSA-392195 (Reactome)  | ||
| ADP:P2RY12:G-protein Gi (active) | R-HSA-392202 (Reactome) | |||
| ADP:P2RY12:G-protein Gi (inactive) | Arrow | R-HSA-392187 (Reactome) | ||
| ADP:P2RY12:G-protein Gi (inactive) | R-HSA-392195 (Reactome) | |||
| ADP:P2RY12:G-protein Gi (inactive) | mim-catalysis | R-HSA-392195 (Reactome) | ||
| ADP:P2RY12 | Arrow | R-HSA-417829 (Reactome) | ||
| ADP:P2RY12 | R-HSA-392187 (Reactome) | |||
| ADP:P2RY1:G-protein Gq (active) | Arrow | R-HSA-418579 (Reactome) | ||
| ADP:P2RY1:G-protein Gq (active) | R-HSA-418576 (Reactome) | |||
| ADP:P2RY1:G-protein Gq/11 (inactive) | Arrow | R-HSA-418581 (Reactome) | ||
| ADP:P2RY1:G-protein Gq/11 (inactive) | R-HSA-418579 (Reactome) | |||
| ADP:P2RY1:G-protein Gq/11 (inactive) | mim-catalysis | R-HSA-418579 (Reactome) | ||
| ADP:P2RY1 | Arrow | R-HSA-417908 (Reactome) | ||
| ADP:P2RY1 | R-HSA-418581 (Reactome) | |||
| ADP | Arrow | R-HSA-392202 (Reactome) | ||
| ADP | Arrow | R-HSA-418576 (Reactome) | ||
| ADP | Arrow | R-HSA-428941 (Reactome) | ||
| ADP | Arrow | R-HSA-428961 (Reactome) | ||
| ADP | R-HSA-417829 (Reactome) | |||
| ADP | R-HSA-417908 (Reactome) | |||
| ATP | R-HSA-428941 (Reactome) | |||
| ATP | R-HSA-428961 (Reactome) | |||
| G-protein alpha (13):GTP | Arrow | R-HSA-428918 (Reactome) | ||
| G-protein alpha (q/11): GTP | Arrow | R-HSA-418576 (Reactome) | ||
| G-protein alpha (q/11): GTP | Arrow | R-HSA-428752 (Reactome) | ||
| G-protein alpha (q/11): GTP | mim-catalysis | R-HSA-428941 (Reactome) | ||
| G-protein alpha (i): GTP | Arrow | R-HSA-392202 (Reactome) | ||
| G-protein beta-gamma complex | Arrow | R-HSA-392202 (Reactome) | ||
| G-protein beta-gamma complex | Arrow | R-HSA-418576 (Reactome) | ||
| G-protein beta-gamma complex | Arrow | R-HSA-428752 (Reactome) | ||
| G-protein beta-gamma complex | Arrow | R-HSA-428918 (Reactome) | ||
| GDP | Arrow | R-HSA-392195 (Reactome) | ||
| GDP | Arrow | R-HSA-418579 (Reactome) | ||
| GDP | Arrow | R-HSA-428750 (Reactome) | ||
| GDP | Arrow | R-HSA-428917 (Reactome) | ||
| GTP | R-HSA-392195 (Reactome) | |||
| GTP | R-HSA-418579 (Reactome) | |||
| GTP | R-HSA-428750 (Reactome) | |||
| GTP | R-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) | |||
| MAPK14 | R-HSA-428941 (Reactome) | |||
| P2RY12 | Arrow | R-HSA-392202 (Reactome) | ||
| P2RY12 | R-HSA-417829 (Reactome) | |||
| P2RY1 | Arrow | R-HSA-418576 (Reactome) | ||
| P2RY1 | R-HSA-417908 (Reactome) | |||
| PLA2G4A | R-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-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-417829 (Reactome) | P2RY12 (Bodor et al. 2003) is found on the surface of blood platelet cells and is an important regulator in blood clotting. It is one of two ADP receptors expressed in platelets, the other is P2RY1. Activation leads to irreversible platelet aggregation. Defects in this receptor are associated with bleeding disorders. Its preferred ligand is ADP. The platelet anticoagulant drug clopidogrel binds to this receptor (Hollopeter G et al. 2001). | |||
| R-HSA-417908 (Reactome) | P2RY1 binds ADP (Leon et al. 1996). It is one of two platelet ADP receptors, the other is P2RY12, that initiate platelet activation when stimulated in concert. P2RY1 signals through Gq, while P2Y12 signals through Gi. This results in mobilization of intracellular calcium ions via activation of phospholipase C, which leads to a change in platelet shape and probably to platelet aggregation (Schachter et al. 1997). | |||
| 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-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-1 | R-HSA-418662 (Reactome) | |||
| TBXA2R | Arrow | R-HSA-428752 (Reactome) | ||
| TBXA2R | Arrow | R-HSA-428918 (Reactome) | ||
| TBXA2R | R-HSA-391939 (Reactome) | |||
| TP receptor:Thromboxane A2:G-protein G13 (active) | Arrow | R-HSA-428917 (Reactome) | ||
| TP receptor:Thromboxane A2:G-protein G13 (active) | R-HSA-428918 (Reactome) | |||
| TP receptor:Thromboxane A2:G-protein G13 (inactive) | Arrow | R-HSA-428909 (Reactome) | ||
| TP receptor:Thromboxane A2:G-protein G13 (inactive) | R-HSA-428917 (Reactome) | |||
| TP receptor:Thromboxane A2:G-protein G13 (inactive) | mim-catalysis | R-HSA-428917 (Reactome) | ||
| TP receptor:Thromboxane A2:G-protein Gq (active) | Arrow | R-HSA-428750 (Reactome) | ||
| TP receptor:Thromboxane A2:G-protein Gq (active) | R-HSA-428752 (Reactome) | |||
| TP receptor:Thromboxane A2:G-protein Gq (inactive) | Arrow | R-HSA-428749 (Reactome) | ||
| TP receptor:Thromboxane A2:G-protein Gq (inactive) | R-HSA-428750 (Reactome) | |||
| TP receptor:Thromboxane A2:G-protein Gq (inactive) | mim-catalysis | R-HSA-428750 (Reactome) | ||
| TP receptor:Thromboxane A2 | Arrow | R-HSA-391939 (Reactome) | ||
| TP receptor:Thromboxane A2 | R-HSA-428749 (Reactome) | |||
| TP receptor:Thromboxane A2 | R-HSA-428909 (Reactome) | |||
| TXA2 | Arrow | R-HSA-428752 (Reactome) | ||
| TXA2 | Arrow | R-HSA-428918 (Reactome) | ||
| TXA2 | R-HSA-391939 (Reactome) | |||
| p-S505,S727-PLA2G4A | Arrow | R-HSA-428961 (Reactome) | ||
| p-T180,Y182-MAPK14 | Arrow | R-HSA-428941 (Reactome) | ||
| p-T180,Y182-MAPK14 | mim-catalysis | R-HSA-428961 (Reactome) | ||
| p-Y419-SRC | Arrow | R-HSA-418662 (Reactome) |
