Platelet Aggregation (Plug Formation) (Homo sapiens)

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3, 781, 2, 5cytosolGP1BA GP5 ADRA2B ADRA2A,B,CGpIb-IX-V:Collagentype I fibril:vWFADRA2A GP9 Ca2+ GP1BA GP9 ADRA2C activated thrombin(factor IIa)Ca2+ ADR, NAdGP1BB NAd thrombin heavy chain Collagen type I fibril NAd thrombin heavy chain thrombin light chain THPOADR Collagen type I fibril Integrin alphaIIbbeta3 signalingVWF(23-763) GP5 thrombin light chain MPL VWF(23-763) TPO:ThrombopoietinreceptorGP1b-IX-Vcomplex:activatedthrombin (factorIIa)GP1BB MPLADRA2A ADRA2A,B,C:ADR,NAdADR THPO ADRA2B ADRA2C 10, 144, 6, 9, 11-1310, 1410, 1410, 14


Description

The tethering of platelets to the site of vascular injury is the first step in the formation of a platelet thrombus. Firm adhesion of these tethered platelets, as well as the additional recruitment of others onto their surface leads to the formation of large platelet aggregates. The formation of a thrombus is strictly dependent on the formation of interplatelet bonds. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 76009
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: de Bono, Bernard

Quality Tags

Ontology Terms

 

Bibliography

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  1. Kobilka BK, Matsui H, Kobilka TS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ, Regan JW.; ''Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor.''; PubMed Europe PMC
  2. Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J, Tsujimoto G.; ''Cloning, functional expression and tissue distribution of human cDNA for the alpha 1C-adrenergic receptor.''; PubMed Europe PMC
  3. Varga-Szabo D, Pleines I, Nieswandt B.; ''Cell adhesion mechanisms in platelets.''; PubMed Europe PMC
  4. Shattil SJ, Newman PJ.; ''Integrins: dynamic scaffolds for adhesion and signaling in platelets.''; PubMed Europe PMC
  5. Weinshank RL, Zgombick JM, Macchi M, Adham N, Lichtblau H, Branchek TA, Hartig PR.; ''Cloning, expression, and pharmacological characterization of a human alpha 2B-adrenergic receptor.''; PubMed Europe PMC
  6. Watson SP, Auger JM, McCarty OJ, Pearce AC.; ''GPVI and integrin alphaIIb beta3 signaling in platelets.''; PubMed Europe PMC
  7. Ruggeri ZM, Mendolicchio GL.; ''Adhesion mechanisms in platelet function.''; PubMed Europe PMC
  8. Dumas JJ, Kumar R, Seehra J, Somers WS, Mosyak L.; ''Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation.''; PubMed Europe PMC
  9. Parise LV.; ''Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation.''; PubMed Europe PMC
  10. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC
  11. Calderwood DA.; ''Integrin activation.''; PubMed Europe PMC
  12. Shattil SJ.; ''Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sideways.''; PubMed Europe PMC
  13. Kasirer-Friede A, Kahn ML, Shattil SJ.; ''Platelet integrins and immunoreceptors.''; PubMed Europe PMC
  14. Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101399view11:28, 1 November 2018ReactomeTeamreactome version 66
100937view21:04, 31 October 2018ReactomeTeamreactome version 65
100474view19:38, 31 October 2018ReactomeTeamreactome version 64
100019view16:22, 31 October 2018ReactomeTeamreactome version 63
99572view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99195view12:43, 31 October 2018ReactomeTeamreactome version 62
94001view13:50, 16 August 2017ReactomeTeamreactome version 61
93611view11:28, 9 August 2017ReactomeTeamreactome version 61
88098view09:30, 26 July 2016RyanmillerOntology Term : 'homeostasis pathway' added !
88097view09:29, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86719view09:24, 11 July 2016ReactomeTeamreactome version 56
83350view10:56, 18 November 2015ReactomeTeamVersion54
76986view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76691view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76017view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75726view11:19, 10 June 2014ReactomeTeamReactome 48 Update
75076view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74723view08:48, 30 April 2014ReactomeTeamReactome46
42100view21:57, 4 March 2011MaintBotAutomatic update
39910view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADR MetaboliteCHEBI:28918 (ChEBI)
ADR, NAdComplexR-ALL-390627 (Reactome)
ADRA2A ProteinP08913 (Uniprot-TrEMBL)
ADRA2A,B,C:ADR,NAdComplexR-HSA-390700 (Reactome)
ADRA2A,B,CComplexR-HSA-390664 (Reactome)
ADRA2B ProteinP18089 (Uniprot-TrEMBL)
ADRA2C ProteinP18825 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Collagen type I fibril R-HSA-1474201 (Reactome)
GP1BA ProteinP07359 (Uniprot-TrEMBL)
GP1BB ProteinP13224 (Uniprot-TrEMBL)
GP1b-IX-V

complex:activated thrombin (factor

IIa)
ComplexR-HSA-429532 (Reactome)
GP5 ProteinP40197 (Uniprot-TrEMBL)
GP9 ProteinP14770 (Uniprot-TrEMBL)
GpIb-IX-V:Collagen type I fibril:vWFComplexR-HSA-435464 (Reactome)
Integrin alphaIIb beta3 signalingPathwayR-HSA-354192 (Reactome) At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or 'inside-out signalling'. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction.
In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state.
Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen.
Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.
MPL ProteinP40238 (Uniprot-TrEMBL)
MPLProteinP40238 (Uniprot-TrEMBL)
NAd MetaboliteCHEBI:18357 (ChEBI)
THPO ProteinP40225 (Uniprot-TrEMBL)
THPOProteinP40225 (Uniprot-TrEMBL)
TPO:Thrombopoietin receptorComplexR-HSA-443940 (Reactome)
VWF(23-763) ProteinP04275 (Uniprot-TrEMBL)
activated thrombin (factor IIa)ComplexR-HSA-156786 (Reactome)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADR, NAdR-HSA-390663 (Reactome)
ADRA2A,B,C:ADR,NAdArrowR-HSA-390663 (Reactome)
ADRA2A,B,CR-HSA-390663 (Reactome)
GP1b-IX-V

complex:activated thrombin (factor

IIa)
ArrowR-HSA-429529 (Reactome)
GpIb-IX-V:Collagen type I fibril:vWFR-HSA-429529 (Reactome)
MPLR-HSA-443926 (Reactome)
R-HSA-390663 (Reactome) Alpha-2 adrenoceptors couple with G protein alpha-i subtype which decreases adenylyl cyclase activity, thus reducing cAMP intracellular levels resulting in smooth muscle contraction. There are three alpha-2 subtypes in humans; 2A (Kobilka BK et al, 1987), 2B (Weinshank RL et al, 1990) and 2C (Hirasawa A et al, 1993).
R-HSA-429529 (Reactome) Thrombin binds to the GP1b-IX-V receptor during platelet aggregation. This leads to increased PAR activation, possibly due to favourable orientation of thrombin towards the PAR extracellular domain.
R-HSA-443926 (Reactome) Thrombopoietin (TPO) is a primary regulator of megakaryocytopoiesis. Binding of TPO to its receptor TPOR (c-Mpl) mediates pleiotropic effects on megakaryocyte development leading to significant increase in circulating platelet numbers. TPOR knockout mice show a marked reduction in bone marrow megakaryocytes and blood platelets. Although thrombopoietin (TPO) by itself has little or no effect on platelet aggregation, pretreatment of platelets with TPO augments the aggregation induced by various agonists such as ADP, thrombin, collagen, and adrenaline.
THPOR-HSA-443926 (Reactome)
TPO:Thrombopoietin receptorArrowR-HSA-443926 (Reactome)
activated thrombin (factor IIa)R-HSA-429529 (Reactome)
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