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

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18799996752-49, 1099cytosolThrombin-activated PAR:Gq (active)Activated PAR1:Beta-arrestin-1:Activated Src:Activated ERKThrombin-activated PAR:Gq (inactive)G-protein alpha (q/11): GTPActivated PAR1:Beta-arrestin-1:Src:ERKActivated PAR1:Beta-arrestin-1Activated PAR1:Beta-arrestin-1:Activated Src:ERKG-protein G12/G13 (inactive)PAR N-teminal fragmentsThrombin activated PAR:G12/13 (active)G-protein G12/G13 (active)GDPPAR1, 3, 4G-protein beta-gamma complexActivated thrombin (factor IIa)Activated PAR1Activated PAR1:Beta-arrestin-2Thrombin activated PAR:G12/13 (inactive)ERKHeterotrimeric G-protein Gq/11 (inactive)G-protein alpha (12/13):GTPSRCBeta-arrestin-2Thrombin-activated PARActivated PAR1:Beta-arrestin-2:Src:ERKBeta-arrestin-1GTP


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.

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

History

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CompareRevisionActionTimeUserComment
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
Activated PAR1 ProteinP25116 (UniProt)
Activated PAR1:Beta-

arrestin-1

ComplexREACT_24414 (Reactome)
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-2

ComplexREACT_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 PAR1:Beta-

arrestin-2:Src:ERK

ComplexREACT_24842 (Reactome)
Activated thrombin

(factor IIa)

ComplexREACT_3298 (Reactome)
Beta-arrestin-1 ProteinP49407 (UniProt)
Beta-arrestin-2 ProteinP32121 (UniProt)
ERK ProteinREACT_24485 (Reactome)
G-protein

G12/G13 (inactive)

ComplexREACT_17117 (Reactome)
G-protein

G12/G13 (active)

ComplexREACT_17446 (Reactome)
G-protein alpha

(12/13):GTP

ComplexREACT_20092 (Reactome)
G-protein alpha

(q/11): GTP

ComplexREACT_5863 (Reactome)
G-protein beta-

gamma complex

ComplexREACT_15674 (Reactome)
GDP Metabolite17552 (ChEBI)
GTP Metabolite15996 (ChEBI)
Heterotrimeric G-

protein Gq/11 (inactive)

ComplexREACT_5130 (Reactome)
PAR N-teminal

fragments

ProteinREACT_21736 (Reactome)
PAR1, 3, 4 ProteinREACT_21743 (Reactome)
SRC ProteinP12931-1 (UniProt)
Thrombin activated

PAR:G12/13 (active)

ComplexREACT_17549 (Reactome)
Thrombin activated

PAR:G12/13 (inactive)

ComplexREACT_18059 (Reactome)
Thrombin-

activated PAR

ProteinREACT_5629 (Reactome)
Thrombin-activated

PAR:Gq (active)

ComplexREACT_17562 (Reactome)
Thrombin-activated

PAR:Gq (inactive)

ComplexREACT_17676 (Reactome)

Annotated Interactions

No annotated interactions

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