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{{protein | {{infobox protein | ||
| Name = [[coagulation factor II receptor|coagulation factor II (thrombin) receptor]] | | Name = [[coagulation factor II receptor|coagulation factor II (thrombin) receptor]] | ||
| caption = | | caption = | ||
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| LocusSupplementaryData = | | LocusSupplementaryData = | ||
}} | }} | ||
{{protein | {{infobox protein | ||
| Name = [[F2RL1|coagulation factor II (thrombin) receptor-like 1]] | | Name = [[F2RL1|coagulation factor II (thrombin) receptor-like 1]] | ||
| caption = | | caption = | ||
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| LocusSupplementaryData = | | LocusSupplementaryData = | ||
}} | }} | ||
{{protein | {{infobox protein | ||
| Name = [[F2RL2|coagulation factor II (thrombin) receptor-like 2]] | | Name = [[F2RL2|coagulation factor II (thrombin) receptor-like 2]] | ||
| caption = | | caption = | ||
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| LocusSupplementaryData = | | LocusSupplementaryData = | ||
}} | }} | ||
{{protein | {{infobox protein | ||
| Name = [[F2RL3|coagulation factor II (thrombin) receptor-like 3]] | | Name = [[F2RL3|coagulation factor II (thrombin) receptor-like 3]] | ||
| caption = | | caption = | ||
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| LocusSupplementaryData = | | LocusSupplementaryData = | ||
}} | }} | ||
'''Protease-activated receptor'''s are a subfamily of related [[G protein-coupled receptor]]s that are activated by cleavage of part of their extracellular domain. They are highly expressed in [[platelet]]s, | '''Protease-activated receptor'''s are a subfamily of related [[G protein-coupled receptor]]s that are activated by cleavage of part of their extracellular domain. They are highly expressed in [[platelet]]s, and also on endothelial cells, myocytes and neurons.<ref name="Macfarlane_2001">{{cite journal |vauthors=Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R |title=Proteinase-activated receptors |journal= Pharmacol Rev |volume= 53 |issue= 2 |pages= 245–82 |year= 2001| doi = |pmid= 11356985 | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/53/2/245 |format=abstract}}</ref> | ||
==Classification== | ==Classification== | ||
There are 4 known | There are 4 known protease-activated receptors, PAR1, PAR2, PAR3, and PAR4. They are members of the seven-transmembrane [[G-protein-coupled receptor]] superfamily, and are expressed throughout the body. | ||
==Activation== | ==Activation== | ||
Most of the PAR family act through the actions of [[G-proteins]] [[Gi alpha subunit|i]] (cAMP inhibitory), [[G12/G13|12/13]] ( | Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor.<ref>Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.</ref> Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases cleave and activate PARs receptors, including proteases from: a) the coagulation cascade, b) inflammatory cells, and c) the digestive tract. The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology.<ref>Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.</ref> Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.<ref>Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.</ref> | ||
'''PARs''' are activated by the action of [[serine protease]]s such as [[thrombin]] (acts on PARs 1, 3 and 4) and [[trypsin]] (PAR 2).<ref name="pmid12511583">{{cite journal | vauthors = Coughlin SR, Camerer E | title = PARticipation in inflammation | journal = J. Clin. Invest. | volume = 111 | issue = 1 | pages = 25–7 |date=January 2003 | pmid = 12511583 | pmc = 151847 | doi = 10.1172/JCI17564 | url = }}</ref> These [[enzymes]] cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response. | |||
Most of the PAR family act through the actions of [[G-proteins]] [[Gi alpha subunit|i]] (cAMP inhibitory), [[G12/G13|12/13]] (Rho and Ras activation) and [[Gq protein|q]] (calcium signalling) to cause cellular actions. | |||
==Function== | ==Function== | ||
The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in [[platelet]]s contributes to [[hemostasis]] and [[thrombosis]]. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and [[hypertrophy]]. PARs contribute to the pro-inflammatory response observed in [[atherosclerosis]] and [[restenosis]]. Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.<ref name="pmid18278179">{{cite journal | | The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in [[platelet]]s contributes to [[hemostasis]] and [[thrombosis]]. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and [[hypertrophy]]. PARs contribute to the pro-inflammatory response observed in [[atherosclerosis]] and [[restenosis]]. Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.<ref name="pmid18278179">{{cite journal | vauthors = Martorell L, Martínez-González J, Rodríguez C, Gentile M, Calvayrac O, Badimon L | title = Thrombin and protease-activated receptors (PARs) in atherothrombosis | journal = Thromb. Haemost. | volume = 99 | issue = 2 | pages = 305–15 |date=February 2008 | pmid = 18278179 | doi = 10.1160/TH07-08-0481 | url = }}</ref> | ||
In [[T cell]]s, activation of PAR1, PAR2 and PAR3 induce [[tyrosine]] [[phosphorylation]] of [[VAV1]]. Activation of PARs also led to an increase in tyrosine phosphorylation of [[ZAP-70]] and [[Lymphocyte cytosolic protein 2|SLP-76]], two key proteins in [[T cell receptor]] (TCR) signalling.<ref name="pmid11849313">{{cite journal | | In [[T cell]]s, activation of PAR1, PAR2 and PAR3 induce [[tyrosine]] [[phosphorylation]] of [[VAV1]]. Activation of PARs also led to an increase in tyrosine phosphorylation of [[ZAP-70]] and [[Lymphocyte cytosolic protein 2|SLP-76]], two key proteins in [[T cell receptor]] (TCR) signalling.<ref name="pmid11849313">{{cite journal | vauthors = Bar-Shavit R, Maoz M, Yongjun Y, Groysman M, Dekel I, Katzav S | title = Signalling pathways induced by protease-activated receptors and integrins in T cells | journal = Immunology | volume = 105 | issue = 1 | pages = 35–46 |date=January 2002 | pmid = 11849313 | pmc = 1782632 | doi = 10.1046/j.0019-2805.2001.01351.x | url = }}</ref> | ||
== References == | == References == | ||
| Line 95: | Line 98: | ||
==External links== | ==External links== | ||
* | *{{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1351 | title = Protease-Activated Receptors | accessdate = | author = | date = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = }} | ||
* {{MeshName|Proteinase-Activated+Receptors}} | * {{MeshName|Proteinase-Activated+Receptors}} | ||
{{G protein-coupled receptors}} | {{G protein-coupled receptors}} | ||
[[Category:G protein coupled receptors]] | [[Category:G protein coupled receptors]] | ||
Revision as of 15:10, 16 August 2017
| coagulation factor II (thrombin) receptor | |
|---|---|
| Identifiers | |
| Symbol | F2R |
| Alt. symbols | PAR1 |
| Entrez | 2149 |
| HUGO | 3537 |
| OMIM | 187930 |
| RefSeq | NM_001992 |
| UniProt | P25116 |
| Other data | |
| Locus | Chr. 5 q13 |
| coagulation factor II (thrombin) receptor-like 1 | |
|---|---|
| Identifiers | |
| Symbol | F2RL1 |
| Alt. symbols | PAR2, GPR11 |
| Entrez | 2150 |
| HUGO | 3538 |
| OMIM | 600933 |
| RefSeq | NM_005242 |
| UniProt | P55085 |
| Other data | |
| Locus | Chr. 5 q13 |
| coagulation factor II (thrombin) receptor-like 2 | |
|---|---|
| Identifiers | |
| Symbol | F2RL2 |
| Alt. symbols | PAR3 |
| Entrez | 2151 |
| HUGO | 3539 |
| OMIM | 601919 |
| RefSeq | NM_004101 |
| UniProt | O00254 |
| Other data | |
| Locus | Chr. 5 q13 |
| coagulation factor II (thrombin) receptor-like 3 | |
|---|---|
| Identifiers | |
| Symbol | F2RL3 |
| Alt. symbols | PAR4 |
| Entrez | 9002 |
| HUGO | 3540 |
| OMIM | 602779 |
| RefSeq | NM_003950 |
| UniProt | Q96RI0 |
| Other data | |
| Locus | Chr. 19 p12 |
Protease-activated receptors are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.[1]
Classification
There are 4 known protease-activated receptors, PAR1, PAR2, PAR3, and PAR4. They are members of the seven-transmembrane G-protein-coupled receptor superfamily, and are expressed throughout the body.
Activation
Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor.[2] Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases cleave and activate PARs receptors, including proteases from: a) the coagulation cascade, b) inflammatory cells, and c) the digestive tract. The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology.[3] Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.[4]
PARs are activated by the action of serine proteases such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR 2).[5] These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response.
Most of the PAR family act through the actions of G-proteins i (cAMP inhibitory), 12/13 (Rho and Ras activation) and q (calcium signalling) to cause cellular actions.
Function
The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in platelets contributes to hemostasis and thrombosis. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and hypertrophy. PARs contribute to the pro-inflammatory response observed in atherosclerosis and restenosis. Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.[6]
In T cells, activation of PAR1, PAR2 and PAR3 induce tyrosine phosphorylation of VAV1. Activation of PARs also led to an increase in tyrosine phosphorylation of ZAP-70 and SLP-76, two key proteins in T cell receptor (TCR) signalling.[7]
References
- ↑ Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (2001). "Proteinase-activated receptors" (abstract). Pharmacol Rev. 53 (2): 245–82. PMID 11356985.
- ↑ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
- ↑ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
- ↑ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
- ↑ Coughlin SR, Camerer E (January 2003). "PARticipation in inflammation". J. Clin. Invest. 111 (1): 25–7. doi:10.1172/JCI17564. PMC 151847. PMID 12511583.
- ↑ Martorell L, Martínez-González J, Rodríguez C, Gentile M, Calvayrac O, Badimon L (February 2008). "Thrombin and protease-activated receptors (PARs) in atherothrombosis". Thromb. Haemost. 99 (2): 305–15. doi:10.1160/TH07-08-0481. PMID 18278179.
- ↑ Bar-Shavit R, Maoz M, Yongjun Y, Groysman M, Dekel I, Katzav S (January 2002). "Signalling pathways induced by protease-activated receptors and integrins in T cells". Immunology. 105 (1): 35–46. doi:10.1046/j.0019-2805.2001.01351.x. PMC 1782632. PMID 11849313.
External links
- "Protease-Activated Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- Proteinase-Activated+Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)