Advanced glycosylation endproduct receptor signaling (Homo sapiens)

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52613, 4AGE adducts S100B homodimer ERK S100B homodimer AGER ligandsAGER AGE adducts AGER ligands AGE adducts S100B homodimer F-actin capping protein fragment TRTK12S100B homodimer AGE adductsPeptide AGER ligands cytosolAGER ligandsAGERERK AGE adducts AGE adductsPeptide S100A12 dimer AGE adductsPeptideAGER-1,2,3 S100B homodimer AGE adductsPeptide AGER-1, 2, 3 F-actin capping protein alpha protein fragment TRTK-12 S100A12 dimer AGE adductsPeptide AGER ligandsAGER HMGB1 N-epsilon-APPAPPS100B homodimerPRKCSH AGER ligandsAGERAGE adductsPeptideS100A12 LGALS3 AGER-1, 2, 3SAA1NECML S100B NECML N-epsilon-N-epsilon-Peptide DDOST APPPeptide AGER S100B Peptide AGER ligandsAGERERKPeptide NECML HMGB1 AGE adductsPeptideAGER-1,2,3ERKSAA1MAPK3 S100A12 N-epsilon-AGER ligandsNECML AGERAPPF-actin capping protein fragment TRTK12S100B homodimerMAPK1 CAPZA2S100B CAPZA1F-actin capping protein alpha protein fragment TRTK-12S100B AGER


Description

Advanced Glycosylation End- product-specific Receptor (AGER) also known as Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand membrane receptor belonging to the immunoglobulin superfamily. It is considered to be a Pattern Recognition Receptor (Liliensiek et al. 2004). It recognizes a large variety of modified proteins known as advanced glycation/glycosylation endproducts (AGEs), a heterogenous group of structures that are generated by the Maillard reaction, a consequence of long-term incubation of proteins with glucose (Ikeda et al. 1996). Their accumulation is associated with diabetes, atherosclerosis, renal failure and ageing (Schmidt et al. 1999). The most prevalent class of AGE in vivo are N(6)-carboxymethyllysine (NECML) adducts (Kislinger et al. 1991). In addition to AGEs, AGER is a signal transduction receptor for amyloid-beta peptide (Ab) (Yan et al. 1996), mediating Ab neurotoxicity and promoting Ab influx into the brain. AGER also responds to the proinflammatory S100/calgranulins (Hofmann et al. 1999) and High mobility group protein B1 (HMGB1/Amphoterin/DEF), a protein linked to neurite outgrowth and cellular motility (Hori et al. 1995).

The major inflammatory pathway stimulated by AGER activation is NFkappaB. Though the signaling cascade is unclear, several pieces of experimental data suggest that activation of AGER leads to sustained activation and upregulation of NFkappaB, measured as NFkappaB translocation to the nucleus, and increased levels of de novo synthesized NFkappaB (Bierhaus et al. 2001). As this is clearly an indirect effect it is represented here as positive regulation of NFkappaB translocation to the nucleus. AGER can bind ERK1/2 and thereby activate the MAPK and JNK cascades (Bierhaus et al. 2005). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=879415

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Bibliography

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  1. Inman KG, Yang R, Rustandi RR, Miller KE, Baldisseri DM, Weber DJ.; ''Solution NMR structure of S100B bound to the high-affinity target peptide TRTK-12.''; PubMed Europe PMC Scholia
  2. Vlassara H, Li YM, Imani F, Wojciechowicz D, Yang Z, Liu FT, Cerami A.; ''Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): a new member of the AGE-receptor complex.''; PubMed Europe PMC Scholia
  3. Yang Z, Makita Z, Horii Y, Brunelle S, Cerami A, Sehajpal P, Suthanthiran M, Vlassara H.; ''Two novel rat liver membrane proteins that bind advanced glycosylation endproducts: relationship to macrophage receptor for glucose-modified proteins.''; PubMed Europe PMC Scholia
  4. Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T.; ''The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site.''; PubMed Europe PMC Scholia
  5. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP.; ''Understanding RAGE, the receptor for advanced glycation end products.''; PubMed Europe PMC Scholia
  6. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM.; ''N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115021view16:55, 25 January 2021ReactomeTeamReactome version 75
113466view11:54, 2 November 2020ReactomeTeamReactome version 74
112297view15:12, 9 October 2020ReactomeTeamReactome version 73
101582view11:44, 1 November 2018ReactomeTeamreactome version 66
101118view21:28, 31 October 2018ReactomeTeamreactome version 65
100646view20:02, 31 October 2018ReactomeTeamreactome version 64
100196view16:47, 31 October 2018ReactomeTeamreactome version 63
99747view15:13, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99312view12:46, 31 October 2018ReactomeTeamreactome version 62
94012view13:51, 16 August 2017ReactomeTeamreactome version 61
93631view11:29, 9 August 2017ReactomeTeamreactome version 61
86742view09:25, 11 July 2016ReactomeTeamreactome version 56
83274view10:37, 18 November 2015ReactomeTeamVersion54
81392view12:55, 21 August 2015ReactomeTeamVersion53
76860view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76565view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75898view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75598view10:44, 10 June 2014ReactomeTeamReactome 48 Update
74953view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74597view08:38, 30 April 2014ReactomeTeamReactome46
68963view17:39, 8 July 2013MaintBotUpdated to 2013 gpml schema
44945view12:31, 6 October 2011MartijnVanIerselOntology Term : 'protein modification pathway' added !
42005view21:49, 4 March 2011MaintBotAutomatic update
39807view05:50, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AGE adducts

Peptide

AGER-1,2,3		ComplexREACT_26619 (Reactome)
AGE adducts PeptideComplexREACT_24245 (Reactome)
AGER ProteinQ15109 (Uniprot-TrEMBL)
AGER ligands

AGER

ERK		ComplexREACT_26296 (Reactome)
AGER ligands AGERComplexREACT_24620 (Reactome)
AGER ligandsProteinREACT_24759 (Reactome)
AGER-1, 2, 3ProteinREACT_25689 (Reactome)
AGERProteinQ15109 (Uniprot-TrEMBL)
APPProteinP05067 (Uniprot-TrEMBL)
CAPZA1ProteinP52907 (Uniprot-TrEMBL)
CAPZA2ProteinP47755 (Uniprot-TrEMBL)
DDOST ProteinP39656 (Uniprot-TrEMBL)
ERKProteinREACT_24485 (Reactome)
F-actin capping protein alpha protein fragment TRTK-12ProteinREACT_26814 (Reactome)
F-actin capping protein fragment TRTK12 S100B homodimerComplexREACT_26773 (Reactome)
HMGB1 ProteinP09429 (Uniprot-TrEMBL)
LGALS3 ProteinP17931 (Uniprot-TrEMBL)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
N-epsilon-MetaboliteCHEBI:60125 (ChEBI)
NECML MetaboliteCHEBI:53014 (ChEBI)
PRKCSH ProteinP14314 (Uniprot-TrEMBL)
Peptide MetaboliteCHEBI:16670 (ChEBI)
S100A12 ProteinP80511 (Uniprot-TrEMBL)
S100B ProteinP04271 (Uniprot-TrEMBL)
S100B homodimerComplexREACT_24848 (Reactome)
SAA1ProteinP0DJI8 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AGE adducts PeptideREACT_25269 (Reactome)
AGER ligands AGERREACT_25020 (Reactome)
AGER ligandsREACT_25382 (Reactome)
AGER-1, 2, 3REACT_25269 (Reactome)
AGERREACT_25382 (Reactome)
ERKREACT_25020 (Reactome)
F-actin capping protein alpha protein fragment TRTK-12REACT_25219 (Reactome)
REACT_25020 (Reactome) Binding of ligand to AGER results in the activation of multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade (Lander et al. 1997), cdc42/Rac (Huttunen et al. 1999), and activation of NF-?B (Tanaka et al. 2000). A membrane-proximal cytoplasmic region of the advanced glycation end-products receptor (AGER) is responsible for binding to extracellular signal-regulated protein kinase-1 and -2 (ERK1/2 or MAPK3/1). This region is similar to the D-domain, an ERK docking site which is conserved in some ERK substrates (Ishihara et al. 2003).
REACT_25219 (Reactome) The TRTK-12 fragment of the F-actin capping protein alpha subunit binds S100B in a calcium dependent manner. S100B undergoes a conformational change that is required for subsequent binding to effector proteins (Inman et al. 2002). S100B is a ligand for AGER (Hofmann et al. 1999). In addition this interaction between S100B andF-actin capping protein alpha could be important for regulating actin filament extension (Ivenkov et al. 1995).
REACT_25269 (Reactome) In addition to AGER/RAGE, several other proteins have been identified as AGE-binding proteins. AGE binding proteins p60 and p90 (Yang et al. 1991) were subsequently identified as the Oligosaccharyl transferase 48 kDa subunit (Ost-48) and Glucosidease-2 subunit beta (Li et al. 1996). A third member was identified as Galectin-3 (Vlassara et al. 1995). These 3 proteins have been shown to be present on the plasma membrane of many cell types including vascular endothelium (Stitt et al. 1999). They have been designated AGE-R1, -R2 and -R3. Their suggested function is the removal and degradation of AGEs, but AGER-1 was found to negatively regulate AGER/RAGE (Lu et al. 2004), with kinetics that suggested a more complex interaction than simple competition for the same ligand.
REACT_25382 (Reactome) Advanced glycosylation end product specific receptor (AGER) also known as Receptor for advanced glycation end products (RAGE) is a multi-ligand membrane receptor belonging to the immunoglobulin superfamily. It recognizes a large variety of modified proteins known as advanced glycation/glycosylation endproducts (AGEs) a heterogenous group of structures (Ikeda et al. 1996) that accumulate in patients with diabetes, atherosclerosis, renal failure or ageing (Schmidt et al. 1999). The most prevalent class of AGE in vivo are N(6)-carboxymethyllysine (NECML) adducts (Kislinger et al. 1991). AGER is a receptor for amyloid-beta peptide (Ab)(Yan et al. 1996), mediating Ab neurotoxicity and promoting Ab influx into the brain (Zhang et al. 2009). AGER also responds to the proinflammatory S100/calgranulins (Hofmann et al. 1999) and High mobility group protein B1 (HMGB1/Amphoterin/DEF) (Hori et al. 1995). The major pathway is NFkappaB activation, but AGER can also activate rho-GTPases and thereby MAPK and JNK cascades. (Bierhaus et al. 2005).
S100B homodimerREACT_25219 (Reactome)
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