Advanced glycosylation endproduct receptor signaling (Homo sapiens)
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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
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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Ontology Terms
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- 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
- 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
- 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
- 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
- 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
- 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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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| AGE adducts:Peptide:AGER-1,2,3 | Complex | REACT_26619 (Reactome)  | |
| AGE adducts:Peptide | Complex | REACT_24245 (Reactome) | |
| AGER ligands:AGER:ERK | Complex | REACT_26296 (Reactome) | |
| AGER [plasma membrane] | Protein | Q15109 (Uniprot-TrEMBL) | |
| AGER ligands:AGER | Complex | REACT_24620 (Reactome) | |
| AGER ligands | Protein | REACT_24759 (Reactome) | |
| AGER-1, 2, 3 | Protein | REACT_25689 (Reactome) | |
| AGER | Protein | Q15109 (Uniprot-TrEMBL) | |
| APP(672-711)
[extracellular region] | Protein | P05067 (Uniprot-TrEMBL) | |
| APP(672-713)
[extracellular region] | Protein | P05067 (Uniprot-TrEMBL) | |
| CAPZA1(265-276)
[extracellular region] | Protein | P52907 (Uniprot-TrEMBL) | |
| CAPZA2(265-276)
[extracellular region] | Protein | P47755 (Uniprot-TrEMBL) | |
| DDOST [plasma membrane] | Protein | P39656 (Uniprot-TrEMBL) | |
| ERK | Protein | REACT_24485 (Reactome) | |
| F-actin capping
protein alpha protein fragment TRTK-12 | Protein | REACT_26814 (Reactome) | |
| F-actin capping
protein fragment TRTK12:S100B homodimer | Complex | REACT_26773 (Reactome) | |
| HMGB1 [extracellular region] | Protein | P09429 (Uniprot-TrEMBL) | |
| LGALS3 [plasma membrane] | Protein | P17931 (Uniprot-TrEMBL) | |
| MAPK1 [cytosol] | Protein | P28482 (Uniprot-TrEMBL) | |
| MAPK3 [cytosol] | Protein | P27361 (Uniprot-TrEMBL) | |
| N-epsilon-(1-(1-carboxy)ethyl)lysine
[extracellular region] | Metabolite | CHEBI:60125 (ChEBI) | |
| NECML [extracellular region] | Metabolite | CHEBI:53014 (ChEBI) | |
| PRKCSH [plasma membrane] | Protein | P14314 (Uniprot-TrEMBL) | |
| Peptide
[extracellular region] | Metabolite | CHEBI:16670 (ChEBI) | |
| S100A12
[extracellular region] | Protein | P80511 (Uniprot-TrEMBL) | |
| S100B [extracellular region] | Protein | P04271 (Uniprot-TrEMBL) | |
| S100B homodimer | Complex | REACT_24848 (Reactome) | |
| SAA1(19-122)
[extracellular region] | Protein | P0DJI8 (Uniprot-TrEMBL) |
Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| AGE adducts:Peptide:AGER-1,2,3 | Arrow | REACT_25269 (Reactome) | ||
| AGE adducts:Peptide | REACT_25269 (Reactome) | |||
| AGER ligands:AGER:ERK | Arrow | REACT_25020 (Reactome) | ||
| AGER ligands:AGER | Arrow | REACT_25382 (Reactome) | ||
| AGER ligands:AGER | REACT_25020 (Reactome) | |||
| AGER ligands | REACT_25382 (Reactome) | |||
| AGER-1, 2, 3 | REACT_25269 (Reactome) | |||
| AGER | REACT_25382 (Reactome) | |||
| ERK | REACT_25020 (Reactome) | |||
| F-actin capping
protein alpha protein fragment TRTK-12 | REACT_25219 (Reactome) | |||
| F-actin capping
protein fragment TRTK12:S100B homodimer | Arrow | REACT_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 homodimer | REACT_25219 (Reactome) |
