RAGE (receptor)

RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[5] Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

AGER
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ENS, 2M1K, 2LE9, 4LP5, 2MOV, 3O3U, 2LMB, 4LP4, 4OF5, 4OI8, 4XYN, 2MJW, 2E5E, 2L7U, 3CJJ, 4OFV, 4P2Y, 4OI7, 4YBH,%%s1PWI, 2BJP, 2E5E, 2ENS, 2L7U, 2LE9, 2LMB, 2M1K, 2MJW, 2MOV, 3CJJ, 3O3U, 4LP4, 4LP5, 4OF5, 4OFV, 4OI7, 4OI8, 4P2Y, 4XYN
Identifiers
Aliases	AGER, Ager, RAGE, SCARJ1, advanced glycosylation end product-specific receptor, advanced glycosylation end-product specific receptor
External IDs	OMIM: 600214 MGI: 893592 HomoloGene: 883 GeneCards: AGER
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.32 Start 32,180,968 bp[1] End 32,184,322 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 B1 Start 34,597,862 bp[2] End 34,600,936 bp[2]
Gene ontology Molecular function • S100 protein binding • GO:0001948 protein binding • identical protein binding • transmembrane signaling receptor activity • advanced glycation end-product binding • heparin binding • amyloid-beta binding • scavenger receptor activity • signaling receptor activity • advanced glycation end-product receptor activity • GO:0032403 macromolecular complex binding Cellular component • integral component of membrane • membrane • integral component of plasma membrane • extracellular region • fibrillar center • cell membrane • cell junction • cell surface • apical plasma membrane • postsynapse Biological process • negative regulation of interleukin-10 production • positive regulation of interleukin-12 production • cell surface receptor signaling pathway • response to wounding • positive regulation of NF-kappaB transcription factor activity • positive regulation of dendritic cell differentiation • innate immune system • inflammatory response • regulation of T cell mediated cytotoxicity • regulation of CD4-positive, alpha-beta T cell activation • positive regulation of activated T cell proliferation • negative regulation of advanced glycation end-product receptor activity • protein localization to membrane • positive regulation of JUN kinase activity • regulation of DNA binding • induction of positive chemotaxis • regulation of inflammatory response • response to hypoxia • astrocyte development • neuron projection development • negative regulation of connective tissue replacement involved in inflammatory response wound healing • positive regulation of monocyte chemotactic protein-1 production • positive regulation of protein phosphorylation • receptor-mediated endocytosis • learning or memory • glucose mediated signaling pathway • positive regulation of heterotypic cell-cell adhesion • transcytosis • positive regulation of JNK cascade • regulation of synaptic plasticity • positive regulation of astrocyte activation • positive regulation of ERK1 and ERK2 cascade • modulation of age-related behavioral decline • regulation of spontaneous synaptic transmission • regulation of long-term synaptic potentiation • negative regulation of long-term synaptic potentiation • negative regulation of long term synaptic depression • regulation of p38MAPK cascade • positive regulation of p38MAPK cascade • regulation of NIK/NF-kappaB signaling • positive regulation of NIK/NF-kappaB signaling • positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process • negative regulation of blood circulation • positive regulation of microglial cell activation • positive regulation of endothelin secretion • response to amyloid-beta • cellular response to amyloid-beta • positive regulation of monocyte extravasation • endocytosis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	177	11596
Ensembl	ENSG00000237405 ENSG00000206320 ENSG00000231268 ENSG00000234729 ENSG00000229058 ENSG00000204305 ENSG00000230514	ENSMUSG00000015452
UniProt	Q15109	Q62151
RefSeq (mRNA)	NM_001136 NM_001206929 NM_001206932 NM_001206934 NM_001206936 NM_001206940 NM_001206954 NM_001206966 NM_172197	NM_001271422 NM_001271423 NM_001271424 NM_007425
RefSeq (protein)	NP_001127 NP_001193858 NP_001193861 NP_001193863 NP_001193865 NP_001193869 NP_001193883 NP_001193895 NP_751947	NP_001258351 NP_001258352 NP_001258353 NP_031451
Location (UCSC)	Chr 6: 32.18 – 32.18 Mb	Chr 17: 34.6 – 34.6 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Schematic of the relation between an immunoglobulin and RAGE

Schematic of the RAGE gene and its products

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation.[6] [7] Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.

Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.

Gene and polymorphisms

The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene.[8] About 30 polymorphisms are known most of which are single-nucleotide polymorphisms.[9]

RNA and alternative splicing

The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.

Structure

RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE.[10]

The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.

Ligands

RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:

• AGE
• HMGB1 (Amphoterin)[11]
• S100A12 (EN-RAGE)
• S100B
• S100A7 (psoriasin) but not highly homologous S100A15 (koebnerisin)
• S100P[12][13]
• S100A8/A9 complex referred to as calprotectin[14]
• Amyloid-β-protein
• Mac-1
• Phosphatidylserine.
• S100A4[15]

RAGE and disease

RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of RAGE ligands (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure.[16] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis.[10] Diseases that have been linked to RAGE are:

• Alzheimer's disease
• Arthritis[17]
• Atherosclerosis
• Congestive heart failure
• Congenital diaphragmatic hernia [18]
• Diabetes[10]
• Myocardial infarction
• Peripheral vascular disease
• Psoriasis
• Rheumatoid arthritis[19]
• Takayasu's arteritis[20]

RAGE is expressed at the highest levels in the lung compared to other tissues, in particular in alveolar type I cells, and is lost in idiopathic pulmonary fibrosis (IPF) indicating that expression and regulation of RAGE in the pulmonary system differs from that in the vascular system. Blockade/knockdown of RAGE resulted in impaired cell adhesion, and increased cell proliferation and migration[21]

Inhibitors

A number of small molecule RAGE inhibitors or antagonists have been reported.[22][23][24][25]

Azeliragon

vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.[26][27] These trials were halted in 2018.[28]

AGE receptors

Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:

• SR-A (Macrophage scavenger receptor Type I and II)
• OST-48 (Oligosaccharyl transferase-4) (AGE-R1)
• 80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2)
• Galectin-3 (AGE-R3)
• LOX-1 (Lectin-like oxidized low density lipoprotein receptor-1)
• CD36

References

1. ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 GRCh38: Ensembl release 89: ENSG00000237405, ENSG00000206320, ENSG00000231268, ENSG00000234729, ENSG00000229058, ENSG00000204305, ENSG00000230514 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000015452 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (July 1992). "Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins". The Journal of Biological Chemistry. 267 (21): 14998–5004. PMID 1378843.
6. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP (December 2001). "Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB". Diabetes. 50 (12): 2792–808. doi:10.2337/diabetes.50.12.2792. PMID 11723063.
7. Gasparotto, J; Girardi, CS; Somensi, N; Ribeiro, CT; Moreira, JCF; Michels, M; Sonai, B; Rocha, M; Steckert, AV; Barichello, T; Quevedo, J; Dal-Pizzol, F; Gelain, DP (Nov 2017). "Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment". J Biol Chem. 293 (1): 226–244. doi:10.1074/jbc.M117.786756. PMC 5766916. PMID 29127203.
8. Hudson BI, Stickland MH, Futers TS, Grant PJ (June 2001). "Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy". Diabetes. 50 (6): 1505–11. doi:10.2337/diabetes.50.6.1505. PMID 11375354.
9. Hudson BI, Hofman MA, Bucciarelli L, Wendt T, Moser B, Lu Y, Qu W, Stern DM, D'Agati V, Yan SD, Yan SF, Grant PJ (2002). "Glycation and diabetes: The RAGE connection" (PDF). Current Science. 83 (12): 1515–1521.
10. Oczypok, EA; Perkins, TN; Oury, TD (June 2017). "All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses". Paediatric Respiratory Reviews. 23: 40–49. doi:10.1016/j.prrv.2017.03.012. PMC 5509466. PMID 28416135.
11. Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (December 2013). "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology. 56 (4): 739–44. doi:10.1016/j.molimm.2013.07.008. PMID 23954397.
12. Penumutchu SR, Chou RH, Yu C (2014). "Structural insights into calcium-bound S100P and the V domain of the RAGE complex". PLOS ONE. 9 (8): e103947. Bibcode:2014PLoSO...9j3947P. doi:10.1371/journal.pone.0103947. PMC 4118983. PMID 25084534.
13. Penumutchu SR, Chou RH, Yu C (November 2014). "Interaction between S100P and the anti-allergy drug cromolyn". Biochemical and Biophysical Research Communications. 454 (3): 404–9. doi:10.1016/j.bbrc.2014.10.048. PMID 25450399.
14. Hermani A, De Servi B, Medunjanin S, Tessier PA, Mayer D (January 2006). "S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells". Experimental Cell Research. 312 (2): 184–97. doi:10.1016/j.yexcr.2005.10.013. PMID 16297907.
15. Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, Heizmann CW, Schlag PM, Stein U (May 2014). "RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis". Oncotarget. 5 (10): 3220–33. doi:10.18632/oncotarget.1908. PMC 4102805. PMID 24952599.
16. Gasparotto, J; Ribeiro, CT; da Rosa-Silva, HT; Bortolin, RC; Rabelo, TK; Peixoto, DO; Moreira, JCF; Gelain, DP (May 2019). "Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas". Mol Neurobiol. 56 (5): 3079–3089. doi:10.1007/s12035-018-1291-6. hdl:11323/1858. PMID 30094805. S2CID 51953478.
17. Yammani RR (April 2012). "S100 proteins in cartilage: role in arthritis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1822 (4): 600–6. doi:10.1016/j.bbadis.2012.01.006. PMC 3294013. PMID 22266138.
18. Kipfmueller, Florian (6 March 2019). "Expression of soluble receptor for advanced glycation end products is associated with disease severity in congenital diaphragmatic hernia". Am J Physiol Lung Cell Mol Physiol. 316 (6): L1061–L1069. doi:10.1152/ajplung.00359.2018. PMID 30838867. Retrieved 7 October 2020.
19. Kuroiwa Y, Takakusagi Y, Kusayanagi T, Kuramochi K, Imai T, Hirayama T, Ito I, Yoshida M, Sakaguchi K, Sugawara F (May 2013). "Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein". PLOS ONE. 8 (5): e63073. Bibcode:2013PLoSO...863073K. doi:10.1371/journal.pone.0063073. PMC 3643934. PMID 23658798.
20. Mahajan N, Mahmood S, Jain S, Dhawan V (September 2013). "Receptor for advanced glycation end products (RAGE), inflammatory ligand EN-RAGE and soluble RAGE (sRAGE) in subjects with Takayasu's arteritis". International Journal of Cardiology. 168 (1): 532–4. doi:10.1016/j.ijcard.2013.01.002. PMID 23398829.
21. Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT (September 2008). "Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types". American Journal of Respiratory Cell and Molecular Biology. 39 (3): 337–45. doi:10.1165/rcmb.2007-0244OC. PMID 18421017.
22. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV (April 2012). "A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease". The Journal of Clinical Investigation. 122 (4): 1377–92. doi:10.1172/JCI58642. PMC 3314449. PMID 22406537.
23. Han YT, Choi GI, Son D, Kim NJ, Yun H, Lee S, Chang DJ, Hong HS, Kim H, Ha HJ, Kim YH, Park HJ, Lee J, Suh YG (November 2012). "Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors". Journal of Medicinal Chemistry. 55 (21): 9120–35. doi:10.1021/jm300172z. PMID 22742537.
24. Han YT, Kim K, Choi GI, An H, Son D, Kim H, Ha HJ, Son JH, Chung SJ, Park HJ, Lee J, Suh YG (May 2014). "Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)". European Journal of Medicinal Chemistry. 79: 128–42. doi:10.1016/j.ejmech.2014.03.072. PMID 24727489.
25. Han YT, Kim K, Son D, An H, Kim H, Lee J, Park HJ, Lee J, Suh YG (February 2015). "Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE)". Bioorganic & Medicinal Chemistry. 23 (3): 579–87. doi:10.1016/j.bmc.2014.12.003. PMID 25533401.
26. "Azeliragon". vTv Therapeutics. vTv Therapeutics. Retrieved 23 July 2015.
27. Clinical trial number NCT02080364 for "Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (STEADFAST)" at ClinicalTrials.gov
28. vTv Halts Trials of Alzheimer's Candidate Azeliragon after Phase III Failure Apr 2018

Further reading

• Naka Y, Bucciarelli LG, Wendt T, Lee LK, Rong LL, Ramasamy R, Yan SF, Schmidt AM (August 2004). "RAGE axis: Animal models and novel insights into the vascular complications of diabetes". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (8): 1342–9. doi:10.1161/01.ATV.0000133191.71196.90. PMID 15155381.
• Simm A, Bartling B, Silber RE (June 2004). "RAGE: a new pleiotropic antagonistic gene?". Annals of the New York Academy of Sciences. 1019 (1): 228–31. Bibcode:2004NYASA1019..228S. doi:10.1196/annals.1297.038. PMID 15247020. S2CID 40408461.
• Nawroth P, Bierhaus A, Marrero M, Yamamoto H, Stern DM (February 2005). "Atherosclerosis and restenosis: is there a role for RAGE?". Current Diabetes Reports. 5 (1): 11–6. doi:10.1007/s11892-005-0061-9. PMID 15663911. S2CID 23298217.

External links

• RAGE+receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
• AGER on the Atlas of Genetics and Oncology
• Overview of all the structural information available in the PDB for UniProt: Q15109 (Human Advanced glycosylation end product-specific receptor) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q62151 (Mouse Advanced glycosylation end product-specific receptor) at the PDBe-KB.