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, sRAGE
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 34,816,836 bp[2] End 34,819,910 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lung upper lobe of left lung right lobe of thyroid gland left lobe of thyroid gland spleen blood right uterine tube gastric mucosa lymph node pituitary gland Top expressed in right lung lobe left lung left lung lobe thyroid gland trachea renal corpuscle external carotid artery renal pelvis internal carotid artery otic placode More reference expression data BioGPS n/a
Gene ontology Molecular function S100 protein binding 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 protein-containing complex binding Cellular component integral component of membrane membrane integral component of plasma membrane extracellular region fibrillar center plasma 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 response 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 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 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: 34.82 – 34.82 Mb PubMed search [3] [4]
Wikidata
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Schematic of the relation between an immunoglobulin and RAGE

Schematic of the RAGE gene and its products

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.

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 S100A7A (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 a RAGE ligand present (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]
• Schizophrenia^[21]

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^[22]

Inhibitors

A number of small molecule RAGE inhibitors or antagonists have been reported.^{[23][24][25][26]}

Azeliragon

vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.^[27][28] These trials were halted in 2018.^[29]

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

Further reading

External links

• RAGE+receptor at the U.S. 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.