RAGE (receptor) 4992635 224269951 2008-07-08T02:24:27Z ProteinBoxBot 3991663 Replaced protein Box Template with PBB Template for easy viewing. {{PBB|geneid=177}} [[Image:IgG-RAGE.jpg|thumb|180px|Schematic of the relation between an immunoglobulin and RAGE]] [[Image:RAGEvariants.jpg|thumb|500px|Schematic of the RAGE gene and its products]] '''RAGE''', the [[receptor (biochemistry)|receptor]] for advanced [[glycation]] endproducts is a 35kD transmembrane receptor of the [[immunoglobulin]] super family which was first characterized in 1992 by Neeper ''et al.''<ref>{{cite journal | author = Neeper, M; Schmidt, AM; Brett, J; Yan, SD; Wang, F; Pan, YC; Elliston, K; Stern, D; Shaw, A | title = Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins | journal=J.Biol.Chem. | volume=267 | issue=21 | year=1992 | pages=14998–15004 | pmid=1378843 }}</ref>. Its name comes from its ability to bind advanced glycation endproducts ([[advanced glycation endproduct|AGE]]), a heterogeneous group of non-enzymatically altered proteins. Besides AGEs, RAGE is also able to bind other ligands and is thus often referred to as a pattern-recognition receptor. The interaction between RAGE and its ligands is thought to result in pro-[[inflammation|inflammatory]] [[gene]] activation<ref>{{cite journal | author=Bierhaus, A; Schiekofer, S; Schwaninger, M et al. | title=Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB | journal=Diabetes | volume=50 | issue=12 | year=2001 | pages=2792–2808 | pmid=11723063 | doi=10.2337/diabetes.50.12.2792 }}</ref>. 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 signalling 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/polymorphisms == The [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=177 human 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 pair]]s (bp) including the promoter region, which partly overlaps with the PBX2 gene<ref>{{cite journal | author=Hudson, BI; Stickland, MH; Futers, TS; Grant, PJ | title=Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy | journal=Diabetes | volume=50 | issue=6 | year=2001 | pages=1505–1511 | pmid=11375354 | doi=10.2337/diabetes.50.6.1505 }}</ref>. About 30 [[Polymorphism (biology)|polymorphisms]] are known most of which are [[single nucleotide polymorphisms]] ([[single nucleotide polymorphism|SNP]])<ref>{{cite journal | author=Hudson, BI; Hofman, MA; Bucciarelli, L ''et al.'' | title=Glycation and diabetes: The RAGE connection | journal=Current Science | volume=83 | issue=12 | year=2002 | pages=1515–1521 | url=http://www.ias.ac.in/currsci/dec252002/1515.pdf }}</ref>. == RNA/alternative splicing == The primary transcript of the human RAGE gene ([[pre-mRNA]]) is thought to be [[alternative splicing|alternatively spliced]]. So far about 6 isoforms including the full length transmembrane receptor have been found in different [[biological tissue|tissues]] such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane [[structural domain|domain]] and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE ([[endogeny|endogenous]] secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands. == Structure == The full receptor consists of 5 [[structural domain|domain]]s: 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. == RAGE ligands == RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Proteins which have so far been found to bind RAGE are: *[[advanced glycation endproduct|AGE]] *[[HMGB1]] (Amphoterin) *S100b *Amyloid-β-protein *Mac-1 == 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 the [[nuclear factor]] kappa B (NF-κB). NF-κB controls several [[genes]] which are involved in [[inflammation]]. Interestingly, RAGE itself will also be up-regulated by NF-κB. Given a condition, where there is a large amount of RAGE ligands (e.g. [[advanced glycation endproduct|AGE]] in [[Diabetes mellitus|diabetes]] or [[amyloid beta|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 in a fatal way which ends in organ damage or even organ failure. Diseases that have been linked to RAGE are: *[[Atherosclerosis]] *[[Peripheral vascular disease]] *[[Myocardial infarction]] *[[Congestive heart failure]] *[[Diabetic retinopathy]] *[[Diabetic neuropathy]] *[[Diabetic nephropathy]] *[[Alzheimer's disease]] == AGE receptors == Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in removal of AGE rather than in signal transduction as it 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) *[[CD-36]] ==References== <div class="references-small"><references/></div> ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{cite journal | author=Naka Y, Bucciarelli LG, Wendt T, ''et al.'' |title=RAGE axis: Animal models and novel insights into the vascular complications of diabetes. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=24 |issue= 8 |pages= 1342–9 |year= 2005 |pmid= 15155381 |doi= 10.1161/01.ATV.0000133191.71196.90 }} *{{cite journal | author=Simm A, Bartling B, Silber RE |title=RAGE: a new pleiotropic antagonistic gene? |journal=Ann. N. Y. Acad. Sci. |volume=1019 |issue= |pages= 228–31 |year= 2004 |pmid= 15247020 |doi= 10.1196/annals.1297.038 }} *{{cite journal | author=Nawroth P, Bierhaus A, Marrero M, ''et al.'' |title=Atherosclerosis and restenosis: is there a role for RAGE? |journal=Curr. Diab. Rep. |volume=5 |issue= 1 |pages= 11–6 |year= 2005 |pmid= 15663911 |doi= }} }} {{refend}} ==External links== * {{MeshName|RAGE+receptor}} [[Category:Receptors]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}