AGE/RAGE pathway (Homo sapiens)

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MAPK9PSMAD3PMAPK3PSMAD3PSTAT5BPIKBKBPAGERPNeuriteAGE/RAGE Signaling PathwayCalcification of smooth muscle cellsAGERPCDC42GTPRAC1GTPGgRHOAGTPCASP3IRS1PRKCAMYD88PIRAK4MSNPTIRAPROCK1PHRASSRCGTPPMAPK1PFOXO1SP1dePNFKB1RELAPPAKT1dePPMAPK14MAPK8PPFOXO4JAK2STAT1PPSTAT3CHUKPCASP8PNFKBIAUbPNFKB1RELAPPSMAD2PSMAD2PTubular epithelium myofibroblast transitionDIAPH1PLCPLA2G4APNa+ K+ ATPaseNeutrophilRearrangement of the actin cytoskeletonAutophagy in vascular smooth muscle cellsDissolution of gap junctions in human hepatoma cellsCell proliferationATF2JUNPPFibroblastsCASP9Retinal pericytesOsteoblastsINS-1 cellsNONeuroblastoma cellsIncrease in monolayer permeabilityRenal cellular hypertrophyMitogeneis in NRK-49F cellsMAP2K1PRAF1PALPLMonocyte adhesion to retinal endothelial cellsNCF1PSTAT5APSP1NOXApoptosis inFOXO1FOXO4Osteogenicdifferentiationof VSMCsRenal proximal tubular cellsNOS2NOS3Endothelial cellDegradationDissociationH2O2MitochondrialPRKCBPRKCZProteinDissociation of PPIReceptorProteinTransportLeads toInduced catalysisProtein-protein interaction (PPI)LEGENDPhosphorylationNucleusCytoplasmCYNUEnzymeEnzyme complex or specific component unknownCYNUCYNUCYNUCYNUCYNUCYNUCMLCELAGE-modified albuminPentosidineLigandSmall moleculesEnzymeProteins activated (identified by assays)MTMitochondriaCYMTApoptosis inPodocytesFibroblastsCYCSCYCSSOD1burstTGF-betaindependentDephosphorylationInhibition of proliferation and migration ofbone marrow mesenchymal stem cellsT-cellsEndothelial cell permeabilityPIP2DAGCa2+Arachidonic acidROSoutgrowthpermeabilitytransitiondysfunctionsGlyc-FBSPhosphorylated stateUbUbiquitinated stateGgGeranylgeranylated statedePDephosphrylated stateRegulation ofcytoskeletonCML-CollagenFormation of F-actin stress fibersSHC1PEGFRPDDOSTInternalizationAGE removalandAGEsMSR1AGEsINSINSRHIF1AHIF1ACYNUInhibition oftubulogenesis ofproximal tubule cellsEZRdePPPlacenta andgestational membranesProstaglandin F2alphaProstaglandin E2Released fromChondrocytesLGALS3AGEsincreasedPRKCDPInhibition ofMicroglial cellsMMP2MMP14MMP13MMP9MMP7


Advanced glycation end products (AGEs) are heterogeneous group of non-enzymatic malliard reaction products of aldose sugar with proteins and lipids. Formation of AGEs is an indicator of one of the many chemical modifications of proteins and DNA that occur within the biological systems. Research over past two decades have implicated the role of AGEs in most of the age-related diseases like Alzheimer's disease, cancer, cardiovascular disease, diabetes, renal disorders, hypertension, stroke, visual impairment and skin disorders. AGEs also modify the skin collagen and accelerates the aging process. In diabetic patients, AGE formation occurs in large scale and manifests with clinical symptoms such as cataract, atherosclerosis, nephropathy and neuropathy.

AGEs are known to bind with different cell surface receptors such as receptor for advanced glycation end products (RAGE), dolichyldiphosphooligosaccharide-protein glycosyltransferase (AGE-R1), protein kinase C substrate, 80KH phosphoprotein (AGE-R2), galectin-3 (AGE-R3), and class A macrophage scavenger receptor types I and II. RAGE, is the well-studied receptor for AGEs and the signaling events mediated by others are either not been identified or are considered as negative regulators of RAGE signaling. RAGE is an integral membrane protein of the immunoglobulin superfamily. RAGE is constituted of an extracellular domain, a transmembrane domain and a short cytoplasmic domain. RAGE is expressed in a wide range of tissues such as lung, heart, kidney, brain, skeletal muscles, and in different types of cells including endothelial cells, macrophages/monocytes, neutrophils, and lymphocytes. Besides AGEs, RAGE also mediate the effects of its other extracellular ligands namely extracellular high mobility group box-1 (HMGB1), S100 family of calcium binding proteins and amyloid-beta peptide, among many others. Although a large number of advanced glycation end products have been identified in humans, AGE/RAGE signaling ex-vivo is mostly studied using the AGEs such as AGE-modified albumin, N(6)(carboxymethyl)lysine, N(6)(carboxyethyl)lysine and pentosidine.

The signaling events mediated by RAGE are complex due to the diversity of its ligands and their effects in different cell types. Homodimerization of RAGE has been identified to be essential for RAGE signaling. Depending on the intensity and duration of RAGE ligation, specific signaling modules such as ERK1/2, p38 MAPK, CDC42/RAC, SAPK/JNK and NF-κB has been shown to be regulated in different cell types. AGEs have been shown to induce the formation of complexes containing RAGE with DIAPH1, SRC/IRS1/PKC-alpha, TIRAP/MYD88/IRAK4 and RHOA. RAGE-DIAPH1 interaction is required for the activation of RAC1/CDC42 pathway leading to neurite outgrowth and regulation of cytoskeleton.Activation of PKC-alpha through RAGE/SRC/IRS1/PKC-alpha by AGEs has been suggested as a mechanism of insulin resistance in skeletal muscle cells. RAGE also shares the adaptor molecules such as TIRAP, MYD88 and IRAK4 of toll-like receptors and induce the activation of AKT, p38MAPK and NFKB pathways. AGEs have also been shown to induce the formation of complex between RAGE and RHOA. RHOA/ROCK dependent phosphorylation of ezrin/radixin/moesin (ERM) is required for the regulation of gap formation and actin reorganization, and thereby endothelial permeability. However, in tubular cells, AGEs inhibit phosphorylation of ERMs leading to inhibition of tubulogenesis. Similarly, AKT have been shown to be activated by AGEs and induce proliferation of primary acute myeloid leukemia (AML) cells where as phosphorylation of AKT is shown to be inhibited in podocytes leading to FOXO4 activation and apoptosis. The major component of AGE/RAGE signaling is the oxidative stress induced pathways. AGEs induce the oxidative stress through the activation of NADPH oxidases. Increased intracellular oxidative stress leads to stimulation of PKC and ERK1/2, resulting in the translocation and activation of NF-κB and subsequent up regulation of NF-κB dependent genes which ultimately produce deleterious effects to cells. Please access this pathway at NetSlim database.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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  1. Sakaguchi M, Murata H, Yamamoto K, Ono T, Sakaguchi Y, Motoyama A, Hibino T, Kataoka K, Huh NH; ''TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding.''; PLoS One, 2011 PubMed Europe PMC Scholia
  2. Alikhani Z, Alikhani M, Boyd CM, Nagao K, Trackman PC, Graves DT; ''Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways.''; J Biol Chem, 2005 PubMed Europe PMC Scholia
  3. Lin FL, Chang CI, Chuang KP, Wang CY, Liu HJ; ''Advanced glycation end products down-regulate gap junctions in human hepatoma SKHep 1 cells via the activation of Src-dependent ERK1/2 and JNK/SAPK/AP1 signaling pathways.''; J Agric Food Chem, 2010 PubMed Europe PMC Scholia
  4. Mamputu JC, Renier G; ''Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants.''; J Leukoc Biol, 2004 PubMed Europe PMC Scholia
  5. Li JH, Wang W, Huang XR, Oldfield M, Schmidt AM, Cooper ME, Lan HY; ''Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway.''; Am J Pathol, 2004 PubMed Europe PMC Scholia


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105867view23:29, 15 August 2019KhanspersModified description
105429view04:30, 8 August 2019KhanspersModified description
96980view18:21, 24 April 2018AlexanderPicoReverted to version '04:26, 6 October 2016' by AlexanderPico
96974view15:49, 24 April 2018WpblockedModified title
89798view11:26, 6 October 2016Mkutmonfixed special character in description
78487view10:28, 7 January 2015MaintBotadded missing graphIds
71701view19:53, 17 October 2013MaintBotremoved data source from nodes without identifier
67034view09:56, 26 June 2013Christine ChichesterOntology Term : 'receptor for advanced glycation end-products signaling pathway' added !
63150view20:17, 8 May 2013MaintBotUpdating GPML version
53381view04:53, 6 November 2012NetPathModified description
53109view01:19, 30 October 2012MaintBotModified categories
52521view10:22, 15 October 2012NetPathModified description
52516view10:14, 15 October 2012NetPathNew pathway

External references


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NameTypeDatabase referenceComment
AGE-modified albuminProtein
AGERProtein177 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
ALPLProtein249 (Entrez Gene)
ATF2Protein1386 (Entrez Gene)
CASP3Protein836 (Entrez Gene)
CASP8Protein841 (Entrez Gene)
CASP9Protein842 (Entrez Gene)
CDC42Protein998 (Entrez Gene)
CHUKProtein1147 (Entrez Gene)
CYCSProtein54205 (Entrez Gene)
DDOSTProtein1650 (Entrez Gene)
DIAPH1Protein1729 (Entrez Gene)
EGFRProtein1956 (Entrez Gene)
EZRProtein7430 (Entrez Gene)
FOXO1Protein2308 (Entrez Gene)
FOXO4Protein4303 (Entrez Gene)
HIF1AProtein3091 (Entrez Gene)
HRASProtein3625 (Entrez Gene)
IKBKBProtein3551 (Entrez Gene)
INSProtein3630 (Entrez Gene)
INSRProtein3643 (Entrez Gene)
IRAK4Protein51135 (Entrez Gene)
IRS1Protein3667 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
LGALS3Protein3958 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
MMP13Protein4322 (Entrez Gene)
MMP14Protein4323 (Entrez Gene)
MMP2Protein4313 (Entrez Gene)
MMP7Protein4316 (Entrez Gene)
MMP9Protein4318 (Entrez Gene)
MSNProtein4478 (Entrez Gene)
MSR1Protein4481 (Entrez Gene)
MYD88Protein4615 (Entrez Gene)
NCF1Protein653361 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NFKBIAProtein4792 (Entrez Gene)
NOS2Protein4843 (Entrez Gene)
NOS3Protein4846 (Entrez Gene)
Na+ K+ ATPaseProtein
PLA2G4AProtein5321 (Entrez Gene)
PRKCAProtein5578 (Entrez Gene)
PRKCBProtein5579 (Entrez Gene)
PRKCDProtein5580 (Entrez Gene)
PRKCZProtein5590 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
RELAProtein5970 (Entrez Gene)
RHOAProtein387 (Entrez Gene)
ROCK1Protein6093 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
SMAD2Protein4087 (Entrez Gene)
SMAD3Protein4088 (Entrez Gene)
SOD1Protein6647 (Entrez Gene)
SP1Protein6667 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
STAT5AProtein6776 (Entrez Gene)
STAT5BProtein6777 (Entrez Gene)
TIRAPProtein114609 (Entrez Gene)

Annotated Interactions

No annotated interactions

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