AGE/RAGE pathway (WP2324)

Homo sapiens

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]


NetPath , Christine Chichester , Martina Summer-Kutmon , Alex Pico , Kristina Hanspers , Eric Weitz , and Egon Willighagen


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Homo sapiens



Pathway Ontology

receptor for advanced glycation end-products signaling pathway


Label Type Compact URI Comment
MAPK9 Protein ncbigene:5601
SMAD3 Protein ncbigene:4088
MAPK3 Protein ncbigene:5595
SMAD3 Protein ncbigene:4088
STAT5B Protein ncbigene:6777
IKBKB Protein ncbigene:3551
AGER Protein ncbigene:177
AGER Protein ncbigene:177
CDC42 Protein ncbigene:998
RAC1 Protein ncbigene:5879
RHOA Protein ncbigene:387
CASP3 Protein ncbigene:836
IRS1 Protein ncbigene:3667
PRKCA Protein ncbigene:5578
MYD88 Protein ncbigene:4615
IRAK4 Protein ncbigene:51135
MSN Protein ncbigene:4478
TIRAP Protein ncbigene:114609
ROCK1 Protein ncbigene:6093
HRAS Protein ncbigene:3625
SRC Protein ncbigene:6714
MAPK1 Protein ncbigene:5594
FOXO1 Protein ncbigene:2308
SP1 Protein ncbigene:6667
NFKB1 Protein ncbigene:4790
RELA Protein ncbigene:5970
AKT1 Protein ncbigene:207
MAPK14 Protein ncbigene:1432
MAPK8 Protein ncbigene:5599
FOXO4 Protein ncbigene:4303
JAK2 Protein ncbigene:3717
STAT1 Protein ncbigene:6772
STAT3 Protein ncbigene:6774
CHUK Protein ncbigene:1147
CASP8 Protein ncbigene:841
NFKBIA Protein ncbigene:4792
NFKB1 Protein ncbigene:4790
RELA Protein ncbigene:5970
SMAD2 Protein ncbigene:4087
SMAD2 Protein ncbigene:4087
DIAPH1 Protein ncbigene:1729
PLA2G4A Protein ncbigene:5321
ATF2 Protein ncbigene:1386
JUN Protein ncbigene:3725
CASP9 Protein ncbigene:842
MAP2K1 Protein ncbigene:5604
RAF1 Protein ncbigene:5894
ALPL Protein ncbigene:249
NCF1 Protein ncbigene:653361
STAT5A Protein ncbigene:6776
SP1 Protein ncbigene:6667
FOXO1 Protein ncbigene:2308
FOXO4 Protein ncbigene:4303
NOS2 Protein ncbigene:4843
NOS3 Protein ncbigene:4846
PRKCB Protein ncbigene:5579
PRKCZ Protein ncbigene:5590
CYCS Protein ncbigene:54205
CYCS Protein ncbigene:54205
SOD1 Protein ncbigene:6647
SHC1 Protein ncbigene:6464
EGFR Protein ncbigene:1956
DDOST Protein ncbigene:1650
MSR1 Protein ncbigene:4481
INS Protein ncbigene:3630
INSR Protein ncbigene:3643
HIF1A Protein ncbigene:3091
HIF1A Protein ncbigene:3091
EZR Protein ncbigene:7430
LGALS3 Protein ncbigene:3958
PRKCD Protein ncbigene:5580
MMP2 Protein ncbigene:4313
MMP14 Protein ncbigene:4323
MMP13 Protein ncbigene:4322
MMP9 Protein ncbigene:4318
MMP7 Protein ncbigene:4316