AGE/RAGE pathway (WP3124)

Bos taurus

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 [http://www.netpath.org/netslim/age_signaling_pathways.html NetSlim] database.

Authors

Martina Summer-Kutmon

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

receptor for advanced glycation end-products signaling pathway

Participants

Label Type Compact URI Comment
MAPK9 Protein ensembl:ENSBTAG00000004709 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
SMAD3 Protein ensembl:ENSBTAG00000012599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4088
MAPK3 Protein ensembl:ENSBTAG00000016156 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
STAT5B Protein ensembl:ENSBTAG00000010125 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6777
IKBKB Protein ensembl:ENSBTAG00000007599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
AGER Protein ensembl:ENSBTAG00000014420 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:177
CDC42 Protein ensembl:ENSBTAG00000001700 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
RAC1 Protein ensembl:ENSBTAG00000009233 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RHOA Protein ensembl:ENSBTAG00000004279 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:387
CASP3 Protein ensembl:ENSBTAG00000015874 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:836
IRS1 Protein ensembl:ENSBTAG00000021308 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3667
PRKCA Protein ensembl:ENSBTAG00000001061 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5578
MYD88 Protein ensembl:ENSBTAG00000000563 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4615
IRAK4 Protein ensembl:ENSBTAG00000021105 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51135
MSN Protein ensembl:ENSBTAG00000003418 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4478
TIRAP Protein ensembl:ENSBTAG00000021504 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:114609
ROCK1 Protein ensembl:ENSBTAG00000008403 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6093
INHBB Protein ensembl:ENSBTAG00000032017 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3625
SRC Protein ensembl:ENSBTAG00000008938 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
MAPK1 Protein ensembl:ENSBTAG00000010312 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
FOXO1 Protein ensembl:ENSBTAG00000044105 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2308
SP1 Protein ensembl:ENSBTAG00000003021 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
RELA Protein ensembl:ENSBTAG00000013895 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
MAPK14 Protein ensembl:ENSBTAG00000020783 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK8 Protein ensembl:ENSBTAG00000007876 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
FOXO4 Protein ensembl:ENSBTAG00000004879 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4303
JAK2 Protein ensembl:ENSBTAG00000012047 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
STAT1 Protein ensembl:ENSBTAG00000007867 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6772
STAT3 Protein ensembl:ENSBTAG00000021523 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
CHUK Protein ensembl:ENSBTAG00000007591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CASP8 Protein ensembl:ENSBTAG00000015718 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:841
BIKBA Protein ensembl:ENSBTAG00000016683 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
SMAD2 Protein ensembl:ENSBTAG00000039916 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4087
DIAPH1 Protein ensembl:ENSBTAG00000030499 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1729
PLA2G4A Protein ensembl:ENSBTAG00000013298 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5321
ATF2 Protein ensembl:ENSBTAG00000002295 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1386
JUN Protein ensembl:ENSBTAG00000004037 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
CASP9 Protein ensembl:ENSBTAG00000002472 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:842
MAP2K1 Protein ensembl:ENSBTAG00000033983 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
RAF1 Protein ensembl:ENSBTAG00000045748 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
ALPL Protein ensembl:ENSBTAG00000008951 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:249
NCF1 Protein ensembl:ENSBTAG00000003305 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:653361
STAT5A Protein ensembl:ENSBTAG00000009496 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6776
INOS Protein ensembl:ENSBTAG00000006894 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4843
NOS3 Protein ensembl:ENSBTAG00000017680 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4846
PRKCB Protein ensembl:ENSBTAG00000020921 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5579
PRKCZ Protein ensembl:ENSBTAG00000014119 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5590
CYCS Protein ensembl:ENSBTAG00000022613 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54205
SOD1 Protein ensembl:ENSBTAG00000018854 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6647
SHC1 Protein ensembl:ENSBTAG00000019838 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
EGFR Protein ensembl:ENSBTAG00000011628 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1956
DDOST Protein ensembl:ENSBTAG00000006085 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1650
MSR1 Protein ensembl:ENSBTAG00000002885 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4481
IR-A Protein ensembl:ENSBTAG00000012687 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3643
HIF1A Protein ensembl:ENSBTAG00000020935 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3091
EZR Protein ensembl:ENSBTAG00000010347 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7430
LGALS3 Protein ensembl:ENSBTAG00000002326 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3958
PRKCD Protein ensembl:ENSBTAG00000008719 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5580
MMP2 Protein ensembl:ENSBTAG00000019267 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4313
MMP14 Protein ensembl:ENSBTAG00000014824 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4323
MMP13 Protein ensembl:ENSBTAG00000015059 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4322
MMP9 Protein ensembl:ENSBTAG00000020676 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4318
MMP7 Protein ensembl:ENSBTAG00000004594 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4316

References