AGE/RAGE pathway (Bos taurus)

From WikiPathways

Revision as of 11:24, 6 October 2016 by Mkutmon (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
MAPK9PSMAD3PMAPK3PSMAD3PSTAT5BPIKBKBPAGERPCalcification of smooth muscle cellsAGE/RAGE Signaling PathwayNeuriteAGERPCDC42GTPRAC1GgGTPRHOAGTPCASP3IRS1PRKCAMYD88PIRAK4MSNPTIRAPROCK1PINHBBGTPSRCPMAPK1PFOXO1dePSP1NFKB1PRELAPAKT1dePMAPK14PPMAPK8PFOXO4JAK2STAT1PSTAT3PPCHUKPCASP8BIKBAUbPNFKB1RELAPPSMAD2PSMAD2PTubular epithelium myofibroblast transitionDIAPH1PLCPLA2G4ANa+ K+ ATPasePNeutrophilRearrangement of the actin cytoskeletonAutophagy in vascular smooth muscle cellsDissolution of gap junctions in human hepatoma cellsCell proliferationATF2PJUNPFibroblastsCASP9Retinal pericytesOsteoblastsINS-1 cellsNONeuroblastoma cellsIncrease in monolayer permeabilityRenal cellular hypertrophyMitogeneis in NRK-49F cellsMAP2K1PRAF1PALPLMonocyte adhesion to retinal endothelial cellsNCF1PSTAT5APSP1NOXApoptosis inFOXO1FOXO4Osteogenicdifferentiationof VSMCsRenal proximal tubular cellsINOSNOS3Endothelial 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 removalandAGEsMSR1AGEsINSIR-AHIF1AHIF1ACYNUInhibition oftubulogenesis ofproximal tubule cellsEZRdePPPlacenta andgestational membranesProstaglandin F2alphaProstaglandin E2Released fromChondrocytesLGALS3AGEsincreasedPRKCDInhibition ofPMicroglial cellsMMP2MMP14MMP13MMP9MMP7


Description

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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2324(78487) with a 81.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

  1. 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
  2. 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
  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
  4. 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
  5. 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

History

CompareRevisionActionTimeUserComment
89797view11:24, 6 October 2016Mkutmonfixed special character in description
80675view15:21, 30 June 2015MkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AGE-modified albuminProtein
AGERProteinENSBTAG00000014420 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:177
AGEsProtein
AKT1ProteinENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
ALPLProteinENSBTAG00000008951 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:249
ATF2ProteinENSBTAG00000002295 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1386
BIKBAProteinENSBTAG00000016683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
CASP3ProteinENSBTAG00000015874 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:836
CASP8ProteinENSBTAG00000015718 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:841
CASP9ProteinENSBTAG00000002472 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:842
CDC42ProteinENSBTAG00000001700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
CELProtein
CHUKProteinENSBTAG00000007591 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CMLProtein
CML-CollagenProtein
CYCSProteinENSBTAG00000022613 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54205
DDOSTProteinENSBTAG00000006085 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1650
DIAPH1ProteinENSBTAG00000030499 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1729
EGFRProteinENSBTAG00000011628 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1956
EZRProteinENSBTAG00000010347 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7430
FOXO1ProteinENSBTAG00000044105 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2308
FOXO4ProteinENSBTAG00000004879 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4303
Glyc-FBSProtein
H2O2Protein
HIF1AProteinENSBTAG00000020935 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3091
IKBKBProteinENSBTAG00000007599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
INHBBProteinENSBTAG00000032017 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3625
INOSProteinENSBTAG00000006894 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4843
INSProtein
IR-AProteinENSBTAG00000012687 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3643
IRAK4ProteinENSBTAG00000021105 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51135
IRS1ProteinENSBTAG00000021308 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3667
JAK2ProteinENSBTAG00000012047 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
JUNProteinENSBTAG00000004037 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
LGALS3ProteinENSBTAG00000002326 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3958
LigandProtein
MAP2K1ProteinENSBTAG00000033983 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAPK14ProteinENSBTAG00000020783 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK1ProteinENSBTAG00000010312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3ProteinENSBTAG00000016156 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8ProteinENSBTAG00000007876 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9ProteinENSBTAG00000004709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
MMP13ProteinENSBTAG00000015059 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4322
MMP14ProteinENSBTAG00000014824 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4323
MMP2ProteinENSBTAG00000019267 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4313
MMP7ProteinENSBTAG00000004594 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4316
MMP9ProteinENSBTAG00000020676 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4318
MSNProteinENSBTAG00000003418 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4478
MSR1ProteinENSBTAG00000002885 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4481
MYD88ProteinENSBTAG00000000563 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4615
NCF1ProteinENSBTAG00000003305 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:653361
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NOProtein
NOS3ProteinENSBTAG00000017680 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4846
NOXProtein
Na+ K+ ATPaseProtein
PLA2G4AProteinENSBTAG00000013298 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5321
PLCProtein
PRKCAProteinENSBTAG00000001061 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5578
PRKCBProteinENSBTAG00000020921 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5579
PRKCDProteinENSBTAG00000008719 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5580
PRKCZProteinENSBTAG00000014119 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5590
PentosidineProtein
ProteinGeneProduct
RAC1ProteinENSBTAG00000009233 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RAF1ProteinENSBTAG00000045748 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
RELAProteinENSBTAG00000013895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RHOAProteinENSBTAG00000004279 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:387
ROCK1ProteinENSBTAG00000008403 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6093
SHC1ProteinENSBTAG00000019838 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
SMAD2ProteinENSBTAG00000039916 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4087
SMAD3ProteinENSBTAG00000012599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4088
SOD1ProteinENSBTAG00000018854 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6647
SP1ProteinENSBTAG00000003021 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6667
SRCProteinENSBTAG00000008938 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
STAT1ProteinENSBTAG00000007867 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6772
STAT3ProteinENSBTAG00000021523 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
STAT5AProteinENSBTAG00000009496 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6776
STAT5BProteinENSBTAG00000010125 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6777
TIRAPProteinENSBTAG00000021504 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:114609

Annotated Interactions

No annotated interactions
Personal tools