KEGG   PATHWAY: mcf04071
Entry
mcf04071                    Pathway                                
Name
Sphingolipid signaling pathway - Macaca fascicularis (crab-eating macaque)
Description
Sphingomyelin (SM) and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. Particularly, the sphingolipid metabolites, ceramide (Cer) and sphingosine-1-phosphate (S1P), have emerged as a new class of potent bioactive molecules. Ceramide can be generated de novo or by hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase). Ceramide is subsequently metabolized by ceramidase to generate sphingosine (Sph) which in turn produces S1P through phosphorylation by sphingosine kinases 1 and 2 (SphK1, 2). Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects. S1P functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms.
Class
Environmental Information Processing; Signal transduction
Pathway map
mcf04071  Sphingolipid signaling pathway
mcf04071

Organism
Macaca fascicularis (crab-eating macaque) [GN:mcf]
Gene
102123629  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
102141632  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
101864870  SPTLC1; serine palmitoyltransferase 1 isoform X3 [KO:K00654] [EC:2.3.1.50]
101925319  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
102126963  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
107128159  CERS1; ceramide synthase 1 isoform X2 [KO:K04710] [EC:2.3.1.299]
102116814  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
101926302  CERS4; ceramide synthase 4 isoform X1 [KO:K24621] [EC:2.3.1.297]
102143963  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
101926756  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
102116993  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
102125533  DEGS1; sphingolipid delta(4)-desaturase DES1 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
102146231  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
102136513  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
102126212  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 isoform X1 [KO:K04714] [EC:2.7.8.27]
101867034  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 isoform X1 [KO:K04714] [EC:2.7.8.27]
102139631  TNF; tumor necrosis factor isoform X1 [KO:K03156]
102135285  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
102134999  NSMAF; protein FAN isoform X1 [KO:K18953]
102139997  LOW QUALITY PROTEIN: protein FAN-like [KO:K18953]
102138369  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
102118393  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
102125051  ASAH2; neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
102122495  ACER1; alkaline ceramidase 1 isoform X1 [KO:K01441] [EC:3.5.1.23]
102122205  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
102125087  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X2 [KO:K03171]
101925175  TRAF2; TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
102125635  CTSD; cathepsin D isoform X1 [KO:K01379] [EC:3.4.23.5]
102143226  BID; BH3-interacting domain death agonist isoform X2 [KO:K04726]
102132255  BAX; apoptosis regulator BAX isoform X6 [KO:K02159]
101925657  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
102118497  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102126339  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102121272  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101867352  MAPK13; mitogen-activated protein kinase 13 isoform X2 [KO:K04441] [EC:2.7.11.24]
101926770  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102134421  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
101867305  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
101925905  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
102144461  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102142406  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102132744  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102138212  BCL2; apoptosis regulator Bcl-2 isoform X2 [KO:K02161]
102137928  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
101864925  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X2 [KO:K04382] [EC:3.1.3.16]
101867273  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
101865477  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X4 [KO:K03456]
101926525  PPP2R2C; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform X2 [KO:K04354]
102125257  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
102142696  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X4 [KO:K04354]
101926197  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X2 [KO:K04354]
102144364  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
102144074  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
102138311  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
101865748  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
101926512  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
101925723  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X2 [KO:K11584]
101865955  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
102129607  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
102139541  LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform-like [KO:K11584]
102135998  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
102128482  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
102127416  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
102120026  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
102126878  FYN; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
102121794  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
102143464  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102142026  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102122725  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102137291  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
101866246  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102124804  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102132109  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
102130012  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
101926057  SPHK1; sphingosine kinase 1 isoform X2 [KO:K04718] [EC:2.7.1.91]
102116114  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
102124671  KNG1; kininogen-1 [KO:K03898]
107126378  BDKRB2; B2 bradykinin receptor [KO:K03916]
102131320  OPRD1; delta-type opioid receptor [KO:K04213]
102119905  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 isoform X1 [KO:K04630]
102140224  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
101926144  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
101925220  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
102140615  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
102136896  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
102123165  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
102127282  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
102145011  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102116996  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
102142274  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
102135818  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
102133648  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
102120317  SGPL1; sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
102127318  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
102137829  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
102118744  HRAS; GTPase HRas isoform X1 [KO:K02833]
102131483  KRAS; GTPase KRas isoform X1 [KO:K07827]
102137913  NRAS; GTPase NRas [KO:K07828]
102125312  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102141214  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102140855  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101866379  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
102143504  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
101866593  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
102134837  ras-related C3 botulinum toxin substrate 1-like [KO:K04392]
102137056  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
102143597  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
102126442  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
102130397  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
102135875  PRKCA; protein kinase C alpha type isoform X4 [KO:K02677] [EC:2.7.11.13]
102116992  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101865773  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
102124282  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
102145253  S1PR5; sphingosine 1-phosphate receptor 5 isoform X1 [KO:K04295]
101867258  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
102127819  GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X1 [KO:K04639]
101865630  RHOA; transforming protein RhoA [KO:K04513]
102140851  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
102133054  ROCK2; rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
101867036  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X2 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102138273  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101867324  RELA; transcription factor p65 isoform X1 [KO:K04735]
Compound
C00065  L-Serine
C00154  Palmitoyl-CoA
C00165  Diacylglycerol
C00195  N-Acylsphingosine
C00212  Adenosine
C00319  Sphingosine
C00346  Ethanolamine phosphate
C00533  Nitric oxide
C00550  Sphingomyelin
C00836  Sphinganine
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06124  Sphingosine 1-phosphate
C12126  Dihydroceramide
C16845  Peroxynitrite
Reference
PMID:18216770
  Authors
Hannun YA, Obeid LM
  Title
Principles of bioactive lipid signalling: lessons from sphingolipids.
  Journal
Nat Rev Mol Cell Biol 9:139-50 (2008)
DOI:10.1038/nrm2329
Reference
PMID:17161984
  Authors
Taha TA, Mullen TD, Obeid LM
  Title
A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death.
  Journal
Biochim Biophys Acta 1758:2027-36 (2006)
DOI:10.1016/j.bbamem.2006.10.018
Reference
PMID:23919551
  Authors
Liu J, Beckman BS, Foroozesh M
  Title
A review of ceramide analogs as potential anticancer agents.
  Journal
Future Med Chem 5:1405-21 (2013)
DOI:10.4155/fmc.13.107
Reference
PMID:18675379
  Authors
Kono M, Allende ML, Proia RL
  Title
Sphingosine-1-phosphate regulation of mammalian development.
  Journal
Biochim Biophys Acta 1781:435-41 (2008)
DOI:10.1016/j.bbalip.2008.07.001
Reference
PMID:18403224
  Authors
Olivera A
  Title
Unraveling the complexities of sphingosine-1-phosphate function: the mast cell model.
  Journal
Prostaglandins Other Lipid Mediat 86:1-11 (2008)
DOI:10.1016/j.prostaglandins.2008.02.005
Reference
PMID:25309325
  Authors
Brunkhorst R, Vutukuri R, Pfeilschifter W
  Title
Fingolimod for the treatment of neurological diseases-state of play and future perspectives.
  Journal
Front Cell Neurosci 8:283 (2014)
DOI:10.3389/fncel.2014.00283
Reference
PMID:15999095
  Authors
Rosen H, Goetzl EJ
  Title
Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.
  Journal
Nat Rev Immunol 5:560-70 (2005)
DOI:10.1038/nri1650
Reference
PMID:10880336
  Authors
Pyne S, Pyne NJ
  Title
Sphingosine 1-phosphate signalling in mammalian cells.
  Journal
Biochem J 349:385-402 (2000)
DOI:10.1042/bj3490385
Reference
PMID:21705677
  Authors
Egom EE, Mohamed TM, Mamas MA, Shi Y, Liu W, Chirico D, Stringer SE, Ke Y, Shaheen M, Wang T, Chacko S, Wang X, Solaro RJ, Fath-Ordoubadi F, Cartwright EJ, Lei M
  Title
Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury.
  Journal
Am J Physiol Heart Circ Physiol 301:H1487-95 (2011)
DOI:10.1152/ajpheart.01003.2010
Reference
PMID:15451787
  Authors
Jin ZQ, Goetzl EJ, Karliner JS
  Title
Sphingosine kinase activation mediates ischemic preconditioning in murine heart.
  Journal
Circulation 110:1980-9 (2004)
DOI:10.1161/01.CIR.0000143632.06471.93
Reference
PMID:17913601
  Authors
Melendez AJ
  Title
Sphingosine kinase signalling in immune cells: potential as novel therapeutic targets.
  Journal
Biochim Biophys Acta 1784:66-75 (2008)
DOI:10.1016/j.bbapap.2007.07.013
Reference
PMID:22654878
  Authors
Halova I, Draberova L, Draber P
  Title
Mast cell chemotaxis - chemoattractants and signaling pathways.
  Journal
Front Immunol 3:119 (2012)
DOI:10.3389/fimmu.2012.00119
Reference
PMID:17438574
  Authors
Kraft S, Kinet JP
  Title
New developments in FcepsilonRI regulation, function and inhibition.
  Journal
Nat Rev Immunol 7:365-78 (2007)
DOI:10.1038/nri2072
Reference
PMID:16470226
  Authors
Gilfillan AM, Tkaczyk C.
  Title
Integrated signalling pathways for mast-cell activation.
  Journal
Nat Rev Immunol 6:218-30 (2006)
DOI:10.1038/nri1782
Reference
PMID:11418646
  Authors
Osawa Y, Banno Y, Nagaki M, Brenner DA, Naiki T, Nozawa Y, Nakashima S, Moriwaki H
  Title
TNF-alpha-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes.
  Journal
J Immunol 167:173-80 (2001)
DOI:10.4049/jimmunol.167.1.173
Reference
PMID:20534702
  Authors
Montfort A, Martin PG, Levade T, Benoist H, Segui B
  Title
FAN (factor associated with neutral sphingomyelinase activation), a moonlighting protein in TNF-R1 signaling.
  Journal
J Leukoc Biol 88:897-903 (2010)
DOI:10.1189/jlb.0410188
Reference
PMID:11001563
  Authors
Chatterjee S
  Title
Neutral sphingomyelinase: past, present and future.
  Journal
Chem Phys Lipids 102:79-96 (1999)
DOI:10.1016/S0009-3084(99)00077-8
Related
pathway
mcf00600  Sphingolipid metabolism
mcf04010  MAPK signaling pathway
mcf04142  Lysosome
mcf04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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