KEGG   PATHWAY: oas04071
Entry
oas04071                    Pathway                                
Name
Sphingolipid signaling pathway - Ovis aries (sheep)
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
oas04071  Sphingolipid signaling pathway
oas04071

Organism
Ovis aries (sheep) [GN:oas]
Gene
101110257  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
101105721  SPTLC1; serine palmitoyltransferase 1 isoform X2 [KO:K00654] [EC:2.3.1.50]
101115373  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
114109040  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
101103775  SPTSSB; serine palmitoyltransferase small subunit B isoform X2 [KO:K26384]
101107095  CERS1; ceramide synthase 1 isoform X3 [KO:K04710] [EC:2.3.1.299]
101109498  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
101102559  CERS4; ceramide synthase 4 isoform X1 [KO:K24621] [EC:2.3.1.297]
101110093  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
101122252  CERS6; ceramide synthase 6 isoform X4 [KO:K23727] [EC:2.3.1.291]
101117661  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
100192315  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101118389  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101120481  sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
100307047  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
101118575  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
101123121  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
443540  TNF; tumor necrosis factor [KO:K03156]
100135698  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
101110070  NSMAF; protein FAN isoform X2 [KO:K18953]
101107873  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
101117904  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
101121732  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
101123535  ACER2; alkaline ceramidase 2 isoform X2 [KO:K01441] [EC:3.5.1.23]
101106585  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
101111042  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
101105235  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
443060  CTSD; cathepsin D isoform X2 [KO:K01379] [EC:3.4.23.5]
101117837  BID; BH3-interacting domain death agonist isoform X2 [KO:K04726]
443059  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
101121018  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X2 [KO:K04426] [EC:2.7.11.25]
101116201  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120826  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120665  MAPK10; mitogen-activated protein kinase 10 isoform X2 [KO:K04440] [EC:2.7.11.24]
100194428  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100217411  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
101116223  MAPK11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
101115956  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
101122295  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
101118462  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101119242  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100294652  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101119602  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
101114930  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
443009  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
101108352  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform-like [KO:K04382] [EC:3.1.3.16]
101115302  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
101108511  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X2 [KO:K03456]
101109519  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform-like [KO:K03456]
114111443  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform-like [KO:K03456]
101110299  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X5 [KO:K04354]
101102148  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
101113409  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X6 [KO:K04354]
101116812  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X3 [KO:K11583]
101114233  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X2 [KO:K11583]
101119424  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
101117264  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
101104699  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
101107792  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
101102015  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X8 [KO:K11584]
101110885  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
443421  TP53; cellular tumor antigen p53 [KO:K04451]
100144427  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
443203  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
443204  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma isoform X2 [KO:K07983]
101109363  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
101115743  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
101109759  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101110015  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101117348  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101123247  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101111546  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101121455  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
101110687  PLD2; phospholipase D2 isoform X2 [KO:K01115] [EC:3.1.4.4]
101114661  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
101105263  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
101106964  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
101112781  KNG1; kininogen-1 isoform X1 [KO:K03898]
101109816  ADORA1; adenosine receptor A1 isoform X2 [KO:K04265]
443330  ADORA3; adenosine receptor A3 [KO:K04268]
101120781  BDKRB2; B2 bradykinin receptor [KO:K03916]
101109600  OPRD1; delta-type opioid receptor [KO:K04213]
101103693  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
101116393  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100302341  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101103585  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101113074  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
101116105  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101106864  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X9 [KO:K05858] [EC:3.1.4.11]
101110314  PRKCE; protein kinase C epsilon type isoform X2 [KO:K18050] [EC:2.7.11.13]
101115485  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
101123008  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101108492  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
101116130  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
101110991  ABCC1; multidrug resistance-associated protein 1 isoform X2 [KO:K05665] [EC:7.6.2.3]
101111155  SGPL1; sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
101115839  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101112052  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
101104357  HRAS; GTPase HRas isoform X1 [KO:K02833]
114114919  GTPase HRas-like [KO:K02833]
101114005  KRAS; GTPase KRas isoform X1 [KO:K07827]
101102438  NRAS; GTPase NRas [KO:K07828]
101103190  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
101123635  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
101113846  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101117211  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
443077  NOS3; nitric oxide synthase 3 isoform X1 [KO:K13242] [EC:1.14.13.39]
100101233  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
101107592  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X2 [KO:K07860]
101112406  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X2 [KO:K07861]
101103373  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
101112295  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101110074  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
101118410  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101116423  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
101118697  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
101117761  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
101111070  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346]
101117003  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
100302078  RHOA; transforming protein RhoA [KO:K04513]
114116812  transforming protein RhoA-like [KO:K04513]
101106246  transforming protein RhoA [KO:K04513]
101102442  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
101103800  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
101119351  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]
101108228  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]
101102191  RELA; transcription factor p65 [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
oas00600  Sphingolipid metabolism
oas04010  MAPK signaling pathway
oas04142  Lysosome
oas04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
LinkDB

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