KEGG   PATHWAY: oor04071
Entry
oor04071                    Pathway                                
Name
Sphingolipid signaling pathway - Orcinus orca (killer whale)
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
oor04071  Sphingolipid signaling pathway
oor04071

Organism
Orcinus orca (killer whale) [GN:oor]
Gene
101283585  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
101275360  SPTLC3; serine palmitoyltransferase 3 isoform X1 [KO:K00654] [EC:2.3.1.50]
101273901  SPTLC2; serine palmitoyltransferase 2 isoform X3 [KO:K00654] [EC:2.3.1.50]
101285153  SPTSSA; serine palmitoyltransferase small subunit A isoform X2 [KO:K26384]
117195363  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
101273399  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
101271239  CERS2; ceramide synthase 2 isoform X1 [KO:K24621] [EC:2.3.1.297]
101289498  CERS4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
101287722  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
101282056  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
101282990  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
101269383  DEGS1; sphingolipid delta(4)-desaturase DES1 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101281613  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101271703  SMPD1; sphingomyelin phosphodiesterase isoform X1 [KO:K12350] [EC:3.1.4.12]
101278460  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 isoform X1 [KO:K04714] [EC:2.7.8.27]
101288900  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
101269870  TNF; tumor necrosis factor [KO:K03156]
101282502  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
101276603  NSMAF; protein FAN isoform X7 [KO:K18953]
101285754  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
101276356  ASAH1; acid ceramidase isoform X3 [KO:K12348] [EC:3.5.1.23]
101280545  ASAH2; neutral ceramidase isoform X3 [KO:K12349] [EC:3.5.1.23]
101274534  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
101278345  ACER1; alkaline ceramidase 1 isoform X2 [KO:K01441] [EC:3.5.1.23]
101271709  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
101281303  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
101280086  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
101277745  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
101285349  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
101277232  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
101287701  MAPK9; mitogen-activated protein kinase 9 isoform X5 [KO:K04440] [EC:2.7.11.24]
101277656  MAPK10; mitogen-activated protein kinase 10 isoform X4 [KO:K04440] [EC:2.7.11.24]
101281228  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
101269212  MAPK13; mitogen-activated protein kinase 13 isoform X7 [KO:K04441] [EC:2.7.11.24]
101269458  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101287579  mitogen-activated protein kinase 12 isoform X6 [KO:K04441] [EC:2.7.11.24]
101287833  mitogen-activated protein kinase 11 isoform X5 [KO:K04441] [EC:2.7.11.24]
101283233  PRKCZ; protein kinase C zeta type isoform X3 [KO:K18952] [EC:2.7.11.13]
101272095  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101288103  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101273316  AKT1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101276750  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
101289109  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
101286814  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
101282700  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
101274740  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
101275690  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
101279135  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
101287295  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
101279750  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X2 [KO:K04354]
101281621  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
101280203  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X2 [KO:K11583]
101288655  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X2 [KO:K11583]
101276619  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
101273899  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
101277447  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
101281869  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
101284355  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X7 [KO:K11584]
101289796  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
101285670  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
101277892  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha isoform X1 [KO:K08089]
101289768  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
101277161  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
101279266  FYN; tyrosine-protein kinase Fyn isoform X2 [KO:K05703] [EC:2.7.10.2]
101269992  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
101278075  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101278974  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
101283011  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101277568  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101285437  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101281352  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101278706  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
101284082  PLD1; phospholipase D1 isoform X6 [KO:K01115] [EC:3.1.4.4]
101289072  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
101286291  SPHK1; sphingosine kinase 1 isoform X2 [KO:K04718] [EC:2.7.1.91]
101283768  KNG1; kininogen-1 isoform X1 [KO:K03898]
101288190  ADORA1; adenosine receptor A1 isoform X1 [KO:K04265]
101287085  ADORA3; adenosine receptor A3 isoform X1 [KO:K04268]
101271639  BDKRB2; B2 bradykinin receptor [KO:K03916]
101283141  OPRD1; delta-type opioid receptor [KO:K04213]
101276500  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101277471  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
101271719  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101274558  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
101270548  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101270961  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101281417  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X9 [KO:K05858] [EC:3.1.4.11]
101276402  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
101273287  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101289394  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101274550  SGPP1; sphingosine-1-phosphate phosphatase 1 isoform X1 [KO:K04716] [EC:3.1.3.-]
101276880  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
101289237  ABCC1; multidrug resistance-associated protein 1 isoform X2 [KO:K05665] [EC:7.6.2.3]
101288258  SGPL1; sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
101286404  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101276279  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
101271947  GTPase HRas-like isoform X4 [KO:K02833]
101286301  HRAS; GTPase HRas isoform X2 [KO:K02833]
101281897  KRAS; GTPase KRas isoform X2 [KO:K07827]
101276138  NRAS; GTPase NRas [KO:K07828]
101272984  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101286388  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101287162  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
101270868  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101280520  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
101274018  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X3 [KO:K04392]
101269741  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
101278177  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
101280217  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
101279781  guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
101276350  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101277002  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101276418  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101270194  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
101279326  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
101281075  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
101277931  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
101273830  RHOA; transforming protein RhoA [KO:K04513]
101278979  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
101289250  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
101289838  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
101279857  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101270342  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
oor00600  Sphingolipid metabolism
oor04010  MAPK signaling pathway
oor04142  Lysosome
oor04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
LinkDB

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