KEGG   PATHWAY: ocu04071
Entry
ocu04071                    Pathway                                
Name
Sphingolipid signaling pathway - Oryctolagus cuniculus (rabbit)
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
ocu04071  Sphingolipid signaling pathway
ocu04071

Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
100339302  serine palmitoyltransferase 3 isoform X1 [KO:K00654] [EC:2.3.1.50]
100358555  serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
100344536  serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
100338261  serine palmitoyltransferase small subunit A [KO:K26384]
100355061  serine palmitoyltransferase small subunit B [KO:K26384]
127485960  ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
100352973  ceramide synthase 4 isoform X2 [KO:K24621] [EC:2.3.1.297]
100337851  ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
100344726  ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
100339974  ceramide synthase 5 [KO:K23727] [EC:2.3.1.291]
100355393  sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
100345221  sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
100353898  sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
100354454  phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
100357932  phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
100009088  TNF; tumor necrosis factor precursor [KO:K03156]
100346106  tumor necrosis factor receptor superfamily member 1A isoform X2 [KO:K03158]
100338130  protein FAN isoform X1 [KO:K18953]
100348153  sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
100338209  acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
100357673  neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
100337862  alkaline ceramidase 2 isoform X3 [KO:K01441] [EC:3.5.1.23]
100337888  tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X2 [KO:K03171]
100355991  BH3-interacting domain death agonist [KO:K04726]
100355675  apoptosis regulator BAX isoform X2 [KO:K02159]
100340498  LOW QUALITY PROTEIN: mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
100346929  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100342664  mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
100337999  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100350614  mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
103346035  mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100344161  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100341695  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100009538  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
100342852  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100353706  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
127486116  RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103349397  apoptosis regulator Bcl-2 [KO:K02161]
100009252  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
100009300  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
100355092  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
100355758  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X3 [KO:K03456]
100328617  PPP2R2C; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform [KO:K04354]
100009139  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
100328616  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
100348286  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
100355159  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X2 [KO:K11583]
100356580  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
100353545  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X2 [KO:K11583]
100009434  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
100346997  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
100009533  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
100009216  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
100009215  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
100009292  TP53; cellular tumor antigen p53 [KO:K04451]
100349846  high affinity immunoglobulin epsilon receptor subunit alpha isoform X2 [KO:K08089]
100351385  high affinity immunoglobulin epsilon receptor subunit beta isoform X1 [KO:K08090]
103350027  high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
100339741  tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
100349301  GRB2-associated-binding protein 2 [KO:K08091]
100348663  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100345181  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100337822  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100357841  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100345250  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100339661  phospholipase D1 [KO:K01115] [EC:3.1.4.4]
103351479  phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100357790  sphingosine kinase 1 isoform X3 [KO:K04718] [EC:2.7.1.91]
103346370  sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
100101602  kininogen-1 isoform X1 [KO:K03898]
100328615  ADORA1; adenosine receptor A1 [KO:K04265]
100008725  ADORA3; adenosine receptor A3 [KO:K04268]
100338359  B2 bradykinin receptor isoform X1 [KO:K03916]
100351268  delta-type opioid receptor [KO:K04213]
100338391  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100359147  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100339066  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100348672  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X4 [KO:K05858] [EC:3.1.4.11]
100350395  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100341512  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
103347536  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100009103  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
100347345  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
108178643  sphingosine-1-phosphate phosphatase 1 isoform X1 [KO:K04716] [EC:3.1.3.-]
100357833  sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
100345841  ABCC1; multidrug resistance-associated protein 1 isoform X1 [KO:K05665] [EC:7.6.2.3]
100338930  sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
100008820  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
100008828  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
127486605  GTPase HRas isoform X1 [KO:K02833]
100347487  GTPase KRas isoform X1 [KO:K07827]
127489236  GTPase KRas-like [KO:K07827]
100344241  GTPase NRas [KO:K07828]
100347407  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100009316  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
127489461  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
100347954  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100009498  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
127493711  nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
100339873  ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
100356520  ras-related C3 botulinum toxin substrate 2 [KO:K07860]
103348690  sphingosine 1-phosphate receptor 3 [KO:K04290]
100340719  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
100037720  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100037719  PRKCB; protein kinase C beta type isoform I [KO:K19662] [EC:2.7.11.13]
100009102  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100350217  sphingosine 1-phosphate receptor 5 [KO:K04295]
100347293  guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
100352794  guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
100356250  transforming protein RhoA [KO:K04513]
100348967  transforming protein RhoA-like [KO:K04513]
100340661  transforming protein RhoA [KO:K04513]
100346856  LOW QUALITY PROTEIN: transforming protein RhoA [KO:K04513]
100343368  transforming protein RhoA-like [KO:K04513]
100343680  transforming protein RhoA-like [KO:K04513]
127489660  transforming protein RhoA-like [KO:K04513]
100009220  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
100346837  rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
100358716  phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
100349426  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
127485184  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
ocu00600  Sphingolipid metabolism
ocu04010  MAPK signaling pathway
ocu04142  Lysosome
ocu04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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