KEGG   PATHWAY: bta04071
Entry
bta04071                    Pathway                                
Name
Sphingolipid signaling pathway - Bos taurus (cow)
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
bta04071  Sphingolipid signaling pathway
bta04071

Organism
Bos taurus (cow) [GN:bta]
Gene
100134966  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100138102  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100138150  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X4 [KO:K03456]
100298789  [KO:K11583]
100298939  HRAS; GTPase HRas isoform 1 [KO:K02833]
100336736  ASAH2; putative neutral ceramidase C isoform X4 [KO:K12349] [EC:3.5.1.23]
100336940  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
100337041  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
100847184  [KO:K02833]
101905399  [KO:K04368] [EC:2.7.12.2]
132342097  [KO:K11583]
132344360  [KO:K03456]
280730  BAX; apoptosis regulator BAX [KO:K02159]
280833  KNG1; kininogen-1 isoform II precursor [KO:K03898]
280943  TNF; tumor necrosis factor [KO:K03156]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
281020  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
281135  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
281440  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
281542  TP53; cellular tumor antigen p53 [KO:K04451]
281588  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
281790  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
281791  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
281985  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
282001  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
282002  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
282041  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.39]
282133  ADORA1; adenosine receptor A1 [KO:K04265]
282226  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
282320  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
282325  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
282527  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
282883  CTSD; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
286877  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
287024  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
287026  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
327671  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
338049  RHOA; transforming protein RhoA [KO:K04513]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
504707  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
505097  SMPD1; sphingomyelin phosphodiesterase precursor [KO:K12350] [EC:3.1.4.12]
505233  CERS4; ceramide synthase 4 [KO:K24621]
505611  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
505757  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
505915  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
506322  NRAS; GTPase NRas [KO:K07828]
506783  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
507041  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
507290  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
508045  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
508233  RELA; transcription factor p65 [KO:K04735]
508888  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
509018  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
509290  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
509626  NSMAF; LOW QUALITY PROTEIN: protein FAN [KO:K18953]
510373  BID; BH3-interacting domain death agonist [KO:K04726]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
510620  ASAH1; acid ceramidase precursor [KO:K12348] [EC:3.5.1.23]
512355  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
512943  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
514554  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
515159  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
515669  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
516881  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
517533  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
518021  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
520954  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
522159  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
522515  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
524361  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
527263  FYN; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
529346  GAB2; GRB2-associated-binding protein 2 isoform X3 [KO:K08091]
530776  CERS5; ceramide synthase 5 [KO:K23727]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
531987  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
533103  SPHK2; sphingosine kinase 2 isoform X2 [KO:K04718] [EC:2.7.1.91]
533147  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
533538  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
533617  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
533788  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
534492  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
535321  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
535327  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
536654  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
537380  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
537972  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
538896  BDKRB2; B2 bradykinin receptor [KO:K03916]
539123  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
539223  CERS2; ceramide synthase 2 [KO:K24621]
539521  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
539534  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
540305  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
540732  ACER2; alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
540786  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]
540994  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
541140  KRAS; GTPase KRas [KO:K07827]
614165  SPTLC1; serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
614354  CERS3; ceramide synthase 3 [KO:K24622]
615296  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
615641  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
616115  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
616695  [KO:K03456]
616901  CERS6; ceramide synthase 6 [KO:K23727]
618605  SPHK1; sphingosine kinase 1 isoform X3 [KO:K04718] [EC:2.7.1.91]
618906  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
619066  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
780785  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
780806  ADORA3; adenosine receptor A3 isoform 1 [KO:K04268]
781956  OPRD1; delta-type opioid receptor [KO:K04213]
782110  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
785911  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.39]
787607  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X3 [KO:K11583]
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
bta00600  Sphingolipid metabolism
bta04010  MAPK signaling pathway
bta04142  Lysosome
bta04151  PI3K-Akt signaling pathway
KO pathway
ko04071   

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