KEGG   PATHWAY: bta04071
bta04071                    Pathway                                

Sphingolipid signaling pathway - Bos taurus (cow)
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.
Environmental Information Processing; Signal transduction
Pathway map
bta04071  Sphingolipid signaling pathway

Bos taurus (cow) [GN:bta]
537972  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:]
614165  SPTLC1; serine palmitoyltransferase 1 [KO:K00654] [EC:]
100336940  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:]
615296  CERS1; ceramide synthase 1 [KO:K04710] [EC:]
539223  CERS2; ceramide synthase 2 [KO:K24621] [EC:]
505233  CERS4; ceramide synthase 4 [KO:K24621] [EC:]
614354  CERS3; ceramide synthase 3 [KO:K24622] [EC:]
616901  CERS6; ceramide synthase 6 [KO:K23727] [EC:]
530776  CERS5; ceramide synthase 5 [KO:K23727] [EC:]
507290  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:]
540994  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:]
505097  SMPD1; sphingomyelin phosphodiesterase precursor [KO:K12350] [EC:]
520954  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:]
533538  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:]
280943  TNF; tumor necrosis factor [KO:K03156]
282527  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
509626  NSMAF; LOW QUALITY PROTEIN: protein FAN [KO:K18953]
509018  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:]
510620  ASAH1; acid ceramidase precursor [KO:K12348] [EC:]
100336736  ASAH2; putative neutral ceramidase C [KO:K12349] [EC:]
540732  ACER2; alkaline ceramidase 2 [KO:K01441] [EC:]
518021  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:]
504707  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
512355  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:]
282883  CTSD; cathepsin D precursor [KO:K01379] [EC:]
510373  BID; BH3-interacting domain death agonist [KO:K04726]
280730  BAX; apoptosis regulator BAX [KO:K02159]
537380  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:]
534492  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
535327  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
512943  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
618906  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
286877  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
281020  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
282320  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:]
524361  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:]
616695  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
535321  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
100138150  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
508045  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
509290  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
782110  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
533147  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
100298789  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
787607  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X2 [KO:K11583]
505915  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
505757  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
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]
100134966  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
281542  TP53; cellular tumor antigen p53 [KO:K04451]
506783  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
531987  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta isoform X1 [KO:K08090]
282226  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
527263  FYN; tyrosine-protein kinase Fyn [KO:K05703] [EC:]
529346  GAB2; GRB2-associated-binding protein 2 isoform X2 [KO:K08091]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
522159  PLD2; phospholipase D2 [KO:K01115] [EC:]
514554  PLD1; phospholipase D1 [KO:K01115] [EC:]
618605  SPHK1; sphingosine kinase 1 isoform X2 [KO:K04718] [EC:]
533103  SPHK2; sphingosine kinase 2 isoform X2 [KO:K04718] [EC:]
280833  KNG1; kininogen-2 isoform II precursor [KO:K03898]
282133  ADORA1; adenosine receptor A1 [KO:K04265]
780806  ADORA3; adenosine receptor A3 isoform 1 [KO:K04268]
538896  BDKRB2; B2 bradykinin receptor [KO:K03916]
781956  OPRD1; delta-type opioid receptor [KO:K04213]
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]
539521  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
287026  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:]
281985  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:]
515669  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:]
508888  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:]
507041  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
516881  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
100337041  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
281588  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:]
522515  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:]
281135  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
540305  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
100298939  HRAS; GTPase HRas isoform 1 [KO:K02833]
100847184  GTPase HRas-like [KO:K02833]
541140  KRAS; GTPase KRas [KO:K07827]
506322  NRAS; GTPase NRas [KO:K07828]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
100138102  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:]
287024  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:]
281440  RAC1; ras-related C3 botulinum toxin substrate 1 precursor [KO:K04392]
327671  RAC2; ras-related C3 botulinum toxin substrate 2 precursor [KO:K07860]
619066  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
539123  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
536654  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
282001  PRKCA; protein kinase C alpha type [KO:K02677] [EC:]
282325  PRKCB; protein kinase C beta type [KO:K19662] [EC:]
282002  PRKCG; protein kinase C gamma type [KO:K19663] [EC:]
539534  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
517533  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
515159  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
505611  GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X2 [KO:K04639]
338049  RHOA; transforming protein RhoA precursor [KO:K04513]
785911  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:]
282041  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:]
540786  PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
616115  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
508233  RELA; transcription factor p65 [KO:K04735]
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
Hannun YA, Obeid LM
Principles of bioactive lipid signalling: lessons from sphingolipids.
Nat Rev Mol Cell Biol 9:139-50 (2008)
Taha TA, Mullen TD, Obeid LM
A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death.
Biochim Biophys Acta 1758:2027-36 (2006)
Liu J, Beckman BS, Foroozesh M
A review of ceramide analogs as potential anticancer agents.
Future Med Chem 5:1405-21 (2013)
Kono M, Allende ML, Proia RL
Sphingosine-1-phosphate regulation of mammalian development.
Biochim Biophys Acta 1781:435-41 (2008)
Olivera A
Unraveling the complexities of sphingosine-1-phosphate function: the mast cell model.
Prostaglandins Other Lipid Mediat 86:1-11 (2008)
Brunkhorst R, Vutukuri R, Pfeilschifter W
Fingolimod for the treatment of neurological diseases-state of play and future perspectives.
Front Cell Neurosci 8:283 (2014)
Rosen H, Goetzl EJ
Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.
Nat Rev Immunol 5:560-70 (2005)
Pyne S, Pyne NJ
Sphingosine 1-phosphate signalling in mammalian cells.
Biochem J 349:385-402 (2000)
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
Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury.
Am J Physiol Heart Circ Physiol 301:H1487-95 (2011)
Jin ZQ, Goetzl EJ, Karliner JS
Sphingosine kinase activation mediates ischemic preconditioning in murine heart.
Circulation 110:1980-9 (2004)
Melendez AJ
Sphingosine kinase signalling in immune cells: potential as novel therapeutic targets.
Biochim Biophys Acta 1784:66-75 (2008)
Halova I, Draberova L, Draber P
Mast cell chemotaxis - chemoattractants and signaling pathways.
Front Immunol 3:119 (2012)
Kraft S, Kinet JP
New developments in FcepsilonRI regulation, function and inhibition.
Nat Rev Immunol 7:365-78 (2007)
Gilfillan AM, Tkaczyk C.
Integrated signalling pathways for mast-cell activation.
Nat Rev Immunol 6:218-30 (2006)
Osawa Y, Banno Y, Nagaki M, Brenner DA, Naiki T, Nozawa Y, Nakashima S, Moriwaki H
TNF-alpha-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes.
J Immunol 167:173-80 (2001)
Montfort A, Martin PG, Levade T, Benoist H, Segui B
FAN (factor associated with neutral sphingomyelinase activation), a moonlighting protein in TNF-R1 signaling.
J Leukoc Biol 88:897-903 (2010)
Chatterjee S
Neutral sphingomyelinase: past, present and future.
Chem Phys Lipids 102:79-96 (1999)
bta00600  Sphingolipid metabolism
bta04010  MAPK signaling pathway
bta04142  Lysosome
bta04151  PI3K-Akt signaling pathway
KO pathway

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