KEGG   PATHWAY: biu04071
Entry
biu04071                    Pathway                                
Name
Sphingolipid signaling pathway - Bos indicus (zebu cattle)
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
biu04071  Sphingolipid signaling pathway
biu04071

Organism
Bos indicus (zebu cattle) [GN:biu]
Gene
109564421  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
109567923  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
109563274  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
109575568  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
109558604  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
109560813  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
109555312  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
109561659  CERS4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
109575125  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
109575194  ceramide synthase 6-like [KO:K23727] [EC:2.3.1.291]
109575183  CERS6; ceramide synthase 6 [KO:K23727] [EC:2.3.1.291]
109559116  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
109575437  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
109570649  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
109569729  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
109553156  phosphatidylcholine:ceramide cholinephosphotransferase 1-like [KO:K04714] [EC:2.7.8.27]
109560269  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
109579164  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 isoform X1 [KO:K04714] [EC:2.7.8.27]
109577428  TNF; tumor necrosis factor [KO:K03156]
109559729  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
109568446  NSMAF; protein FAN [KO:K18953]
109563837  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
109553501  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
109578966  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
109561210  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
109562861  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
109572519  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
109566626  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
109554428  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
109559782  BH3-interacting domain death agonist-like isoform X1 [KO:K04726]
109559783  BH3-interacting domain death agonist-like isoform X1 [KO:K04726]
109571977  apoptosis regulator BAX [KO:K02159]
109571778  BAX; apoptosis regulator BAX [KO:K02159]
109563980  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
109561331  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109560650  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553773  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109577010  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
109577419  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
109570580  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
109572496  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109570286  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109577782  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
109553505  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
109562017  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
109572651  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
109554937  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform-like [KO:K03456]
109569423  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
109560078  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma [KO:K04354]
109563149  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
109562172  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
109579044  PPP2R2D; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform [KO:K04354]
109575432  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
109563246  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
109565236  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
109575398  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
109554577  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
109570478  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
109576873  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
109575470  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform-like isoform X1 [KO:K11584]
109574238  TP53; cellular tumor antigen p53 [KO:K04451]
109556970  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha isoform X1 [KO:K08089]
109569969  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
109578311  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
109563811  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
109554314  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
109559805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109570415  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109557823  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
109574805  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
109561418  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109556345  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109574235  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
109558091  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
109572468  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
109573990  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
109562726  kininogen-1-like [KO:K03898]
109575666  BDKRB2; B2 bradykinin receptor [KO:K03916]
109572743  OPRD1; delta-type opioid receptor [KO:K04213]
109557337  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
109576257  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
109555970  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
109554384  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
109567852  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
109567854  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
109564927  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
109566044  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
109578667  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109570973  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109565238  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
109575817  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
109578115  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
109553759  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
109556004  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
109561578  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
109560940  GTPase HRas-like [KO:K02833]
109559581  KRAS; GTPase KRas isoform X1 [KO:K07827]
109555890  NRAS; GTPase NRas [KO:K07828]
109576053  RAF1; LOW QUALITY PROTEIN: RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
109564697  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109561751  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
109578066  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
109557793  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
109578192  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
109559531  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
109574290  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
109563288  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
109562978  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
109573366  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
109578560  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
109572998  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
109561776  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
109561592  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
109578204  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
109573379  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
109576171  RHOA; transforming protein RhoA [KO:K04513]
109577829  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
109566382  ROCK2; rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
109552991  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]
109560296  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
109554392  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
biu00600  Sphingolipid metabolism
biu04010  MAPK signaling pathway
biu04142  Lysosome
biu04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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