KEGG   PATHWAY: ssc04071
Entry
ssc04071                    Pathway                                
Name
Sphingolipid signaling pathway - Sus scrofa (pig)
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
ssc04071  Sphingolipid signaling pathway
ssc04071

Organism
Sus scrofa (pig) [GN:ssc]
Gene
100158010  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
100519280  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
100739638  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
100156815  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
100623291  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
100525450  CERS1; ceramide synthase 1 isoform X1 [KO:K04710] [EC:2.3.1.299]
100156737  CERS2; ceramide synthase 2 isoform X2 [KO:K24621] [EC:2.3.1.297]
100127167  CERS4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
100152265  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
100126279  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
110260661  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
100135677  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
100739329  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
100518980  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
100037303  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
100518796  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
397086  TNF; tumor necrosis factor [KO:K03156]
397020  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
100153039  NSMAF; protein FAN isoform X1 [KO:K18953]
100152155  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
100512932  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
100157065  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
100622165  ACER1; alkaline ceramidase 1 isoform X2 [KO:K01441] [EC:3.5.1.23]
100155321  ACER2; LOW QUALITY PROTEIN: alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
100620340  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
100513840  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
494568  CTSD; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
594852  BID; BH3-interacting domain death agonist [KO:K04726]
396633  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
100622769  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
396610  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100521736  MAPK10; mitogen-activated protein kinase 10 isoform X3 [KO:K04440] [EC:2.7.11.24]
396609  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
574062  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100156630  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100155841  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
110260605  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100533200  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
100126861  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100513811  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100127478  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100049703  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
397656  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
397136  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
397088  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
397470  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X3 [KO:K03456]
397089  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
397090  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
100737053  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
102160080  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
110258189  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
110261574  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
100134967  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
100101925  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
100516242  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
100525377  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
100620346  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
397276  TP53; cellular tumor antigen p53 [KO:K04451]
100152827  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha isoform X1 [KO:K08089]
397166  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
397406  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
791125  FYN; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
100513609  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
100518131  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100621789  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100622559  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100511937  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100739510  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100623707  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
100519446  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
414900  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100519210  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
100738292  SPHK2; LOW QUALITY PROTEIN: sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
396568  KNG1; kininogen-1 isoform X2 [KO:K03898]
606743  ADORA1; adenosine receptor A1 [KO:K04265]
606753  ADORA3; adenosine A3 receptor [KO:K04268]
110255240  BDKRB2; B2 bradykinin receptor isoform X2 [KO:K03916]
397216  OPRD1; delta-type opioid receptor isoform X1 [KO:K04213]
100144421  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100144419  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
397523  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100152679  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100157641  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
100516581  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100525148  PLCB3; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100524932  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
100153927  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
445013  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100626032  SGPP1; sphingosine-1-phosphate phosphatase 1 isoform X1 [KO:K04716] [EC:3.1.3.-]
100524832  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
733619  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
100525187  SGPL1; sphingosine-1-phosphate lyase 1 isoform X4 [KO:K01634] [EC:4.1.2.27]
100621202  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
100511551  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
110259208  HRAS; GTPase HRas isoform X1 [KO:K02833]
100518251  KRAS; GTPase KRas isoform X2 [KO:K07827]
100739349  NRAS; GTPase NRas precursor [KO:K07828]
100737448  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100233191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100525505  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100192445  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
397557  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
100627149  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100621675  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
110255928  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
100154607  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
654405  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
397184  PRKCA; LOW QUALITY PROTEIN: protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100522792  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100518074  PRKCG; protein kinase C gamma type isoform X3 [KO:K19663] [EC:2.7.11.13]
100517997  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
100141401  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
100525156  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346]
100522824  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
396849  RHOA; transforming protein RhoA [KO:K04513]
397447  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
397445  ROCK2; rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
100156264  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]
751869  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
100135665  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
ssc00600  Sphingolipid metabolism
ssc04010  MAPK signaling pathway
ssc04142  Lysosome
ssc04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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