KEGG   PATHWAY: pvp04071
Entry
pvp04071                    Pathway                                
Name
Sphingolipid signaling pathway - Pteropus vampyrus (large flying fox)
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
pvp04071  Sphingolipid signaling pathway
pvp04071

Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105290098  SPTLC2; serine palmitoyltransferase 2 isoform X1 [KO:K00654] [EC:2.3.1.50]
105298846  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
105306940  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
105305307  SPTSSB; serine palmitoyltransferase small subunit B isoform X1 [KO:K26384]
105305298  serine palmitoyltransferase small subunit B [KO:K26384]
105296670  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
105307708  CERS4; LOW QUALITY PROTEIN: ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
105303823  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
105290275  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
105290776  CERS6; ceramide synthase 6 [KO:K23727] [EC:2.3.1.291]
105297590  CERS5; ceramide synthase 5 [KO:K23727] [EC:2.3.1.291]
105292590  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
105302285  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
105309094  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
105293007  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
105293117  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
105305325  TNF; tumor necrosis factor [KO:K03156]
105295979  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
105291413  NSMAF; protein FAN isoform X1 [KO:K18953]
105295245  SMPD2; sphingomyelin phosphodiesterase 2 isoform X3 [KO:K12351] [EC:3.1.4.12]
105295539  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
105293143  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
105301075  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
105295597  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
105305700  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
105298613  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
105299530  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
105311653  cathepsin D-like [KO:K01379] [EC:3.4.23.5]
105311654  uncharacterized protein LOC105311654 [KO:K01379] [EC:3.4.23.5]
105297238  BID; BH3-interacting domain death agonist isoform X2 [KO:K04726]
105301762  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
105289473  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
105288933  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105289628  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
105299978  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105308283  mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
105301035  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
105301036  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
105303610  PRKCZ; LOW QUALITY PROTEIN: protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
105303899  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105300159  RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
105298702  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105292717  BCL2; apoptosis regulator Bcl-2 isoform X2 [KO:K02161]
105299964  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
105293570  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
105306596  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform isoform X1 [KO:K03456]
105295648  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
105304489  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma [KO:K04354]
105292175  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
105297060  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
105300821  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
105309591  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X2 [KO:K11583]
105303199  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
105288460  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
105297866  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
105308612  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
105299291  PPP2R5C; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
105295010  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
105291226  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
105300730  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
105305030  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
105303397  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
105295260  FYN; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
105297599  GAB2; GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
105307215  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105307575  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105308956  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
105296605  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105297140  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105299371  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
105306010  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
105291755  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
105293381  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
105301772  SPHK2; LOW QUALITY PROTEIN: sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
105306731  KNG1; kininogen-1 isoform X1 [KO:K03898]
105296923  ADORA1; adenosine receptor A1 [KO:K04265]
105296892  ADORA3; adenosine receptor A3 [KO:K04268]
105298796  BDKRB2; B2 bradykinin receptor [KO:K03916]
105290542  OPRD1; delta-type opioid receptor [KO:K04213]
105297202  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105295155  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105295517  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105297846  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
105288781  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
105298737  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
105299444  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
105292973  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
105289326  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
105304566  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105310002  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
105291100  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
105290974  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
105300140  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
105297525  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
105305587  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
105305933  HRAS; GTPase HRas isoform X1 [KO:K02833]
105294059  KRAS; GTPase KRas isoform X2 [KO:K07827]
105296550  NRAS; GTPase NRas isoform X1 [KO:K07828]
105299021  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105309827  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
105306744  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105303144  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105303769  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
105294623  RAC1; LOW QUALITY PROTEIN: ras-related C3 botulinum toxin substrate 1 [KO:K04392]
105311532  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X2 [KO:K07860]
105301137  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
105300256  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
105302452  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
105297702  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105308818  protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105309462  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105300438  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
105305603  S1PR5; sphingosine 1-phosphate receptor 5 isoform X2 [KO:K04295]
105294560  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346]
105297699  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
105302383  RHOA; transforming protein RhoA [KO:K04513]
105292284  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.39]
105295461  ROCK2; LOW QUALITY PROTEIN: rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.39]
105293112  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X2 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
105293029  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105297999  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
pvp00600  Sphingolipid metabolism
pvp04010  MAPK signaling pathway
pvp04142  Lysosome
pvp04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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