KEGG   PATHWAY: opi04071
Entry
opi04071                    Pathway                                
Name
Sphingolipid signaling pathway - Ochotona princeps (American pika)
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
opi04071  Sphingolipid signaling pathway
opi04071

Organism
Ochotona princeps (American pika) [GN:opi]
Gene
101533167  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
101518727  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
101520563  SPTLC1; serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
101521162  LOW QUALITY PROTEIN: serine palmitoyltransferase small subunit A [KO:K26384]
101535079  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
101528668  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
101517601  CERS4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
101525914  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
101520281  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
101531778  CERS5; ceramide synthase 5 [KO:K23727] [EC:2.3.1.291]
101516066  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
105942315  ceramide synthase 5-like [KO:K23727] [EC:2.3.1.291]
101520988  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101532189  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101534073  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
101525177  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
101536125  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
101525561  TNF; tumor necrosis factor isoform X2 [KO:K03156]
101530319  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
101535185  NSMAF; protein FAN [KO:K18953]
101522779  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
101531935  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
101530923  ASAH2; neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
101526762  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
101529025  ACER2; alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
101518461  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
101527835  TRAF2; TNF receptor-associated factor 2 isoform X2 [KO:K03173] [EC:2.3.2.27]
101527187  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
101530204  BID; LOW QUALITY PROTEIN: BH3-interacting domain death agonist [KO:K04726]
101517703  BAX; apoptosis regulator BAX [KO:K02159]
101530376  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
101531453  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101524844  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101518695  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
101525120  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101525684  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101524339  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101524571  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
101536130  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
101533296  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101519021  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101525801  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101517543  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
101532400  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
101527218  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
101535531  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X3 [KO:K03456]
101518020  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
101533099  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
101518605  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
101533552  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
101521052  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta [KO:K11583]
101535530  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
101530123  PPP2R3A; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
101518001  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
101525183  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
101528309  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
101523167  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
101535804  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
101528346  TP53; cellular tumor antigen p53 [KO:K04451]
101536761  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
101516352  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
101521326  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
101517134  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
101524341  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
101519449  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101533851  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101533024  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101532354  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101517982  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101528030  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101523215  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
101521179  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
101522075  SPHK1; sphingosine kinase 1 [KO:K04718] [EC:2.7.1.91]
101529238  SPHK2; sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
101534400  KNG1; LOW QUALITY PROTEIN: kininogen-1 [KO:K03898]
101532500  ADORA1; adenosine receptor A1 [KO:K04265]
105941643  ADORA3; adenosine receptor A3 [KO:K04268]
101529531  BDKRB2; B2 bradykinin receptor [KO:K03916]
101526341  OPRD1; delta-type opioid receptor [KO:K04213]
101525340  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
101516368  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101531957  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101524349  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101524739  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101529337  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101520538  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X2 [KO:K05858] [EC:3.1.4.11]
101520570  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
101530701  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101525427  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101527797  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
101529574  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
101523526  ABCC1; LOW QUALITY PROTEIN: multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
101517640  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
101533483  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101520134  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
101531636  HRAS; GTPase HRas [KO:K02833]
101534080  KRAS; GTPase KRas isoform X1 [KO:K07827]
101524465  NRAS; GTPase NRas [KO:K07828]
101534290  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101533612  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105942099  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
101529486  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101528473  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101520691  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
101532428  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
101527518  ras-related C3 botulinum toxin substrate 1-like [KO:K04392]
101531979  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
101529472  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
101522536  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
101517012  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101523549  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101523439  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101534827  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101534745  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
101525794  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346]
101522146  GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X1 [KO:K04639]
101525255  RHOA; transforming protein RhoA isoform X1 [KO:K04513]
101535305  transforming protein RhoA-like isoform X1 [KO:K04513]
101530829  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
101533973  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
101529935  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]
101531611  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101530066  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
opi00600  Sphingolipid metabolism
opi04010  MAPK signaling pathway
opi04142  Lysosome
opi04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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