KEGG   PATHWAY: cfa04071
Entry
cfa04071                    Pathway                                
Name
Sphingolipid signaling pathway - Canis lupus familiaris (dog)
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
cfa04071  Sphingolipid signaling pathway
cfa04071

Organism
Canis lupus familiaris (dog) [GN:cfa]
Gene
480403  SPTLC2; serine palmitoyltransferase 2 isoform X2 [KO:K00654] [EC:2.3.1.50]
484192  SPTLC1; serine palmitoyltransferase 1 isoform X8 [KO:K00654] [EC:2.3.1.50]
485766  SPTLC3; serine palmitoyltransferase 3 isoform X2 [KO:K00654] [EC:2.3.1.50]
119872801  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
100683817  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
609789  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
483187  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
485008  CERS4; ceramide synthase 4 isoform X2 [KO:K24621] [EC:2.3.1.297]
607925  CERS3; ceramide synthase 3 isoform X1 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
488387  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
477611  CERS5; ceramide synthase 5 isoform X2 [KO:K23727] [EC:2.3.1.291]
490395  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
490854  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
485334  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
477582  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
478505  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
403922  TNF; tumor necrosis factor [KO:K03156]
403634  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X5 [KO:K03158]
477892  NSMAF; protein FAN isoform X1 [KO:K18953]
100856377  SMPD2; sphingomyelin phosphodiesterase 2 isoform X1 [KO:K12351] [EC:3.1.4.12]
482897  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
486461  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
611739  ACER1; alkaline ceramidase 1 isoform X3 [KO:K01441] [EC:3.5.1.23]
100856386  ACER2; alkaline ceramidase 2 isoform X3 [KO:K01441] [EC:3.5.1.23]
611262  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X2 [KO:K03171]
480673  TRAF2; TNF receptor-associated factor 2 isoform X2 [KO:K03173] [EC:2.3.2.27]
483662  CTSD; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
100683675  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
403523  BAX; apoptosis regulator BAX [KO:K02159]
476215  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
477746  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
478464  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
474652  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
403856  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
607019  MAPK11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
607023  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
612821  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
479577  PRKCZ; protein kinase C zeta type isoform X5 [KO:K18952] [EC:2.7.11.13]
442964  AKT3; RAC-gamma serine/threonine-protein kinase isoform X8 [KO:K04456] [EC:2.7.11.1]
449021  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
490878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
403416  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
403608  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
482873  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
484335  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform isoform X1 [KO:K03456]
479444  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
477374  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X6 [KO:K04354]
610262  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X2 [KO:K04354]
491587  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X2 [KO:K04354]
478053  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X2 [KO:K04354]
480289  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X2 [KO:K11583]
485672  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
100855509  PPP2R3B; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
483755  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X2 [KO:K11584]
480436  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X2 [KO:K11584]
481806  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
480349  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X3 [KO:K11584]
490280  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
403869  TP53; cellular tumor antigen p53 [KO:K04451]
478970  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
403799  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
102155967  high affinity immunoglobulin epsilon receptor subunit beta-like [KO:K08090]
102155828  membrane-spanning 4-domains subfamily A member 3-like [KO:K08090]
111091602  high affinity immunoglobulin epsilon receptor subunit beta-like [KO:K08090]
403798  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
475032  FYN; tyrosine-protein kinase Fyn isoform X2 [KO:K05703] [EC:2.7.10.2]
485167  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
488084  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
489644  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
477085  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
609956  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
487235  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100856339  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
488167  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
479473  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
484401  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
483329  SPHK1; sphingosine kinase 1 isoform X4 [KO:K04718] [EC:2.7.1.91]
478666  KNG1; kininogen-1 [KO:K03898]
403961  ADORA1; adenosine receptor A1 [KO:K04265]
403805  ADORA3; adenosine receptor A3 [KO:K04268]
403658  BDKRB2; B2 bradykinin receptor [KO:K03916]
487329  OPRD1; delta-type opioid receptor [KO:K04213]
442957  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
478227  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
611810  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha isoform X2 [KO:K04630]
477160  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
485773  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
476034  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X2 [KO:K05858] [EC:3.1.4.11]
100856190  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
609934  PRKCE; protein kinase C epsilon type isoform X3 [KO:K18050] [EC:2.7.11.13]
477575  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100855877  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
490728  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
610884  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X6 [KO:K04717] [EC:3.1.3.-]
403453  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
489032  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
484959  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
403735  HRAS; GTPase HRas isoform 1 [KO:K02833]
403871  KRAS; GTPase KRas isoform X1 [KO:K07827]
403872  NRAS; GTPase NRas [KO:K07828]
484648  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
478347  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
611939  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
479875  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X3 [KO:K06276] [EC:2.7.11.1]
403784  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
403955  RAC1; ras-related C3 botulinum toxin substrate 1 precursor [KO:K04392]
481271  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
106559217  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
484199  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
403928  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
490904  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
489968  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100855828  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
612082  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
610828  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
102154318  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X3 [KO:K04346]
490901  GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X1 [KO:K04639]
403954  RHOA; transforming protein RhoA [KO:K04513]
480181  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
482970  ROCK2; rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
403832  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]
442859  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
483729  RELA; transcription factor p65 isoform X2 [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
cfa00600  Sphingolipid metabolism
cfa04010  MAPK signaling pathway
cfa04142  Lysosome
cfa04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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