KEGG   PATHWAY: puc04071
Entry
puc04071                    Pathway                                
Name
Sphingolipid signaling pathway - Panthera uncia (snow leopard)
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
puc04071  Sphingolipid signaling pathway
puc04071

Organism
Panthera uncia (snow leopard) [GN:puc]
Gene
125929894  serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
125909303  serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
125936824  serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
125909583  serine palmitoyltransferase small subunit A [KO:K26384]
125921184  serine palmitoyltransferase small subunit B [KO:K26384]
125929270  ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
125912119  ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
125928957  ceramide synthase 4 isoform X1 [KO:K24621] [EC:2.3.1.297]
125910240  ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
125911857  ceramide synthase 6 [KO:K23727] [EC:2.3.1.291]
125920235  ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
125925066  sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
125909178  sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
125936827  sphingomyelin phosphodiesterase isoform X1 [KO:K12350] [EC:3.1.4.12]
125923002  phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
125933184  phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
125938466  tumor necrosis factor [KO:K03156]
125918761  tumor necrosis factor receptor superfamily member 1A [KO:K03158]
125924674  protein FAN isoform X1 [KO:K18953]
125938785  sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
125923438  acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
125933188  neutral ceramidase [KO:K12349] [EC:3.5.1.23]
125914646  alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
125928914  alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
125916585  tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
125923516  TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
125911553  cathepsin D [KO:K01379] [EC:3.4.23.5]
125918699  BH3-interacting domain death agonist [KO:K04726]
125915138  apoptosis regulator BAX isoform X1 [KO:K02159]
125938936  mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
125916877  mitogen-activated protein kinase 10-like [KO:K04440] [EC:2.7.11.24]
125917114  mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
125933328  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
125935352  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
125937867  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
125937868  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
125919741  mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
125919935  mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
125913204  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
125915806  RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125909102  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
125925091  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125914709  apoptosis regulator Bcl-2 [KO:K02161]
125923391  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
125935491  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
125915504  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
125909965  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
125923363  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
125923928  protein phosphatase 2, regulatory subunit B, gamma [KO:K04354]
125933053  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform [KO:K04354]
125935610  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
125931441  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
125909573  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
125921315  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
125931158  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
125925295  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
125909154  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
125917447  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
125910302  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
125918432  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
125927023  LOW QUALITY PROTEIN: cellular tumor antigen p53 [KO:K04451]
125925627  high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
125933015  high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
125925578  high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
125937963  tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
125914481  GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
125921850  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
125913143  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
125921289  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
125913493  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
125935698  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
125929237  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
125927093  phospholipase D2 [KO:K01115] [EC:3.1.4.4]
125921164  phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
125915605  LOW QUALITY PROTEIN: sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
125917403  sphingosine kinase 1-like [KO:K04718] [EC:2.7.1.91]
125917407  sphingosine kinase 1-like [KO:K04718] [EC:2.7.1.91]
125921824  kininogen-1 isoform X1 [KO:K03898]
125925425  adenosine receptor A1 [KO:K04265]
125912257  adenosine receptor A3 [KO:K04268]
125909196  B2 bradykinin receptor [KO:K03916]
125913597  delta-type opioid receptor [KO:K04213]
125929389  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
125929845  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
125912291  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
125931611  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
125909840  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
125935985  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
125936809  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
125936002  protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
125914884  mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
125928028  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
125909442  sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
125911741  sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
125927918  multidrug resistance-associated protein 1 isoform X1 [KO:K05665] [EC:7.6.2.3]
125933270  sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
125912336  sphingosine 1-phosphate receptor 1 [KO:K04288]
125930565  sphingosine 1-phosphate receptor 2 [KO:K04292]
125937753  GTPase HRas isoform X1 [KO:K02833]
125918906  GTPase KRas isoform X1 [KO:K07827]
125912218  GTPase NRas [KO:K07828]
125930728  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
125910082  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
125918032  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125918034  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125927192  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
125930302  LOW QUALITY PROTEIN: nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
125928294  ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
125919577  ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
125927618  ras-related C3 botulinum toxin substrate 3 [KO:K07861]
125929267  sphingosine 1-phosphate receptor 3 [KO:K04290]
125925154  guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
125927372  protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
125927972  protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
125915497  protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
125930518  sphingosine 1-phosphate receptor 4 [KO:K04293]
125930561  sphingosine 1-phosphate receptor 5 [KO:K04295]
125928430  guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
125927373  guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
125929348  transforming protein RhoA [KO:K04513]
125914402  rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
125937677  rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
125933550  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]
125923687  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
125912163  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
puc00600  Sphingolipid metabolism
puc04010  MAPK signaling pathway
puc04142  Lysosome
puc04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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