KEGG   PATHWAY: ncar04071
Entry
ncar04071                   Pathway                                
Name
Sphingolipid signaling pathway - Sciurus carolinensis (gray squirrel)
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
ncar04071  Sphingolipid signaling pathway
ncar04071

Organism
Sciurus carolinensis (gray squirrel) [GN:ncar]
Gene
124977827  serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
124965682  serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
124976634  serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
124977911  serine palmitoyltransferase small subunit A [KO:K26384]
124992412  serine palmitoyltransferase small subunit B [KO:K26384]
124963637  serine palmitoyltransferase small subunit A-like [KO:K26384]
124990940  serine palmitoyltransferase small subunit A-like [KO:K26384]
124969610  ceramide synthase 1 isoform X1 [KO:K04710] [EC:2.3.1.299]
124959721  ceramide synthase 2 isoform X1 [KO:K24621] [EC:2.3.1.297]
124969450  ceramide synthase 4-like [KO:K24621] [EC:2.3.1.297]
124976987  ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
124980060  ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
124983009  LOW QUALITY PROTEIN: ceramide synthase 5-like [KO:K23727] [EC:2.3.1.291]
124976771  sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
124961704  sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
124961857  LOW QUALITY PROTEIN: sphingolipid delta(4)-desaturase DES1-like [KO:K04712] [EC:1.14.19.17 1.14.18.5]
124958684  sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
124994521  phosphatidylcholine:ceramide cholinephosphotransferase 2 isoform X1 [KO:K04714] [EC:2.7.8.27]
124984606  phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
124988890  tumor necrosis factor [KO:K03156]
124984003  tumor necrosis factor receptor superfamily member 1A-like [KO:K03158]
124958299  protein FAN isoform X1 [KO:K18953]
124988884  sphingomyelin phosphodiesterase 2-like [KO:K12351] [EC:3.1.4.12]
124983780  acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
124984417  putative neutral ceramidase C [KO:K12349] [EC:3.5.1.23]
124969506  alkaline ceramidase 1 isoform X1 [KO:K01441] [EC:3.5.1.23]
124964906  alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
124966312  tumor necrosis factor receptor type 1-associated DEATH domain protein-like isoform X1 [KO:K03171]
124964641  TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
124960311  cathepsin D [KO:K01379] [EC:3.4.23.5]
124982226  BH3-interacting domain death agonist-like isoform X1 [KO:K04726]
124966672  apoptosis regulator BAX isoform X1 [KO:K02159]
124988565  mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
124986765  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
124994121  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
124984745  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
124988515  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
124989076  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
124978202  mitogen-activated protein kinase 14-like isoform X1 [KO:K04441] [EC:2.7.11.24]
124982485  mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
124982486  LOW QUALITY PROTEIN: mitogen-activated protein kinase 11-like [KO:K04441] [EC:2.7.11.24]
124983581  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
124962260  LOW QUALITY PROTEIN: RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
124976076  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
124966582  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
124965545  apoptosis regulator Bcl-2 [KO:K02161]
124987135  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
124983945  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
124958287  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
124967003  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
124986762  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
124994837  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform X1 [KO:K04354]
124984746  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
124982397  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
124993238  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
124977718  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
124962449  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma-like [KO:K11583]
124975681  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
124958310  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
124988657  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
124976854  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
124961576  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
124973978  LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform-like [KO:K11584]
124976126  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
124980281  cellular tumor antigen p53 [KO:K04451]
124962110  high affinity immunoglobulin epsilon receptor subunit alpha-like isoform X1 [KO:K08089]
124959715  high affinity immunoglobulin epsilon receptor subunit beta-like [KO:K08090]
124994061  high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
124988460  tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
124960478  GRB2-associated-binding protein 2 isoform X1 [KO:K08091]
124973074  GRB2-associated-binding protein 2-like [KO:K08091]
124993166  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
124993330  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
124963509  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
124986648  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
124968815  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
124992927  phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
124980798  phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
124980283  sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
124966668  sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
124993322  kininogen-1-like isoform X1 [KO:K03898]
124962441  adenosine receptor A1 isoform X1 [KO:K04265]
124978184  B2 bradykinin receptor isoform X1 [KO:K03916]
124981436  delta-type opioid receptor [KO:K04213]
124992673  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
124988012  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
124991078  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
124976705  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
124959812  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
124977474  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
124972679  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
124962983  protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
124990635  LOW QUALITY PROTEIN: mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
124970294  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
124977848  sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
124981069  sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
124969831  multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
124985729  LOW QUALITY PROTEIN: sphingosine-1-phosphate lyase 1-like [KO:K01634] [EC:4.1.2.27]
124964025  sphingosine 1-phosphate receptor 1 [KO:K04288]
124968751  sphingosine 1-phosphate receptor 2 [KO:K04292]
124958599  GTPase HRas isoform X1 [KO:K02833]
124991017  GTPase KRas-like [KO:K07827]
124982118  GTPase KRas isoform X1 [KO:K07827]
124962389  GTPase NRas [KO:K07828]
124971006  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
124977990  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
124969568  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
124970168  3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
124990691  nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
124970154  ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
124971456  ras-related C3 botulinum toxin substrate 1-like [KO:K04392]
124982630  ras-related C3 botulinum toxin substrate 2 [KO:K07860]
124980331  ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
124965518  sphingosine 1-phosphate receptor 3 [KO:K04290]
124964255  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
124979014  protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
124970211  LOW QUALITY PROTEIN: protein kinase C beta type-like [KO:K19662] [EC:2.7.11.13]
124967611  protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
124969531  sphingosine 1-phosphate receptor 4 [KO:K04293]
124968514  LOW QUALITY PROTEIN: sphingosine 1-phosphate receptor 5-like [KO:K04295]
124970276  guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
124979863  LOW QUALITY PROTEIN: guanine nucleotide-binding protein subunit alpha-13-like [KO:K04639]
124973058  LOW QUALITY PROTEIN: guanine nucleotide-binding protein subunit alpha-13-like [KO:K04639]
124993416  transforming protein RhoA [KO:K04513]
124989136  transforming protein RhoA-like isoform X1 [KO:K04513]
124976920  transforming protein RhoA-like [KO:K04513]
124965296  rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
124962770  rho-associated protein kinase 2 isoform X1 [KO:K17388] [EC:2.7.11.1]
124984679  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]
124994613  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
124960546  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
ncar00600  Sphingolipid metabolism
ncar04010  MAPK signaling pathway
ncar04142  Lysosome
ncar04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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