KEGG   PATHWAY: mleu04071
Entry
mleu04071                   Pathway                                
Name
Sphingolipid signaling pathway - Mandrillus leucophaeus (drill)
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
mleu04071  Sphingolipid signaling pathway
mleu04071

Organism
Mandrillus leucophaeus (drill) [GN:mleu]
Gene
105545359  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
105552996  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
105547547  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
105547166  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
105534749  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
105528481  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
105545301  CERS6; ceramide synthase 6 [KO:K23727] [EC:2.3.1.291]
105528019  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
105554481  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
105547987  DEGS2; sphingolipid delta(4)-desaturase/C4-hydroxylase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
105531251  sphingomyelin phosphodiesterase isoform X1 [KO:K12350] [EC:3.1.4.12]
105546572  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
105546952  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
105554159  TNF; tumor necrosis factor [KO:K03156]
105541778  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
105541253  NSMAF; LOW QUALITY PROTEIN: protein FAN [KO:K18953]
105536580  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
105539387  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
105546949  ASAH2; neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
105548580  ACER2; alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
105530065  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
105551442  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
105543266  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
105545336  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
105542917  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
105539167  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
105538551  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
105547365  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
105554734  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105537274  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105543603  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
105543619  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
105544221  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
105544400  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
105544659  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
105540494  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105541755  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105542359  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105535165  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
105531324  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
105537996  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
105528891  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
105537397  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
105540292  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
105554910  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
105542334  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
105555283  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
105553868  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
105550174  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
105551588  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform-like isoform X1 [KO:K11584]
105547866  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
105536391  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
105549120  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
105544321  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
105538435  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
105549866  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
105538791  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha isoform X1 [KO:K08089]
105535313  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta isoform X1 [KO:K08090]
105536720  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma isoform X1 [KO:K07983]
105532442  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
105546498  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
105539923  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105552763  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
105549588  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
105547376  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105543389  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105531763  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105539968  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
105552590  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
105539178  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
105542321  SPHK1; sphingosine kinase 1 [KO:K04718] [EC:2.7.1.91]
105527869  KNG1; kininogen-1 isoform X1 [KO:K03898]
105547086  ADORA1; adenosine receptor A1 isoform X1 [KO:K04265]
105547899  BDKRB2; B2 bradykinin receptor isoform X1 [KO:K03916]
105540977  OPRD1; delta-type opioid receptor [KO:K04213]
105548989  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
105543912  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105530947  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105546224  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
105552818  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
105553023  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
105549095  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
105528827  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
105541405  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105544764  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105538458  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
105550934  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
105547532  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
105547459  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
105548509  S1PR1; sphingosine 1-phosphate receptor 1 isoform X1 [KO:K04288]
105549725  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
105549333  HRAS; GTPase HRas isoform X1 [KO:K02833]
105550009  KRAS; GTPase KRas [KO:K07827]
105554356  NRAS; GTPase NRas isoform X1 [KO:K07828]
105542175  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105530797  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105530027  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105541556  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105542707  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
105551438  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
105546567  ras-related protein Rac1-like [KO:K04392]
105538902  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
105531520  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
105535943  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
105542500  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
105548239  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
105545146  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105539692  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105530010  S1PR4; sphingosine 1-phosphate receptor 4 isoform X1 [KO:K04293]
105549835  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
105537343  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
105532531  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
105540348  RHOA; transforming protein RhoA [KO:K04513]
105551188  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
105528513  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
105546962  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]
105548314  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105528449  RELA; transcription factor p65 isoform X1 [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
mleu00600  Sphingolipid metabolism
mleu04010  MAPK signaling pathway
mleu04142  Lysosome
mleu04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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