KEGG   PATHWAY: mlf04071
Entry
mlf04071                    Pathway                                
Name
Sphingolipid signaling pathway - Myotis lucifugus (little brown bat)
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
mlf04071  Sphingolipid signaling pathway
mlf04071

Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102435808  SPTLC1; serine palmitoyltransferase 1 isoform X2 [KO:K00654] [EC:2.3.1.50]
102420953  SPTLC2; serine palmitoyltransferase 2 isoform X1 [KO:K00654] [EC:2.3.1.50]
102420430  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
102423555  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
102439474  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
102441535  CERS2; ceramide synthase 2 isoform X1 [KO:K24621] [EC:2.3.1.297]
102430176  CERS4; ceramide synthase 4 isoform X2 [KO:K24621] [EC:2.3.1.297]
102428338  CERS3; ceramide synthase 3 isoform X1 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
102440851  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
102436571  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
102421059  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
102441468  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
102443065  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
102439892  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
102430536  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 isoform X1 [KO:K04714] [EC:2.7.8.27]
102437558  TNF; tumor necrosis factor isoform X1 [KO:K03156]
102419664  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
102417042  NSMAF; protein FAN isoform X1 [KO:K18953]
102436498  SMPD2; sphingomyelin phosphodiesterase 2 isoform X1 [KO:K12351] [EC:3.1.4.12]
102425151  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
102434632  neutral ceramidase [KO:K12349] [EC:3.5.1.23]
102426765  putative neutral ceramidase C isoform X1 [KO:K12349] [EC:3.5.1.23]
102436898  alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
102440841  ACER1; alkaline ceramidase 1 isoform X1 [KO:K01441] [EC:3.5.1.23]
106698726  alkaline ceramidase 2-like [KO:K01441] [EC:3.5.1.23]
102433190  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
102423950  BID; BH3-interacting domain death agonist isoform X2 [KO:K04726]
102417074  BAX; apoptosis regulator BAX [KO:K02159]
102439932  MAP3K5; LOW QUALITY PROTEIN: mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
102430582  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102437455  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102418507  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102438914  mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
102437934  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102443221  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102439923  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102432611  BCL2; LOW QUALITY PROTEIN: apoptosis regulator Bcl-2 [KO:K02161]
102432188  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
102430803  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
102421388  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
102442817  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
102431175  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
102423271  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
102440385  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform-like [KO:K04354]
102437363  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
102422214  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
102433629  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
102428034  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
102433480  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
102417642  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
102432946  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
102430062  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X5 [KO:K11584]
102442935  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
102431418  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
102426938  FCER1A; LOW QUALITY PROTEIN: high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
102433982  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
102418095  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
102422740  FYN; tyrosine-protein kinase Fyn isoform X2 [KO:K05703] [EC:2.7.10.2]
102433673  GAB2; LOW QUALITY PROTEIN: GRB2-associated-binding protein 2 [KO:K08091]
102422649  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102441064  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102433534  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102427890  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102441522  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102429230  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102426106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102419324  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102443088  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
102423031  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
102434379  SPHK2; LOW QUALITY PROTEIN: sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
102421251  SPHK1; sphingosine kinase 1 isoform X2 [KO:K04718] [EC:2.7.1.91]
102431641  KNG1; kininogen-1 [KO:K03898]
102432691  kininogen-1-like [KO:K03898]
111825105  kininogen-1-like [KO:K03898]
102433011  kininogen-1 [KO:K03898]
102442936  kininogen-2-like [KO:K03898]
102441373  kininogen-1-like [KO:K03898]
102432377  kininogen-1-like [KO:K03898]
102441590  ADORA1; adenosine receptor A1 [KO:K04265]
111824436  adenosine receptor A1 [KO:K04265]
111826773  ADORA3; adenosine receptor A3 [KO:K04268]
102424220  BDKRB2; B2 bradykinin receptor [KO:K03916]
102420998  OPRD1; delta-type opioid receptor [KO:K04213]
102427230  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102429580  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
102431273  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
102432706  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
102438291  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
102432440  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
102429686  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
102441813  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
102435274  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
102417755  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102422236  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102430160  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
102438562  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
102430361  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
102435463  SGPL1; sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
102436206  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
102440602  LOW QUALITY PROTEIN: sphingosine 1-phosphate receptor 2-like [KO:K04292]
102437458  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
102431999  KRAS; GTPase KRas isoform X1 [KO:K07827]
102430744  NRAS; GTPase NRas [KO:K07828]
102434453  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102417411  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
102423748  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102431196  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102436714  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
102435667  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
102418852  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
102435695  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
102424688  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
102438932  PRKCA; protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
102428240  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102419083  protein kinase C gamma type-like [KO:K19663] [EC:2.7.11.13]
102436608  S1PR4; LOW QUALITY PROTEIN: sphingosine 1-phosphate receptor 4 [KO:K04293]
102432055  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
102436989  GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X2 [KO:K04639]
102422264  RHOA; transforming protein RhoA [KO:K04513]
102430746  transforming protein RhoA-like isoform X1 [KO:K04513]
102419225  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
102431516  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
102428304  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102435748  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102424236  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
mlf00600  Sphingolipid metabolism
mlf04010  MAPK signaling pathway
mlf04142  Lysosome
mlf04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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