KEGG   PATHWAY: ko04071
Entry
ko04071                     Pathway                                
Name
Sphingolipid signaling pathway
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
ko04071  Sphingolipid signaling pathway
ko04071

Orthology
K00654  SPT; serine palmitoyltransferase [EC:2.3.1.50]
K00922  PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K01110  PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67]
K01115  PLD1_2; phospholipase D1/2 [EC:3.1.4.4]
K01379  CTSD; cathepsin D [EC:3.4.23.5]
K01441  ACER1_2, ASAH3; alkaline ceramidase [EC:3.5.1.23]
K01634  SGPL1, DPL1; sphinganine-1-phosphate aldolase [EC:4.1.2.27]
K02159  BAX; apoptosis regulator BAX
K02161  BCL2; apoptosis regulator Bcl-2
K02580  NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649  PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K03156  TNF, TNFA; tumor necrosis factor superfamily, member 2
K03158  TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A
K03171  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein
K03173  TRAF2; TNF receptor-associated factor 2 [EC:2.3.2.27]
K03456  PPP2R1; serine/threonine-protein phosphatase 2A regulatory subunit A
K03898  KNG, BK; kininogen
K03916  BDKRB2; bradykinin receptor B2
K04213  OPRD1; delta-type opioid receptor
K04265  ADORA1; adenosine receptor A1
K04268  ADORA3; adenosine receptor A3
K04288  S1PR1, EDG1, CD363; sphingosine 1-phosphate receptor 1
K04290  S1PR3, EDG3; sphingosine 1-phosphate receptor 3
K04292  S1PR2, EDG5; sphingosine 1-phosphate receptor 2
K04293  S1PR4, EDG6; sphingosine 1-phosphate receptor 4
K04295  S1PR5, EDG8; sphingosine 1-phosphate receptor 5
K04346  GNA12; guanine nucleotide-binding protein subunit alpha-12
K04354  PPP2R2; serine/threonine-protein phosphatase 2A regulatory subunit B
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04382  PPP2C; serine/threonine-protein phosphatase 2A catalytic subunit [EC:3.1.3.16]
K04392  RAC1; Ras-related C3 botulinum toxin substrate 1
K04426  MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25]
K04440  JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04441  P38; p38 MAP kinase [EC:2.7.11.24]
K04451  TP53, P53; tumor protein p53
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04513  RHOA; Ras homolog gene family, member A
K04514  ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04639  GNA13; guanine nucleotide-binding protein subunit alpha-13
K04710  CERS1, LASS1; sphingoid base N-stearoyltransferase [EC:2.3.1.299]
K04712  DEGS; sphingolipid 4-desaturase/C4-monooxygenase [EC:1.14.19.17 1.14.18.5]
K04714  SGMS; sphingomyelin synthase / phosphatidylethanolamine phospholipase C [EC:2.7.8.27 3.1.4.62]
K04716  SGPP1; sphingosine-1-phosphate phosphatase 1 [EC:3.1.3.-]
K04717  SGPP2; sphingosine-1-phosphate phosphotase 2 [EC:3.1.3.-]
K04718  SPHK; sphingosine kinase [EC:2.7.1.91]
K04726  BID; BH3 interacting domain death agonist
K04735  RELA; transcription factor p65
K05665  ABCC1; ATP-binding cassette, subfamily C (CFTR/MRP), member 1 [EC:7.6.2.3]
K05703  FYN; tyrosine-protein kinase Fyn [EC:2.7.10.2]
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K06276  PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K07860  RAC2; Ras-related C3 botulinum toxin substrate 2
K07861  RAC3; Ras-related C3 botulinum toxin substrate 3
K07983  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma
K08089  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha
K08090  MS4A2, FCER1B; high affinity immunoglobulin epsilon receptor subunit beta
K08091  GAB2; GRB2-associated-binding protein 2
K11583  PPP2R3; serine/threonine-protein phosphatase 2A regulatory subunit B''
K11584  PPP2R5; serine/threonine-protein phosphatase 2A regulatory subunit B'
K12348  ASAH1; acid ceramidase [EC:3.5.1.23]
K12349  ASAH2; neutral ceramidase [EC:3.5.1.23]
K12350  SMPD1, ASM; sphingomyelin phosphodiesterase [EC:3.1.4.12]
K12351  SMPD2; sphingomyelin phosphodiesterase 2 [EC:3.1.4.12]
K13242  NOS3; nitric-oxide synthase, endothelial [EC:1.14.13.39]
K17388  ROCK2; Rho-associated protein kinase 2 [EC:2.7.11.39]
K18050  PRKCE; novel protein kinase C epsilon type [EC:2.7.11.13]
K18952  PRKCZ; atypical protein kinase C zeta type [EC:2.7.11.13]
K18953  NSMAF, FAN; factor associated with neutral sphingomyelinase activation
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
K23727  CERS5_6, LASS5_6; sphingoid base N-palmitoyltransferase
K24621  CERS2_4, LASS2_4; very-long-chain ceramide synthase
K24622  CERS3, LASS3; very-long-chain ceramide synthase / ultra-long-chain ceramide synthase
K26384  SPTSS; serine palmitoyltransferase small subunit
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
ko00600  Sphingolipid metabolism
ko04010  MAPK signaling pathway
ko04142  Lysosome
ko04151  PI3K-Akt signaling pathway

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