KEGG   PATHWAY: sara04071
Entry
sara04071                   Pathway                                
Name
Sphingolipid signaling pathway - Sorex araneus (European shrew)
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
sara04071  Sphingolipid signaling pathway
sara04071

Organism
Sorex araneus (European shrew) [GN:sara]
Gene
101558974  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
101555064  SPTLC1; serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
101539685  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
101555292  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
101544283  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
101546837  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
101557274  CERS4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
101543849  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
101550104  CERS3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
101551440  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
101558293  CERS5; ceramide synthase 5 [KO:K23727] [EC:2.3.1.291]
101546437  DEGS2; sphingolipid delta(4)-desaturase/C4-hydroxylase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101543104  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
101554269  SMPD1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
101547429  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
101537189  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27 3.1.4.62]
101558664  TNF; tumor necrosis factor [KO:K03156]
101541261  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
101551270  NSMAF; protein FAN [KO:K18953]
101558586  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
101555645  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
101537453  ASAH2; neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
101553905  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
101537336  ACER2; alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
101557571  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
101550002  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
101543971  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
101546492  BID; BH3-interacting domain death agonist [KO:K04726]
101540951  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
101547499  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
101538553  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556557  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556063  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101536977  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101537598  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101554044  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101545321  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
101557147  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
101543096  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101559009  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101543371  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101545820  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
101558333  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
101558753  serine/threonine-protein phosphatase PP1 isozyme 2-like [KO:K04382] [EC:3.1.3.16]
101550757  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
101557020  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
101558490  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
101544934  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform-like [KO:K04354]
101539891  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma [KO:K04354]
101538755  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
101545349  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform [KO:K04354]
101542532  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
101547290  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
101556548  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
101537802  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
101543373  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X2 [KO:K11584]
101559149  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
101538936  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
101556089  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
101558045  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
101542253  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
101551080  MS4A2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
101555828  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
101538710  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
101540482  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
101542917  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101556597  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101548304  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101547106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101541868  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101540938  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101538228  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
101550489  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
101538217  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
101554247  SPHK1; sphingosine kinase 1 [KO:K04718] [EC:2.7.1.91]
101541147  KNG1; kininogen-1 [KO:K03898]
101537830  ADORA1; adenosine receptor A1 [KO:K04265]
101552570  ADORA3; adenosine receptor A3 [KO:K04268]
101539723  BDKRB2; B2 bradykinin receptor [KO:K03916]
101545729  OPRD1; delta-type opioid receptor [KO:K04213]
101544375  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101538556  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101545200  guanine nucleotide-binding protein G(i) subunit alpha-like [KO:K04630]
101545636  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101551223  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101546811  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101547690  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101559179  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101543045  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
101559341  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101541587  mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
101545848  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101558610  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
101557193  SGPP2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
101537709  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
101546993  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
101545960  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
101539886  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
101546777  HRAS; GTPase HRas [KO:K02833]
101557531  KRAS; GTPase KRas isoform X1 [KO:K07827]
101559343  NRAS; GTPase NRas [KO:K07828]
101545329  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101550720  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101555057  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101540891  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
101538779  3-phosphoinositide-dependent protein kinase 1-like [KO:K06276] [EC:2.7.11.1]
101547011  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
101557373  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
101555118  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
101553997  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
101550203  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
101557809  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101551961  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101547658  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
101539279  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101545336  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
101540937  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
101539799  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
101539190  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
101544191  transforming protein RhoA [KO:K04513]
101557527  LOW QUALITY PROTEIN: transforming protein RhoA-like [KO:K04513]
101540987  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.39]
101539253  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.39]
101558235  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]
101549580  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101543163  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
sara00600  Sphingolipid metabolism
sara04010  MAPK signaling pathway
sara04142  Lysosome
sara04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
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