KEGG   PATHWAY: mlk04071
Entry
mlk04071                    Pathway                                
Name
Sphingolipid signaling pathway - Mustela lutreola (European mink)
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
mlk04071  Sphingolipid signaling pathway
mlk04071

Organism
Mustela lutreola (European mink) [GN:mlk]
Gene
131836819  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
131838509  LOW QUALITY PROTEIN: serine palmitoyltransferase 1-like [KO:K00654] [EC:2.3.1.50]
131812280  SPTLC1; serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
131808110  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
131836456  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
131824909  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
131810315  serine palmitoyltransferase small subunit A-like [KO:K26384]
131823791  CERS1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
131823419  CERS4; ceramide synthase 4 isoform X1 [KO:K24621] [EC:2.3.1.297]
131808785  CERS2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
131835689  CERS3; ceramide synthase 3 isoform X1 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
131838780  CERS5; ceramide synthase 5 isoform X1 [KO:K23727] [EC:2.3.1.291]
131827132  CERS6; ceramide synthase 6 isoform X1 [KO:K23727] [EC:2.3.1.291]
131836983  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 isoform X1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
131814642  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
131808576  SMPD1; sphingomyelin phosphodiesterase isoform X1 [KO:K12350] [EC:3.1.4.12]
131828965  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 isoform X1 [KO:K04714] [EC:2.7.8.27]
131829529  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
131834372  TNF; tumor necrosis factor isoform X1 [KO:K03156]
131838434  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
131826801  NSMAF; protein FAN isoform X1 [KO:K18953]
131833525  SMPD2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
131820512  ASAH1; acid ceramidase isoform X1 [KO:K12348] [EC:3.5.1.23]
131828962  ASAH2; neutral ceramidase isoform X1 [KO:K12349] [EC:3.5.1.23]
131812298  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
131825713  ACER1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
131817910  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
131812685  TRAF2; TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
131817810  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
131838342  BID; BH3-interacting domain death agonist [KO:K04726]
131817775  BAX; apoptosis regulator BAX [KO:K02159]
131833762  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
131828723  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
131831160  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
131832665  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
131839655  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
131839656  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
131834189  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
131834191  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
131808860  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
131837056  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
131815063  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131817507  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131811845  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
131820528  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
131835761  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
131817379  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
131833907  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
131830528  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
131832215  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
131826440  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
131836465  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
131821562  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
131824568  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
131836664  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
131836998  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
131833991  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
131814406  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
131815027  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
131815809  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
131814808  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
131813186  high affinity immunoglobulin epsilon receptor subunit beta-like isoform X1 [KO:K08090]
131813210  high affinity immunoglobulin epsilon receptor subunit beta-like isoform X1 [KO:K08090]
131822708  high affinity immunoglobulin epsilon receptor subunit beta-like [KO:K08090]
131814327  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
131833494  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
131840261  GAB2; GRB2-associated-binding protein 2 [KO:K08091]
131809015  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
131824589  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
131824847  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
131823754  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
131832309  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
131810162  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
131816943  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
131824867  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
131816984  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
131817451  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
131824751  KNG1; kininogen-1 isoform X1 [KO:K03898]
131815141  ADORA1; adenosine receptor A1 isoform X1 [KO:K04265]
131809529  ADORA3; adenosine receptor A3 [KO:K04268]
131836961  BDKRB2; B2 bradykinin receptor isoform X1 [KO:K03916]
131810016  OPRD1; delta-type opioid receptor [KO:K04213]
131829305  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
131823969  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
131810079  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
131836105  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
131814631  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
131808069  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
131808080  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
131808516  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
131811758  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
131820131  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
131836665  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
131827399  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
131819158  ABCC1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
131828863  SGPL1; sphingosine-1-phosphate lyase 1 isoform X1 [KO:K01634] [EC:4.1.2.27]
131809568  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
131823505  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
131818337  HRAS; GTPase HRas isoform X1 [KO:K02833]
131838926  KRAS; GTPase KRas isoform X1 [KO:K07827]
131810307  NRAS; GTPase NRas isoform X1 [KO:K07828]
131810524  LOW QUALITY PROTEIN: GTPase NRas-like [KO:K07828]
131824239  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
131835957  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
131823312  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
131819765  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
131829935  NOS3; LOW QUALITY PROTEIN: nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
131819826  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
131839444  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
131816825  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
131812477  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
131812467  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
131815964  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
131819600  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
131818861  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
131823281  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
131823521  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
131819299  GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346]
131815704  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
131811641  transforming protein RhoA-like [KO:K04513]
131823928  RHOA; transforming protein RhoA [KO:K04513]
131811851  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:2.7.11.1]
131807367  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
131828969  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]
131828977  phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN-like isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
131828978  LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN-like [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
131829020  LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN-like [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
131829855  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
131815578  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
mlk00600  Sphingolipid metabolism
mlk04010  MAPK signaling pathway
mlk04142  Lysosome
mlk04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
LinkDB

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