KEGG   PATHWAY: umr04071
Entry
umr04071                    Pathway                                
Name
Sphingolipid signaling pathway - Ursus maritimus (polar bear)
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
umr04071  Sphingolipid signaling pathway
umr04071

Organism
Ursus maritimus (polar bear) [GN:umr]
Gene
103656234  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
103656765  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X4 [KO:K11584]
103657107  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
103657238  SPHK2; sphingosine kinase 2 isoform X1 [KO:K04718] [EC:2.7.1.91]
103657330  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform isoform X5 [KO:K03456]
103657790  ADORA1; adenosine receptor A1 [KO:K04265]
103657827  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
103658340  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma [KO:K04354]
103658377  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X3 [KO:K04354]
103658775  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
103659105  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
103659527  CERS6; ceramide synthase 6 isoform X1 [KO:K23727]
103659988  CERS3; ceramide synthase 3 [KO:K24622]
103660117  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
103660368  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
103660447  [KO:K01115] [EC:3.1.4.4]
103660958  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
103661038  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103661310  [KO:K08090]
103661312  [KO:K08090]
103661314  [KO:K08090]
103661724  SGMS2; phosphatidylcholine:ceramide cholinephosphotransferase 2 isoform X1 [KO:K04714] [EC:2.7.8.27]
103661914  SGMS1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
103661921  [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
103661994  ASAH2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
103662155  ACER2; alkaline ceramidase 2 isoform X1 [KO:K01441] [EC:3.5.1.23]
103662531  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
103662842  ROCK1; rho-associated protein kinase 1 isoform X3 [KO:K04514] [EC:2.7.11.1]
103662865  SGPP2; sphingosine-1-phosphate phosphatase 2 isoform X1 [KO:K04717] [EC:3.1.3.-]
103663184  S1PR3; sphingosine 1-phosphate receptor 3 [KO:K04290]
103663198  SPTLC1; serine palmitoyltransferase 1 isoform X1 [KO:K00654] [EC:2.3.1.50]
103663281  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
103663496  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X2 [KO:K04426] [EC:2.7.11.25]
103663617  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
103663691  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
103664157  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
103665244  KRAS; GTPase KRas isoform X1 [KO:K07827]
103665451  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
103665538  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
103665670  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
103665907  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
103665951  SPHK1; sphingosine kinase 1 isoform X1 [KO:K04718] [EC:2.7.1.91]
103666008  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
103666113  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
103666328  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta [KO:K11583]
103666688  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103666751  OPRD1; delta-type opioid receptor [KO:K04213]
103666874  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
103667253  DEGS1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
103667533  CERS2; ceramide synthase 2 [KO:K24621]
103667796  SGPL1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
103667893  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
103668498  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
103668839  ABCC1; multidrug resistance-associated protein 1 isoform X1 [KO:K05665] [EC:7.6.2.3]
103668895  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
103669173  [KO:K02833]
103669286  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103669319  S1PR1; sphingosine 1-phosphate receptor 1 [KO:K04288]
103669422  NRAS; GTPase NRas [KO:K07828]
103669540  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103669660  BDKRB2; B2 bradykinin receptor [KO:K03916]
103669942  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
103670095  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
103670766  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
103671035  HRAS; GTPase HRas isoform X3 [KO:K02833]
103671118  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
103671225  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
103672015  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
103672060  FCER1A; high affinity immunoglobulin epsilon receptor subunit alpha [KO:K08089]
103672380  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
103672470  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
103672914  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
103673291  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
103673552  [KO:K05858] [EC:3.1.4.11]
103673578  DEGS2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
103673673  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
103674004  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
103674021  SPTLC2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
103674115  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
103674425  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
103674426  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
103674441  SPTLC3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
103674803  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103674825  RHOA; transforming protein RhoA [KO:K04513]
103675000  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
103675149  CERS1; ceramide synthase 1 isoform X1 [KO:K04710] [EC:2.3.1.299]
103675162  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
103675216  [KO:K04268]
103675245  TRAF2; TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
103675475  CERS5; ceramide synthase 5 isoform X1 [KO:K23727]
103675694  BID; BH3-interacting domain death agonist [KO:K04726]
103676052  KNG1; kininogen-1 isoform X1 [KO:K03898]
103676125  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103676145  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
103676164  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
103676407  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
103676878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
103676947  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
103676988  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
103677025  SMPD2; sphingomyelin phosphodiesterase 2 isoform X1 [KO:K12351] [EC:3.1.4.12]
103677196  SPTSSB; serine palmitoyltransferase small subunit B [KO:K26384]
103677452  NSMAF; protein FAN isoform X1 [KO:K18953]
103677947  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
103678081  GAB2; GRB2-associated-binding protein 2 isoform X3 [KO:K08091]
103678447  PRKCZ; protein kinase C zeta type isoform X2 [KO:K18952] [EC:2.7.11.13]
103678592  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
103678732  S1PR2; sphingosine 1-phosphate receptor 2 [KO:K04292]
103678867  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
103679064  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103679434  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
103679549  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
103679584  RELA; transcription factor p65 [KO:K04735]
103679990  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
103680906  SPTSSA; serine palmitoyltransferase small subunit A [KO:K26384]
103681376  ASAH1; acid ceramidase [KO:K12348] [EC:3.5.1.23]
103681411  SMPD1; sphingomyelin phosphodiesterase isoform X1 [KO:K12350] [EC:3.1.4.12]
103681704  ACER1; alkaline ceramidase 1 isoform X1 [KO:K01441] [EC:3.5.1.23]
103681834  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103681884  CERS4; ceramide synthase 4 [KO:K24621]
103682322  TNF; tumor necrosis factor [KO:K03156]
121099746  [KO:K05858] [EC:3.1.4.11]
121100753  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
121102543  S1PR5; sphingosine 1-phosphate receptor 5 [KO:K04295]
121102576  S1PR4; sphingosine 1-phosphate receptor 4 [KO:K04293]
121105228  SGPP1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
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
umr00600  Sphingolipid metabolism
umr04010  MAPK signaling pathway
umr04142  Lysosome
umr04151  PI3K-Akt signaling pathway
KO pathway
ko04071   

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