KEGG   PATHWAY: rno04071
Entry
rno04071                    Pathway                                
Name
Sphingolipid signaling pathway - Rattus norvegicus (rat)
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
rno04071  Sphingolipid signaling pathway
rno04071

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
366697  Sptlc2; serine palmitoyltransferase 2 [KO:K00654] [EC:2.3.1.50]
361213  Sptlc1; serine palmitoyltransferase 1 [KO:K00654] [EC:2.3.1.50]
296188  Sptlc3; serine palmitoyltransferase 3 [KO:K00654] [EC:2.3.1.50]
500651  Sptssa; serine palmitoyltransferase small subunit A [KO:K26384]
100362555  Sptssb; serine palmitoyltransferase small subunit B [KO:K26384]
290658  Cers1; ceramide synthase 1 [KO:K04710] [EC:2.3.1.299]
310667  Cers2; ceramide synthase 2 [KO:K24621] [EC:2.3.1.297]
304208  Cers4; ceramide synthase 4 [KO:K24621] [EC:2.3.1.297]
499174  Cers3; ceramide synthase 3 [KO:K24622] [EC:2.3.1.297 2.3.1.298]
366065  Cers6; ceramide synthase 6 isoform 1 [KO:K23727] [EC:2.3.1.291]
366984  Cers5; ceramide synthase 5 [KO:K23727] [EC:2.3.1.291]
58970  Degs1; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
314438  Degs2; sphingolipid delta(4)-desaturase/C4-monooxygenase DES2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
289322  Degs1l2; sphingolipid delta(4)-desaturase DES1 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
498300  Degs1l1; sphingolipid delta(4)-desaturase DES1 isoform X2 [KO:K04712] [EC:1.14.19.17 1.14.18.5]
308909  Smpd1; sphingomyelin phosphodiesterase [KO:K12350] [EC:3.1.4.12]
353229  Sgms1; phosphatidylcholine:ceramide cholinephosphotransferase 1 [KO:K04714] [EC:2.7.8.27]
310849  Sgms2; phosphatidylcholine:ceramide cholinephosphotransferase 2 [KO:K04714] [EC:2.7.8.27]
24835  Tnf; tumor necrosis factor [KO:K03156]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
353233  Nsmaf; protein FAN [KO:K18953]
83537  Smpd2; sphingomyelin phosphodiesterase 2 [KO:K12351] [EC:3.1.4.12]
84431  Asah1; acid ceramidase precursor [KO:K12348] [EC:3.5.1.23]
114104  Asah2; neutral ceramidase [KO:K12349] [EC:3.5.1.23]
313339  Acer2; alkaline ceramidase 2 [KO:K01441] [EC:3.5.1.23]
301118  Acer1; alkaline ceramidase 1 [KO:K01441] [EC:3.5.1.23]
246756  Tradd; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
311786  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
171293  Ctsd; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
64625  Bid; BH3-interacting domain death agonist [KO:K04726]
24887  Bax; apoptosis regulator BAX [KO:K02159]
367149  Bax-ps1; apoptosis regulator BAX-like [KO:K02159]
681314  apoptosis regulator BAX-like [KO:K02159]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
25522  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
24672  Ppp2ca; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
24673  Ppp2cb; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
100362453  Ppp2cal1; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform-like [KO:K04382] [EC:3.1.3.16]
117281  Ppp2r1a; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
315648  Ppp2r1b; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
246255  Ppp2r2d; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform [KO:K04354]
60660  Ppp2r2b; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform 1 [KO:K04354]
117256  Ppp2r2c; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform 1 [KO:K04354]
117104  Ppp2r2a; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
682033  Ppp2r3b; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta [KO:K11583]
362739  Ppp2r3c; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
363122  Ppp2r3a; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
309179  Ppp2r5b; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
691318  Ppp2r5c; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform 4 [KO:K11584]
363193  Ppp2r5d; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
299147  Ppp2r5e; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
312754  Ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
25047  Fcer1a; high affinity immunoglobulin epsilon receptor subunit alpha precursor [KO:K08089]
25316  Ms4a2; high affinity immunoglobulin epsilon receptor subunit beta [KO:K08090]
25441  Fcer1g; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
25150  Fyn; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
84477  Gab2; GRB2-associated-binding protein 2 [KO:K08091]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
25097  Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
25096  Pld1; phospholipase D1 isoform 2 [KO:K01115] [EC:3.1.4.4]
308589  Sphk2; sphingosine kinase 2 [KO:K04718] [EC:2.7.1.91]
170897  Sphk1; sphingosine kinase 1 isoform b [KO:K04718] [EC:2.7.1.91]
24903  Kng2; T-kininogen 1 precursor [KO:K03898]
25087  Kng2l1; kininogen-1 isoform 1 precursor [KO:K03898]
288001  Kng1; T-kininogen 2 precursor [KO:K03898]
29290  Adora1; adenosine receptor A1 [KO:K04265]
100911796  Adora3; adenosine receptor A3 isoform b [KO:K04268]
25245  Bdkrb2; B2 bradykinin receptor isoform 2 [KO:K03916]
24613  Oprd1; delta-type opioid receptor [KO:K04213]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
29340  Prkce; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
81536  Sgpp1; sphingosine-1-phosphate phosphatase 1 [KO:K04716] [EC:3.1.3.-]
301543  Sgpp2; sphingosine-1-phosphate phosphatase 2 [KO:K04717] [EC:3.1.3.-]
24565  Abcc1; multidrug resistance-associated protein 1 [KO:K05665] [EC:7.6.2.3]
286896  Sgpl1; sphingosine-1-phosphate lyase 1 [KO:K01634] [EC:4.1.2.27]
29733  S1pr1; sphingosine 1-phosphate receptor 1 [KO:K04288]
29415  S1pr2; sphingosine 1-phosphate receptor 2 [KO:K04292]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
81745  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
24600  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
366957  Rac2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
688319  Rac3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
306792  S1pr3; sphingosine 1-phosphate receptor 3 [KO:K04290]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
314649  S1pr4; sphingosine 1-phosphate receptor 4 [KO:K04293]
60399  S1pr5; sphingosine 1-phosphate receptor 5 [KO:K04295]
81663  Gna12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
303634  Gna13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
117273  Rhoa; transforming protein RhoA [KO:K04513]
297173  RSA-14-44; ras homolog gene family, member A [KO:K04513]
81762  Rock1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
25537  Rock2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.1]
50557  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]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  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
rno00600  Sphingolipid metabolism
rno04010  MAPK signaling pathway
rno04142  Lysosome
rno04151  PI3K-Akt signaling pathway
KO pathway
ko04071   
LinkDB

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