KEGG   PATHWAY: pvp05231
Entry
pvp05231                    Pathway                                
Name
Choline metabolism in cancer - Pteropus vampyrus (large flying fox)
Description
Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.
Class
Human Diseases; Cancer: overview
Pathway map
pvp05231  Choline metabolism in cancer
pvp05231

Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105288668  PLA2G4D; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
105288669  PLA2G4F; cytosolic phospholipase A2 zeta isoform X2 [KO:K16342] [EC:3.1.1.4]
105288785  PLA2G4B; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
105288787  PLA2G4E; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
105288933  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105289137  SLC44A5; choline transporter-like protein 5 [KO:K15377]
105289326  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
105289628  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
105290015  DGKZ; diacylglycerol kinase zeta isoform X8 [KO:K00901] [EC:2.7.1.107]
105290514  WASF2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
105291395  LYPLA1; acyl-protein thioesterase 1 [KO:K06128] [EC:3.1.1.5]
105291671  DGKI; diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
105291755  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
105292138  WASF3; wiskott-Aldrich syndrome protein family member 3 [KO:K06083]
105292199  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
105292949  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105293045  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
105293353  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
105293544  SLC22A5; solute carrier family 22 member 5 isoform X1 [KO:K08202]
105293644  SLC22A4; solute carrier family 22 member 4 [KO:K08202]
105293808  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
105294059  KRAS; GTPase KRas isoform X2 [KO:K07827]
105294429  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105294593  PDGFA; platelet-derived growth factor subunit A [KO:K04359]
105294623  RAC1; LOW QUALITY PROTEIN: ras-related C3 botulinum toxin substrate 1 [KO:K04392]
105295051  DGKB; diacylglycerol kinase beta [KO:K00901] [EC:2.7.1.107]
105295052  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
105295263  WASF1; wiskott-Aldrich syndrome protein family member 1 [KO:K05753]
105295341  SLC44A1; choline transporter-like protein 1 isoform X2 [KO:K06515]
105295420  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
105296521  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
105296550  NRAS; GTPase NRas isoform X1 [KO:K07828]
105296605  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105297140  [KO:K02649]
105297442  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
105297702  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105298078  PDGFB; platelet-derived growth factor subunit B isoform X1 [KO:K17386]
105298463  DGKH; diacylglycerol kinase eta isoform X4 [KO:K00901] [EC:2.7.1.107]
105298655  TSC1; hamartin isoform X1 [KO:K07206]
105298656  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 [KO:K18695] [EC:3.1.4.2]
105298674  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
105298702  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105298946  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
105299021  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105299213  FOS; proto-oncogene c-Fos [KO:K04379]
105299371  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
105299436  PDGFRB; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:2.7.10.1]
105299978  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105300159  [KO:K04456] [EC:2.7.11.1]
105300185  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105300480  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma [KO:K00889] [EC:2.7.1.68]
105301137  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
105301865  DGKQ; diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
105302057  SLC5A7; high affinity choline transporter 1 [KO:K14387]
105302100  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105302255  PLPP2; phospholipid phosphatase 2 [KO:K01080] [EC:3.1.3.4]
105302603  DGKA; diacylglycerol kinase alpha isoform X1 [KO:K00901] [EC:2.7.1.107]
105302655  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
105303144  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105303335  TSC2; LOW QUALITY PROTEIN: tuberin [KO:K07207]
105303436  JUN; transcription factor AP-1 [KO:K04448]
105303777  RHEB; GTP-binding protein Rheb [KO:K07208]
105303834  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X1 [KO:K00889] [EC:2.7.1.68]
105303899  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105304566  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105305297  SLC44A4; choline transporter-like protein 4 isoform X1 [KO:K15377]
105305607  SLC44A2; choline transporter-like protein 2 isoform X1 [KO:K15377]
105305672  SLC22A2; solute carrier family 22 member 2 [KO:K08199]
105305673  [KO:K08200]
105305677  [KO:K08198]
105305810  PLPP1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:3.1.3.4]
105305933  HRAS; GTPase HRas isoform X1 [KO:K02833]
105306002  DGKD; diacylglycerol kinase delta [KO:K00901] [EC:2.7.1.107]
105306010  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
105306141  [KO:K04361] [EC:2.7.10.1]
105306550  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
105306577  CHKA; choline kinase alpha isoform X1 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105306744  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105306912  SLC44A3; choline transporter-like protein 3 [KO:K15282]
105307094  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
105307133  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta [KO:K00889] [EC:2.7.1.68]
105307215  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105307575  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105307815  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:2.7.1.107]
105308269  CHKB; choline/ethanolamine kinase isoform X1 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105308691  HIF1A; hypoxia-inducible factor 1-alpha isoform X2 [KO:K08268]
105308818  [KO:K19662] [EC:2.7.11.13]
105308956  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
105309462  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105309535  SOS2; son of sevenless homolog 2 [KO:K03099]
105309731  PCYT1A; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:2.7.7.15]
105309827  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
105309966  DGKK; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
105310012  WAS; wiskott-Aldrich syndrome protein [KO:K05747]
105310595  CHPT1; cholinephosphotransferase 1 isoform X1 [KO:K00994] [EC:2.7.8.2]
105311532  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X2 [KO:K07860]
Compound
C00093  sn-Glycerol 3-phosphate
C00114  Choline
C00157  Phosphatidylcholine
C00162  Fatty acid
C00165  Diacylglycerol
C00307  CDP-choline
C00416  Phosphatidate
C00588  Choline phosphate
C00670  sn-Glycero-3-phosphocholine
C04230  1-Acyl-sn-glycero-3-phosphocholine
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:22089420
  Authors
Glunde K, Bhujwalla ZM, Ronen SM
  Title
Choline metabolism in malignant transformation.
  Journal
Nat Rev Cancer 11:835-48 (2011)
DOI:10.1038/nrc3162
Reference
PMID:19935796
  Authors
Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO
  Title
Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy.
  Journal
Br J Cancer 102:1-7 (2010)
DOI:10.1038/sj.bjc.6605457
Reference
PMID:22429397
  Authors
Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F
  Title
Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.
  Journal
Breast Cancer Res 14:R50 (2012)
DOI:10.1186/bcr3151
Reference
PMID:19264150
  Authors
Foster DA
  Title
Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells.
  Journal
Biochim Biophys Acta 1791:949-55 (2009)
DOI:10.1016/j.bbalip.2009.02.009
Reference
PMID:16432178
  Authors
Beloueche-Babari M, Jackson LE, Al-Saffar NM, Eccles SA, Raynaud FI, Workman P, Leach MO, Ronen SM
  Title
Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
  Journal
Mol Cancer Ther 5:187-96 (2006)
DOI:10.1158/1535-7163.MCT-03-0220
Reference
PMID:23350810
  Authors
Ridgway ND
  Title
The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.
  Journal
Crit Rev Biochem Mol Biol 48:20-38 (2013)
DOI:10.3109/10409238.2012.735643
Reference
PMID:22921309
  Authors
Awwad HM, Geisel J, Obeid R
  Title
The role of choline in prostate cancer.
  Journal
Clin Biochem 45:1548-53 (2012)
DOI:10.1016/j.clinbiochem.2012.08.012
Reference
PMID:16230400
  Authors
Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D'Ascenzo S, Millimaggi D, Pavan A, Dolo V, Canevari S, Podo F
  Title
Alterations of choline phospholipid metabolism in ovarian tumor progression.
  Journal
Cancer Res 65:9369-76 (2005)
DOI:10.1158/0008-5472.CAN-05-1146
Reference
PMID:14523987
  Authors
Ackerstaff E, Glunde K, Bhujwalla ZM
  Title
Choline phospholipid metabolism: a target in cancer cells?
  Journal
J Cell Biochem 90:525-33 (2003)
DOI:10.1002/jcb.10659
Reference
PMID:23076158
  Authors
Park JB, Lee CS, Jang JH, Ghim J, Kim YJ, You S, Hwang D, Suh PG, Ryu SH
  Title
Phospholipase signalling networks in cancer.
  Journal
Nat Rev Cancer 12:782-92 (2012)
DOI:10.1038/nrc3379
Reference
PMID:19855431
  Authors
Yalcin A, Clem B, Makoni S, Clem A, Nelson K, Thornburg J, Siow D, Lane AN, Brock SE, Goswami U, Eaton JW, Telang S, Chesney J
  Title
Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.
  Journal
Oncogene 29:139-49 (2010)
DOI:10.1038/onc.2009.317
Reference
PMID:21793073
  Authors
Glunde K, Jiang L, Moestue SA, Gribbestad IS
  Title
MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer.
  Journal
NMR Biomed 24:673-90 (2011)
DOI:10.1002/nbm.1751
Reference
PMID:19136975
  Authors
Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
  Title
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
  Journal
Nat Chem Biol 5:108-17 (2009)
DOI:10.1038/nchembio.140
Reference
PMID:14517341
  Authors
Foster DA, Xu L
  Title
Phospholipase D in cell proliferation and cancer.
  Journal
Mol Cancer Res 1:789-800 (2003)
Reference
PMID:20528734
  Authors
Zhou H, Huang S
  Title
mTOR signaling in cancer cell motility and tumor metastasis.
  Journal
Crit Rev Eukaryot Gene Expr 20:1-16 (2010)
DOI:10.1615/critreveukargeneexpr.v20.i1.10
Related
pathway
pvp00564  Glycerophospholipid metabolism
pvp04010  MAPK signaling pathway
pvp04150  mTOR signaling pathway
pvp04151  PI3K-Akt signaling pathway
pvp04810  Regulation of actin cytoskeleton
KO pathway
ko05231   

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