KEGG   PATHWAY: cdk05231
Entry
cdk05231                    Pathway                                
Name
Choline metabolism in cancer - Camelus dromedarius (Arabian camel)
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
cdk05231  Choline metabolism in cancer
cdk05231

Organism
Camelus dromedarius (Arabian camel) [GN:cdk]
Gene
105089905  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
105102061  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
105091934  PDGFB; platelet-derived growth factor subunit B [KO:K17386]
105101177  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
116155424  PDGFD; platelet-derived growth factor D [KO:K05450]
105105749  EGFR; LOW QUALITY PROTEIN: epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
105103397  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
105098486  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
105104642  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
105091467  SOS2; LOW QUALITY PROTEIN: son of sevenless homolog 2 [KO:K03099]
105103654  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105105427  HRAS; GTPase HRas isoform X1 [KO:K02833]
105100066  KRAS; GTPase KRas isoform X1 [KO:K07827]
105089630  NRAS; GTPase NRas [KO:K07828]
105093099  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105093267  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105105302  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
105095214  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105102769  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
105085184  RALGDS; LOW QUALITY PROTEIN: ral guanine nucleotide dissociation stimulator [KO:K08732]
105091591  MAPK10; mitogen-activated protein kinase 10 isoform X4 [KO:K04440] [EC:2.7.11.24]
105094659  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105100625  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105096850  cytosolic phospholipase A2 beta isoform X2 [KO:K16342] [EC:3.1.1.4]
105099290  PLA2G4A; cytosolic phospholipase A2 [KO:K16342] [EC:3.1.1.4]
105101745  PLA2G4E; cytosolic phospholipase A2 epsilon isoform X1 [KO:K16342] [EC:3.1.1.4]
105101759  PLA2G4F; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
105101760  PLA2G4D; cytosolic phospholipase A2 delta isoform X1 [KO:K16342] [EC:3.1.1.4]
105086305  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
105107003  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
105085928  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105084758  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105101867  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
105092913  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
105099701  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X2 [KO:K06276] [EC:2.7.11.1]
105099264  AKT3; RAC-gamma serine/threonine-protein kinase isoform X3 [KO:K04456] [EC:2.7.11.1]
105104845  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105093393  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105085191  TSC1; hamartin isoform X1 [KO:K07206]
105099714  TSC2; LOW QUALITY PROTEIN: tuberin [KO:K07207]
105098696  RHEB; GTP-binding protein Rheb [KO:K07208]
105107024  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
105097829  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105104425  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
105089940  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105105952  PIP5K1B; phosphatidylinositol 4-phosphate 5-kinase type-1 beta isoform X1 [KO:K00889] [EC:2.7.1.68]
105102665  PIP5K1C; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:2.7.1.68]
105103212  PIP5K1A; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha isoform X4 [KO:K00889] [EC:2.7.1.68]
105103310  WAS; wiskott-Aldrich syndrome protein isoform X1 [KO:K05747]
105101582  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
105102215  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
105097105  WASF1; wiskott-Aldrich syndrome protein family member 1 isoform X2 [KO:K05753]
105100710  WASF2; LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
105106341  WASF3; LOW QUALITY PROTEIN: wiskott-Aldrich syndrome protein family member 3 [KO:K06083]
105094564  SP1; transcription factor Sp1 [KO:K04684]
105085948  PLD1; phospholipase D1 isoform X5 [KO:K01115] [EC:3.1.4.4]
105101475  PLD2; phospholipase D2 isoform X2 [KO:K01115] [EC:3.1.4.4]
105099138  SLC5A7; high affinity choline transporter 1 [KO:K14387]
105087953  SLC44A1; choline transporter-like protein 1 isoform X1 [KO:K06515]
105087441  SLC44A4; choline transporter-like protein 4 [KO:K15377]
105087628  SLC44A2; choline transporter-like protein 2 isoform X2 [KO:K15377]
105096686  SLC44A5; choline transporter-like protein 5 [KO:K15377]
116154762  SLC44A3; LOW QUALITY PROTEIN: choline transporter-like protein 3 [KO:K15282]
105100382  SLC22A1; solute carrier family 22 member 1 [KO:K08198]
105086292  SLC22A2; solute carrier family 22 member 2 isoform X1 [KO:K08199]
105086289  SLC22A3; LOW QUALITY PROTEIN: solute carrier family 22 member 3 [KO:K08200]
105090074  SLC22A5; LOW QUALITY PROTEIN: solute carrier family 22 member 5 [KO:K08202]
105090935  SLC22A4; LOW QUALITY PROTEIN: solute carrier family 22 member 4 [KO:K08202]
105106154  CHKB; choline/ethanolamine kinase isoform X3 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105104474  CHKA; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
105086214  HIF1A; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
105092850  JUN; LOW QUALITY PROTEIN: transcription factor AP-1 [KO:K04448]
105086086  FOS; proto-oncogene c-Fos [KO:K04379]
105094646  PCYT1B; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
105101294  PCYT1A; choline-phosphate cytidylyltransferase A isoform X1 [KO:K00968] [EC:2.7.7.15]
105097458  CHPT1; LOW QUALITY PROTEIN: cholinephosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
105085024  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
105087144  PLPP1; phospholipid phosphatase 1 isoform X4 [KO:K01080] [EC:3.1.3.4]
105092818  PLPP3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
105093401  PLPP2; phospholipid phosphatase 2 isoform X1 [KO:K01080] [EC:3.1.3.4]
105106858  DGKZ; diacylglycerol kinase zeta isoform X1 [KO:K00901] [EC:2.7.1.107]
105085854  DGKG; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:2.7.1.107]
105086387  DGKA; diacylglycerol kinase alpha isoform X1 [KO:K00901] [EC:2.7.1.107]
105100871  DGKQ; LOW QUALITY PROTEIN: diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
105105242  DGKD; diacylglycerol kinase delta isoform X3 [KO:K00901] [EC:2.7.1.107]
105097787  DGKE; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
105090091  DGKK; LOW QUALITY PROTEIN: diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
105091657  DGKI; LOW QUALITY PROTEIN: diacylglycerol kinase iota [KO:K00901] [EC:2.7.1.107]
105089770  DGKH; diacylglycerol kinase eta isoform X8 [KO:K00901] [EC:2.7.1.107]
105103471  DGKB; LOW QUALITY PROTEIN: diacylglycerol kinase beta [KO:K00901] [EC:2.7.1.107]
105092299  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105094833  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
105103265  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
105097064  LYPLA1; acyl-protein thioesterase 1 [KO:K06128] [EC:3.1.1.5]
105101383  GPCPD1; glycerophosphocholine phosphodiesterase GPCPD1 isoform X1 [KO:K18695] [EC:3.1.4.2]
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
cdk00564  Glycerophospholipid metabolism
cdk04010  MAPK signaling pathway
cdk04150  mTOR signaling pathway
cdk04151  PI3K-Akt signaling pathway
cdk04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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