KEGG   PATHWAY: mpah05231
Entry
mpah05231                   Pathway                                
Name
Choline metabolism in cancer - Mus pahari (shrew mouse)
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
mpah05231  Choline metabolism in cancer
mpah05231

Organism
Mus pahari (shrew mouse) [GN:mpah]
Gene
110320006  Egf; pro-epidermal growth factor isoform X1 [KO:K04357]
110312881  Pdgfa; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
110334927  Pdgfb; platelet-derived growth factor subunit B [KO:K17386]
110327924  Pdgfd; platelet-derived growth factor D isoform X1 [KO:K05450]
110319957  Pdgfc; platelet-derived growth factor C isoform X1 [KO:K05450]
110330480  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
110331028  Pdgfra; platelet-derived growth factor receptor alpha isoform X1 [KO:K04363] [EC:2.7.10.1]
110333065  Pdgfrb; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:2.7.10.1]
110331195  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
110335780  Sos1; son of sevenless homolog 1 [KO:K03099]
110324314  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
110318967  GTPase HRas-like isoform X1 [KO:K02833]
110319567  Hras; GTPase HRas [KO:K02833]
110338480  GTPase HRas-like [KO:K02833]
110333346  GTPase HRas-like [KO:K02833]
110316221  Kras; GTPase KRas isoform X1 [KO:K07827]
110320340  Nras; GTPase NRas [KO:K07828]
110314893  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110327244  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110326321  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
110329343  Mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
110320020  Mapk3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
110317707  Ralgds; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
110330449  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
110332652  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
110325466  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
110317835  Pla2g4b; cytosolic phospholipase A2 beta [KO:K16342] [EC:3.1.1.4]
110319432  Pla2g4e; cytosolic phospholipase A2 epsilon [KO:K16342] [EC:3.1.1.4]
110318953  Pla2g4d; cytosolic phospholipase A2 delta [KO:K16342] [EC:3.1.1.4]
110336949  Pla2g4c; cytosolic phospholipase A2 gamma [KO:K16342] [EC:3.1.1.4]
110318542  Pla2g4f; cytosolic phospholipase A2 zeta isoform X1 [KO:K16342] [EC:3.1.1.4]
110321382  Pla2g4a; cytosolic phospholipase A2 isoform X1 [KO:K16342] [EC:3.1.1.4]
110323448  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110319750  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110327251  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110328811  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110336420  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
110322865  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110337888  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
110317258  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110324386  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110322284  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110318637  Tsc1; hamartin isoform X1 [KO:K07206]
110338315  Tsc2; tuberin isoform X1 [KO:K07207]
110316300  Rheb; GTP-binding protein Rheb [KO:K07208]
110323363  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
110315992  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
110331448  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
110336761  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
110316115  Pip5k1b; phosphatidylinositol 4-phosphate 5-kinase type-1 beta isoform X1 [KO:K00889] [EC:2.7.1.68]
110326224  Pip5k1c; phosphatidylinositol 4-phosphate 5-kinase type-1 gamma isoform X1 [KO:K00889] [EC:2.7.1.68]
110320843  Pip5k1a; phosphatidylinositol 4-phosphate 5-kinase type-1 alpha [KO:K00889] [EC:2.7.1.68]
110314062  Was; wiskott-Aldrich syndrome protein [KO:K05747]
110339030  Rac1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
110334678  Rac2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
110331528  Rac3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
110326371  Wasf1; wiskott-Aldrich syndrome protein family member 1 [KO:K05753]
110322998  Wasf2; wiskott-Aldrich syndrome protein family member 2 [KO:K05748]
110312868  Wasf3; wiskott-Aldrich syndrome protein family member 3 isoform X1 [KO:K06083]
110334488  Sp1; transcription factor Sp1 isoform X1 [KO:K04684]
110331978  Pld2; LOW QUALITY PROTEIN: phospholipase D2 [KO:K01115] [EC:3.1.4.4]
110320262  Pld1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
110335824  Slc5a7; high affinity choline transporter 1 [KO:K14387]
110322966  Slc44a1; choline transporter-like protein 1 isoform X1 [KO:K06515]
110327355  Slc44a2; choline transporter-like protein 2 isoform X1 [KO:K15377]
110320036  Slc44a5; choline transporter-like protein 5 isoform X1 [KO:K15377]
110335819  Slc44a4; choline transporter-like protein 4 [KO:K15377]
110320541  Slc44a3; choline transporter-like protein 3 isoform X1 [KO:K15282]
110338308  Slc22a1; solute carrier family 22 member 1 [KO:K08198]
110338260  solute carrier family 22 member 2 [KO:K08199]
110338252  Slc22a3; solute carrier family 22 member 3 [KO:K08200]
110331243  solute carrier family 22 member 21 [KO:K08202]
110332109  solute carrier family 22 member 4 isoform X1 [KO:K08202]
110332015  solute carrier family 22 member 5 [KO:K08202]
110334735  Chkb; choline/ethanolamine kinase [KO:K14156] [EC:2.7.1.32 2.7.1.82]
110334224  Chka; choline kinase alpha isoform X1 [KO:K14156] [EC:2.7.1.32 2.7.1.82]
110323979  Hif1a; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
110323252  Jun; transcription factor AP-1 [KO:K04448]
110324365  Fos; proto-oncogene c-Fos isoform X1 [KO:K04379]
110313519  Pcyt1b; choline-phosphate cytidylyltransferase B isoform X1 [KO:K00968] [EC:2.7.7.15]
110329551  Pcyt1a; choline-phosphate cytidylyltransferase A [KO:K00968] [EC:2.7.7.15]
110326383  Chpt1; cholinephosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
110319649  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
110326500  Plpp2; phospholipid phosphatase 2 isoform X1 [KO:K01080] [EC:3.1.3.4]
110328777  Plpp1; phospholipid phosphatase 1 isoform X1 [KO:K01080] [EC:3.1.3.4]
110323294  Plpp3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
110314050  Dgkk; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
110325282  Dgkh; diacylglycerol kinase eta isoform X1 [KO:K00901] [EC:2.7.1.107]
110324186  Dgkb; diacylglycerol kinase beta isoform X1 [KO:K00901] [EC:2.7.1.107]
110331977  Dgke; diacylglycerol kinase epsilon [KO:K00901] [EC:2.7.1.107]
110316028  Dgki; diacylglycerol kinase iota isoform X1 [KO:K00901] [EC:2.7.1.107]
110319038  Dgkz; diacylglycerol kinase zeta isoform X1 [KO:K00901] [EC:2.7.1.107]
110322268  Dgkd; diacylglycerol kinase delta isoform X1 [KO:K00901] [EC:2.7.1.107]
110326436  Dgka; diacylglycerol kinase alpha [KO:K00901] [EC:2.7.1.107]
110330508  Dgkq; diacylglycerol kinase theta [KO:K00901] [EC:2.7.1.107]
110329525  Dgkg; diacylglycerol kinase gamma isoform X1 [KO:K00901] [EC:2.7.1.107]
110332714  Prkca; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
110320075  Prkcb; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
110336366  Prkcg; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
110338757  Lypla1; acyl-protein thioesterase 1 isoform X1 [KO:K06128] [EC:3.1.1.5]
110318489  Gpcpd1; LOW QUALITY PROTEIN: glycerophosphocholine phosphodiesterase GPCPD1 [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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Foster DA, Xu L
  Title
Phospholipase D in cell proliferation and cancer.
  Journal
Mol Cancer Res 1:789-800 (2003)
Reference
  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
mpah00564  Glycerophospholipid metabolism
mpah04010  MAPK signaling pathway
mpah04150  mTOR signaling pathway
mpah04151  PI3K-Akt signaling pathway
mpah04810  Regulation of actin cytoskeleton
KO pathway
ko05231   
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