KEGG   PATHWAY: mmu05231
Entry
mmu05231                    Pathway                                
Name
Choline metabolism in cancer - Mus musculus (house 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
mmu05231  Choline metabolism in cancer
mmu05231

Organism
Mus musculus (house mouse) [GN:mmu]
Gene
100434  Slc44a1; solute carrier family 44, member 1 [KO:K06515]
104418  Dgkz; diacylglycerol kinase zeta [KO:K00901] [EC:2.7.1.107]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]
110197  Dgkg; diacylglycerol kinase, gamma [KO:K00901] [EC:2.7.1.107]
110524  Dgkq; diacylglycerol kinase, theta [KO:K00901] [EC:2.7.1.107]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
12651  Chkb; choline kinase beta [KO:K14156] [EC:2.7.1.32 2.7.1.82]
12660  Chka; choline kinase alpha [KO:K14156] [EC:2.7.1.32 2.7.1.82]
13026  Pcyt1a; phosphate cytidylyltransferase 1, choline, alpha isoform [KO:K00968] [EC:2.7.7.15]
13139  Dgka; diacylglycerol kinase, alpha [KO:K00901] [EC:2.7.1.107]
13645  Egf; epidermal growth factor [KO:K04357]
13649  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
13685  Eif4ebp1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
14281  Fos; FBJ osteosarcoma oncogene [KO:K04379]
14784  Grb2; growth factor receptor bound protein 2 [KO:K04364]
15251  Hif1a; hypoxia inducible factor 1, alpha subunit [KO:K08268]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16476  Jun; jun proto-oncogene [KO:K04448]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
170758  Rac3; Rac family small GTPase 3 [KO:K07861]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
18590  Pdgfa; platelet derived growth factor, alpha [KO:K04359]
18591  Pdgfb; platelet derived growth factor, B polypeptide [KO:K17386]
18595  Pdgfra; platelet derived growth factor receptor, alpha polypeptide [KO:K04363] [EC:2.7.10.1]
18596  Pdgfrb; platelet derived growth factor receptor, beta polypeptide [KO:K05089] [EC:2.7.10.1]
18607  Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
18717  Pip5k1c; phosphatidylinositol-4-phosphate 5-kinase, type 1 gamma [KO:K00889] [EC:2.7.1.68]
18719  Pip5k1b; phosphatidylinositol-4-phosphate 5-kinase, type 1 beta [KO:K00889] [EC:2.7.1.68]
18720  Pip5k1a; phosphatidylinositol-4-phosphate 5-kinase, type 1 alpha [KO:K00889] [EC:2.7.1.68]
18750  Prkca; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
18752  Prkcg; protein kinase C, gamma [KO:K19663] [EC:2.7.11.13]
18777  Lypla1; lysophospholipase 1 [KO:K06128] [EC:3.1.1.5]
18783  Pla2g4a; phospholipase A2, group IVA (cytosolic, calcium-dependent) [KO:K16342] [EC:3.1.1.4]
18803  Plcg1; phospholipase C, gamma 1 [KO:K01116] [EC:3.1.4.11]
18805  Pld1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
18806  Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
19012  Plpp1; phospholipid phosphatase 1 [KO:K01080] [EC:3.1.3.4]
19353  Rac1; Rac family small GTPase 1 [KO:K04392]
19354  Rac2; Rac family small GTPase 2 [KO:K07860]
19730  Ralgds; ral guanine nucleotide dissociation stimulator [KO:K08732]
19744  Rheb; Ras homolog enriched in brain [KO:K07208]
20517  Slc22a1; solute carrier family 22 (organic cation transporter), member 1 [KO:K08198]
20518  Slc22a2; solute carrier family 22 (organic cation transporter), member 2 [KO:K08199]
20519  Slc22a3; solute carrier family 22 (organic cation transporter), member 3 [KO:K08200]
20520  Slc22a5; solute carrier family 22 (organic cation transporter), member 5 [KO:K08202]
20662  Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
20663  Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
20683  Sp1; trans-acting transcription factor 1 [KO:K04684]
211429  Pla2g4b; phospholipase A2, group IVB (cytosolic) [KO:K16342] [EC:3.1.1.4]
212862  Chpt1; choline phosphotransferase 1 [KO:K00994] [EC:2.7.8.2]
213603  Slc44a3; solute carrier family 44, member 3 [KO:K15282]
217480  Dgkb; diacylglycerol kinase, beta [KO:K00901] [EC:2.7.1.107]
22084  Tsc2; TSC complex subunit 2 [KO:K07207]
22376  Was; Wiskott-Aldrich syndrome [KO:K05747]
227333  Dgkd; diacylglycerol kinase, delta [KO:K00901] [EC:2.7.1.107]
232889  Pla2g4c; phospholipase A2, group IVC (cytosolic, calcium-independent) [KO:K16342] [EC:3.1.1.4]
236899  Pcyt1b; phosphate cytidylyltransferase 1, choline, beta isoform [KO:K00968] [EC:2.7.7.15]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
242259  Slc44a5; solute carrier family 44, member 5 [KO:K15377]
242687  Wasf2; WASP family, member 2 [KO:K05748]
245880  Wasf3; WASP family, member 3 [KO:K06083]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
271844  Pla2g4f; phospholipase A2, group IVF [KO:K16342] [EC:3.1.1.4]
30805  Slc22a4; solute carrier family 22 (organic cation transporter), member 4 [KO:K08202]
320127  Dgki; diacylglycerol kinase, iota [KO:K00901] [EC:2.7.1.107]
329502  Pla2g4e; phospholipase A2, group IVE [KO:K16342] [EC:3.1.1.4]
331374  Dgkk; diacylglycerol kinase kappa [KO:K00901] [EC:2.7.1.107]
380921  Dgkh; diacylglycerol kinase, eta [KO:K00901] [EC:2.7.1.107]
50784  Plpp2; phospholipid phosphatase 2 [KO:K01080] [EC:3.1.3.4]
54635  Pdgfc; platelet-derived growth factor, C polypeptide [KO:K05450]
56077  Dgke; diacylglycerol kinase, epsilon [KO:K00901] [EC:2.7.1.107]
56517  Slc22a21; solute carrier family 22 (organic cation transporter), member 21 [KO:K08202]
56717  Mtor; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
58988  Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
63993  Slc5a7; solute carrier family 5 (choline transporter), member 7 [KO:K14387]
64930  Tsc1; TSC complex subunit 1 [KO:K07206]
67916  Plpp3; phospholipid phosphatase 3 [KO:K01080] [EC:3.1.3.4]
68682  Slc44a2; solute carrier family 44, member 2 [KO:K15377]
70129  Slc44a4; solute carrier family 44, member 4 [KO:K15377]
71785  Pdgfd; platelet-derived growth factor, D polypeptide [KO:K05450]
72508  Rps6kb1; ribosomal protein S6 kinase, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
74182  Gpcpd1; glycerophosphocholine phosphodiesterase 1 [KO:K18695] [EC:3.1.4.2]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
78390  Pla2g4d; phospholipase A2, group IVD [KO:K16342] [EC:3.1.1.4]
83767  Wasf1; WASP family, member 1 [KO:K05753]
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
mmu00564  Glycerophospholipid metabolism
mmu04010  MAPK signaling pathway
mmu04150  mTOR signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04810  Regulation of actin cytoskeleton
KO pathway
ko05231   

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