Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K.
Ras proteins are molecular switches that control signaling pathways critical in the onset of a variety of human cancers. The signaling pathways activated by Ras proteins are those controlled by its direct effectors such as the serine-threonine protein kinase Raf-1, the exchange factor for other GTPases Ral-GDS, and the lipid kinase PI3K. As a consequence of Ras activation, a number of additional enzymes are affected, including several members of the serine-threonine intracellular proteins kinases as well as enzymes related to phospholipid metabolism regulation such as phospholipases A2 and D, and choline kinase. The precise mechanisms by which ras oncogenes impinge into these later molecules and their relevance to the onset of the carcinogenic process is still not fully understood. Here we have investigated the mechanism of regulation of choline kinase by Ras proteins and found no direct link between PLD and choline kinase activation. We provide evidence that Ras proteins regulate the activity of choline kinase through its direct effectors Ral-GDS and PI3K, while the Raf pathways seems to be not relevant in this process. The importance of Ras-dependent activation of choline kinase is discussed.
Ramírez de Molina
Ana
A
Instituto de Investigaciones Biomédicas, CSIC, Arturo Duperier 4, 28029 Madrid, Spain.
Penalva
Verónica
V
Lucas
Luisa
L
Lacal
Juan Carlos
JC
D016475:3T3 Cells / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002797:Choline Kinase / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D004790:Enzyme Induction; D011905:Genes, ras; D006160:Guanosine Triphosphate / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D007668:Kidney / Q000166:cytology; D051379:Mice; D020125:Mutation, Missense; D010739:Phospholipase D / Q000235:genetics / Q000502:physiology; D010767:Phosphorylcholine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015290:Second Messenger Systems; D014162:Transfection; D020726:ral Guanine Nucleotide Exchange Factor / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D020726:ral Guanine Nucleotide Exchange Factor; D010767:Phosphorylcholine; D006160:Guanosine Triphosphate; D002797:Choline Kinase; D019908:Proto-Oncogene Proteins c-raf; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins