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 eectors 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 aected, 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 eectors 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. Oncogene (2002) 21, 937 ± 946.

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Lipid-derived metabolites play an important role in the regulation of cell responses to external stimuli, including cell growth control, transformation and apoptosis. Phospholipase D (PLD) is one of the critical elements in the regulation of lipid metabolism and the generation of second messengers, some of them involved in cell growth control. Oncogenic Ras proteins aect the activity of PLD by two alternate mechanisms, involving a positive activation and a feedback negative loop. Here we investigate the involvement of the proto-oncogenic Ras protein in the physiological activation of PLD induced by platelet-derived growth factor (PDGF). Overexpression of the wild type Ras protein or some of its regulatory components, such as Shc or Grb2, induces an ampli®cation of PLD activation by PDGF challenge. Furthermore, blocking the endogenous Ras by expression of the dominant negative mutant, H-Ras-Asn 17 completely eliminated the activation of PLD by PDGF. Thus, PDGF requires a complex system for PLD regulation implying the existence of at least two positive regulatory pathways, a Ras-dependent and a PKC-dependent mechanism. These results imply that PLD is an important element in signaling by Ras proteins that is altered after ras-induced transformation. Oncogene (2000) 19, 431 ± 437.

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