Ras functions

Ral has attracted much interest in recent years, not least because it was demonstrated to mediate part of Ras function as described above. In contrast to Rap, which rather inhibits Ras signaling, Ral is part of one of the essential Ras-activated pathways. Moreover, it has proved to be acting in parallel with the Raf pathway in cell transformation induced by oncogenic Ras [37, 77]. The case of Ral demonstrates the complexity - and the incomplete knowledge and understanding - of signal transduction. Ral can also be activated by Rap mediated by Rif [103] and, alternatively, by binding of a calcium/calmodulin complex to the Ral C-terminus which obviously does not affect the nucleotide state of Ral [111]. 

In future, two developments may be expected. On the one hand, elaborated biophysical methods will measure interactions in the cellular context and dissect complex biological patterns. On the other hand, established physico-chemical techniques mainly based on fluorescence will be utilized in high throughput screens to investigate new substances upon their interference with Ras function. 

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

There are several possible explanations to account for this apparent lack of toxicity. Some geranylgeranylated Ras-related proteins might compensate for the loss of Ras function (see, e.g., [46]). Alternatively inhibition of farnesyl transferase may reduce Ras activity below the level required for transformation, yet allow sufficient Ras activity for maintaining normal cell viability [47]. Alternatively, a different signaling pathway may be activated when Ras is not anchored to the plasma membrane. 

Roy S, Luetterforst R, Harding A, et al. Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains. Nat Cell Biol 1999 1(2) 98-105. 

To function, Ras must be attached to the plasma membrane. Translocation from the cytoplasm to membrane requires a series of posttranslational modifications that begin with farnesylation of the cysteine residue, the fourth amino acid residue from the C terminus of the protein, by famesyl protein transferase (FPTase) (64). Attachment of the hydrophobic 15-carbon lipid farnesyl group allows Ras molecule insertion into the plasma membrane and is crucial for Ras signaling activity and transformation properties. As farnesylation is required for oncogenic Ras function, FPTase inhibitors (FTIs) are obvious candidate antineoplastic agents. Several drugs that inhibit Ras farnesylation are at various stages of clinical development (65). 

Farnesylatlon ofRas mediates Interaction with the cell membrane, which Is regulred for proper Ras function. 

An important step forward in the understanding of the molecular basis of the Ras function was achieved when structural information and biochemical and genetic data became available for the following questions ... 

How does the occurrence of oncogenic mutations favored at particular positions fit into the structural picture of the Ras function ... 

Although this report has emphasized DoD-FDA relations, the discussion has invariably included DoD-contractor relations and FDA-drug firm relations. It has thus led to the complex three-way relationship among DoD, contractors and drug firms, and FDA. One of the important reasons for locating an RA function in DATSD(CBD) is to clarify DoD policy and procedures for managing this three-way relationship other than in an ad hoc manner. Furthermore, FDA deference to private firms when DoD has a major interest in the... 

The potential maximum could not be fitted by a parabola as in the singlet case a rA functional dependence was found to be more adequate. The deep chemical well at 1.045 A was represented by a Morse function, which reproduced Ginter s spectroscopic results.160... 

Interestingly, members of the Faller laboratory demonstrated that chronic PMA treatment of mouse fibroblasts, which depletes PKC activation, caused a K-Ras-dependent apoptotic mechanism [10] that was not well suppressed by the apoptotic inhibitor Z-VADfmk [11]. Thus, any deregulation of PKC activity, whether stimulation or suppression, may alter K-Ras control of cell survival in a context-dependent manner, either directly or indirectly, further highlighting the complexity of interfering in Ras function in a controllable way. 

Roberts, M.J., et al. (2006). Hydrophilic anihnogeranyl diphosphate prenyl analogues Are Ras function inhibitors. Biochemistry 45 15862-15872. 

Lundherg AS, Weinherg RA. Functional inactivation of the 41. retinohlastoma protein requires sequential modihcation by at... 

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