Guanine Nucleotide Dissociation Stimulators
Small Ras-like GTPases function as bipolar molecular switches to control a variety of cellular processes (Bourne et al. 1991a,b). The switches cycle between GTP- and GDP-bound states. Evidence from oncogenic mutants of Ras identified the GTP-bound form as the active state, a conclusion that has been substantiated by the effects of dominant negative mutants and from observations that the Ras GTP to GDP ratio is increased following growth factor or cytokine stimulation of cells (e. g., Stacey et al. 1991; Satoh et al. 1991). Ras and other similar proteins possess slow intrinsic GTPase activities that can be catalytically augmented by GTPase activating proteins (GAPs) (Trahey and McCormick 1987). The existence of a second catalytic factor which would convert Ras to the GTP-bound form was expected because of the very low k off for GDP from the p21 Ras protein (<0.01min−1) in the presence of physiologically relevant concentrations of Mg2+ (Hall and Self 1986; Neal et al. 1988). This slow off-rate would lead to the irreversible accumulation of inactive Ras-GDP if no mechanism existed to catalyze conversion to the Ras-GTP state. Mutations which confer abnormally high nucleotide release rates can, however, abrogate the necessity for such a mechanism and activate the transforming potential of the Ras proteins (Lacal and Aaronson 1986; Feig and Cooper 1988b).
KeywordsSmall GTPases Guanine Nucleotide Guanine Nucleotide Exchange Factor GTPase Activate Protein Nucleoside Diphosphate Kinase
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