Activation of the Ras signalling pathway by GTP loading of Ras proteins is the critical step that connects the events at the plasma membrane with cellular and nuclear responses [1]. The replacement of p21Ras-bound GDP with GTP is facilitated by guanine nucleotide exchange factors that convert inactive p21Ras-GDP proteins into the active p21Ras-GTP conformation, enabling p21Ras-GTP to transduce external signals to internal events [2,3]. Conversely, the return of the active form of p21Ras into the inactive form is preceded by the hydrolysis of p21Ras-GTP to GDP [1±4], a process that is not only intrinsic to Ras proteins but also increased by the GTPase activating protein (GAP).Only post-translationally modified Ras proteins (those that are farnesylated and carboxymethylated) are translocated to the plasma membrane whereby they can be activated by the guanine nucleotide exchange factors [5]. Farnesylation of p21Ras is catalyzed by the enzyme farnesyltransferase (FTase) [6,7] and is an obligatory initial step that targets Ras proteins to the plasma membrane for future activa- Diabetologia (1999) Summary We have recently demonstrated that insulin activates farnesyltransferase (FTase) and thereby increases the amounts of cellular farnesylated p21Ras in 3T3-L1 fibroblasts, adipocytes and vascular smooth muscle cells. We postulated that hyperinsulinaemia might considerably increase the the cellular pool of farnesylated p21Ras available for activation by other growth factors. To examine the role of in vivo hyperinsulinaemia in regulating farnesylated p21Ras, we measured the amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. Liver, aorta, and skeletal muscle of ob/ob mice, and mice made obese and hyperinsulinaemic by injection of gold-thioglucose contained greater amounts of farnesylated p21Ras than tissues of their lean normoinsulinaemic counterparts. Similarly, farnesylated p21Ras was increased (67 vs 35 % in control animals, p < 0.01) in the livers of hyperinsulinaemic Zucker rats (fa/fa). Reduction of hyperinsulinaemia by exercise training (2 h/day for 7±8 weeks) resulted in decreases in the amounts of farnesylated p21Ras in these animals. Increased farnesylated p21Ras in hyperinsulinaemic animals reflected increasing increments in the activity of FTase in ob/ob mice (2-fold increase) and fa/fa Zucker rats (3.5-fold increase), while the total amounts of Ras proteins remained unchanged. In contrast to insulin-resistant hyperinsulinaemic animals, denervated insulin-resistant rat soleus muscle (in the presence of normoinsulinaemia) showed normal amounts of farnesylated p21Ras. In summary, these data confirm increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals. [Diabetologia (1999) 42: 310±316]
We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21 ras (Goalstone, M. L., and Draznin, B. (1996) J. Biol. Chem. 271, 27585-27589). We postulated that this aspect of insulin action might explain the "priming effect" of insulin on the cellular response to other growth factors. In the present study, we show the specificity of the effect of insulin on FTase. Insulin, but not insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), or platelet-derived growth factor (PDGF), stimulated the phosphorylation of the ␣-subunit of FTase and the amounts of farnesylated p21ras . Even though all four growth factors utilized the Ras pathway to stimulate DNA synthesis, only insulin used this pathway to influence FTase. Insulin failed to stimulate FTase in cells expressing the chimeric insulin/ IGF-1 receptor and in cells derived from the insulin receptor knock-out animals. Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, ␣-hydroxyfarnesylphosphonic acid. We conclude that the effect of insulin on FTase is specific, requires the presence of an intact insulin receptor, and serves as a conduit for the "priming" influence of insulin on the nuclear effects of other growth factors.
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