Abstract
We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21 (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 alpha-subunit of FTase and the amounts of farnesylated p21. 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, alpha-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.
Highlights
We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21ras
Because insulin appears to stimulate FTase activity, resulting in increased amounts of farnesylated p21ras that are available for activation, and may regulate the cellular responsiveness to other growth factors, we examined whether the potentiating effects of insulin on the cellular nuclear responses to insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) were mediated by the effect of insulin on FTase
Influence of Growth factors on FTase and BrdUrd Incorporation in 3T3-L1 Fibroblasts—In initial experiments, we compared the effects of insulin on the amounts of farnesylated p21ras in 3T3-L1 fibroblasts with the effects of IGF-1, EGF, and PDGF: the growth-modulating hormones that utilize the Ras pathway
Summary
SPECIFICITY OF INSULIN ACTION AND POTENTIATION OF NUCLEAR EFFECTS OF INSULIN-LIKE GROWTH FACTOR-1, EPIDERMAL GROWTH FACTOR, AND PLATELET-DERIVED GROWTH FACTOR*. 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. A major metabolic hormone and a mild mitogen, recently has been shown to augment the ability of other growth factors to activate p21ras [1, 2] This aspect of insulin action has been attributed to the stimulatory effect of insulin on farnesyltransferase (FTase) activity [3]. Because insulin appears to stimulate FTase activity, resulting in increased amounts of farnesylated p21ras that are available for activation, and may regulate the cellular responsiveness to other growth factors, we examined whether the potentiating effects of insulin on the cellular nuclear responses to IGF-1, EGF, and PDGF were mediated by the effect of insulin on FTase
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