fti-277 and manumycin

Large-conductance Ca(2+)-activated K(+) channels (K(Ca)) in chick ciliary ganglion neurons are regulated by target-derived TGFbeta1. Here we show that TGFbeta1 stimulation of K(Ca) expression was blocked by the structurally dissimilar Ras protein farnesyl transferase inhibitors manumycin-A and FTI-277. A similar effect was produced in ciliary neurons overexpressing RasN17, a widely used dominant-negative form of Ras. Moreover, TGFbeta1-evoked increases in phosphorylation of SMAD2 were reduced by manumycin-A, suggesting that Ras-dependent transduction cascades activated by TGFbeta1 feed back onto SMAD signaling. Thus, Ras is a mediator of pleiotropic TGFbeta1 signaling in developing neurons.

Topics: Alkyl and Aryl Transferases; Animals; Cells, Cultured; Chick Embryo; DNA-Binding Proteins; Enzyme Inhibitors; Farnesyltranstransferase; Ganglia, Parasympathetic; Methionine; Neurons; Phosphorylation; Polyenes; Polyunsaturated Alkamides; Potassium Channels, Calcium-Activated; ras Proteins; Signal Transduction; Smad2 Protein; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1