FIG. 7.

Ras effector pathways in NGF stimulated PC12 cells. Constitutive activation of Raf or PI3 kinase promotes cell cycle arrest and differentiation of PC12 cells into a neuronal phenotype. In contrast, constitutive activation of Ral-GEF promotes proliferation and blocks differentiation upon NGF stimulation. Of the two signaling molecules thought to be influenced by Ral-GEF, PLD and RalBP1, the latter appears to play a more important role in influencing neurite outgrowth in PC12 cells. NGF activates Ras and all three known Ras effector pathways. Ras and the Raf pathway are activated for hours, and this chronic activation is required for NGF-induced neurite outgrowth. In contrast, the Ral-GEF pathway (as assessed by the content of GTP-Ral) is activated by NGF for only ∼20 min. Thus, Ral-GEF signaling may function to delay the onset of cell cycle arrest and neurite outgrowth upon NGF stimulation. Dissociation of the Ral-GEF pathway from Ras activation may be necessary to allow NGF-induced differentiation of PC12 cells to occur.