Neurofibromin GTPase-activating protein-related domains restore normal growth in Nf1-/- cells

Members of the Ras superfamily of signaling proteins modulate fundamental c ellular processes by cycling between ari:active GTP-bound conformation and an inactive GDP-bound form. Neurofibromin, the protein product of the NF1 t urner suppressor gene, and p120GAP are GTPase-activating proteins (GAPs) fo r p21(Ras) (Ras) and negatively regulate output by accelerating GTP hydroly sis On Ras. Neurofibromin and p120GAP differ markedly outside of their cons erved GAP-related domains (GRDs), and it is therefore unknown if the respec tive GRDs contribute functional specificity. To address this question, we e xpressed the GRDs of neurofibromin and p120GAP in primary cells from Nf1 mu tant mice in vitro and in vivo, Here we show that expression of neurofibrom in GRD, but not the p120GAP GRD, restores normal growth and cytokine signal ing in three lineages of primary Nf1-deficient cells that have been implica ted in the pathogenesis of neurofibromatosis type 1 (NF1). Furthermore, uti lizing a GAP-inactive mutant NF1 GRD identified in a family with NF1, we de monstrate that growth restoration is a function of NF1 GRD GAP activity on p21(Ras), Thus, the GRDs of neurofibromin and p120GAP specify nonoverlappin g functions in multiple primary cell types.