Neurofibromin GTPase-activating Protein-related Domains Restore Normal Growth in Nf1-/- Cells

Kelly K. Hiatt, David A. Ingram, Youyan Zhang, Gideon Bollag, D. Wade Clapp

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Members of the Ras superfamily of signaling proteins modulate fundamental cellular processes by cycling between an active GTP-bound conformation and an inactive GDP-bound form. Neurofibromin, the protein product of the NF1 tumor suppressor gene, and p120GAP are GTPase-activating proteins (GAPS) for p21 Ras (Ras) and negatively regulate output by accelerating GTP hydrolysis on Ras. Neurofibromin and p120GAP differ markedly outside of their conserved GAP-related domains (GRDs), and it is therefore unknown if the respective GRDs contribute functional specificity. To address this question, we expressed the GRDs of neurofibromin and p120GAP in primary cells from Nf1 mutant mice in vitro and in vivo. Here we show that expression of neurofibromin GRD, but not the p120GAP GRD, restores normal growth and cytokine signaling in three lineages of primary Nf1-deficient cells that have been implicated in the pathogenesis of neurofibromatosis type 1 (NF1). Furthermore, utilizing a GAP-inactive mutant NF1 GRD identified in a family with NF1, we demonstrate that growth restoration is a function of NF1 GRD GAP activity on p21 Ras. Thus, the GRDs of neurofibromin and p120GAP specify nonoverlapping functions in multiple primary cell types.

Original languageEnglish (US)
Pages (from-to)7240-7245
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number10
DOIs
StatePublished - Mar 9 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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