Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 17

Julie A. Mund, Su Jung Park, Abbi E. Smith, Yongzheng He, Li Jiang, Eric Hawley, Michelle J. Roberson, Dana K. Mitchell, Mohannad Abu-Sultanah, Jin Yuan, Waylan K. Bessler, George Sandusky, Shi Chen, Chi Zhang, Steven D. Rhodes, D. Wade Clapp

Research output: Contribution to journalArticle

Abstract

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1-/- Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal-regulated kinase (ERK) in NF1-/- Schwann cells. Genetically engineered Nf1flox/flox;PostnCre+ mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1flox/flox;PostnCre- littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1flox/floxRac1flox/flox;PostnCre+) were completely free of tumors and had normal phospho-ERK activity compared with Nf1flox/flox ;PostnCre+ mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice.

Original languageEnglish (US)
Pages (from-to)9948-9958
Number of pages11
JournalThe Journal of biological chemistry
Volume295
Issue number29
DOIs
StatePublished - Jul 17 2020

Keywords

  • animal model
  • GTPase-activating protein (GAP)
  • kinase signaling
  • neurofibromatosis type 1
  • Ras-related C3 botulinum toxin substrate 1 (Rac1)
  • Schwann cells
  • short hairpin RNA (shRNA)
  • tumor cell biology
  • tumor suppressor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Mund, J. A., Park, S. J., Smith, A. E., He, Y., Jiang, L., Hawley, E., Roberson, M. J., Mitchell, D. K., Abu-Sultanah, M., Yuan, J., Bessler, W. K., Sandusky, G., Chen, S., Zhang, C., Rhodes, S. D., & Clapp, D. W. (2020). Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 17. The Journal of biological chemistry, 295(29), 9948-9958. https://doi.org/10.1074/jbc.RA119.010981