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Transforming mutations of RAC guanosine triphosphatases in human cancers

Masahito Kawazu1, Toshihide Ueno, Kenji Kontani

  • 1Department of Medical Genomics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2013
PubMed

Insights

Activating mutations in Ras-related C3 botulinum toxin substrate (RAC) GTPases, like RAC1 and RAC2, drive cancer cell growth. These RAC GTPase mutants, found in various cancers, represent promising therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Small guanosine triphosphatases (GTPases) of the RAS superfamily act as molecular switches regulating cellular activities.
  • While HRAS, NRAS, and KRAS mutations are common in cancer, the oncogenic roles of other small GTPases, such as Ras-related C3 botulinum toxin substrate (RAC) proteins, are less understood.

Purpose of the Study:

  • To investigate the oncogenic potential of RAC GTPase mutations.
  • To identify novel cancer-driving mutations in RAC1, RAC2, and RAC3.

Main Methods:

  • Analysis of the human sarcoma cell line HT1080 for NRAS and RAC1 mutations.
  • Fibroblast transformation assays.
  • Screening of cell lines and public databases for RAC GTPase mutations.
  • Biochemical assays to determine GTP-bound state preference and GTPase activity.

Main Results:

  • The HT1080 cell line harbors both NRAS(Q61K) and RAC1(N92I) mutations, with RAC1(N92I) identified as a potential essential growth driver.
  • Several activating and transforming missense mutations in RAC1 and RAC2 were identified, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q).
  • RAC1 mutants (P29S, N92I, C157Y) preferentially bind GTP due to rapid GDP/GTP exchange, not reduced GTPase activity.

Conclusions:

  • Activating RAC GTPase mutations are present in diverse human cancers, albeit at a low frequency.
  • These mutant RAC GTPases possess significant transforming capabilities.
  • Mutant RAC GTPases are potential therapeutic targets for cancer treatment.

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