title: Transforming mutations of RAC guanosine triphosphatases in human cancers.
abstract: Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.
authors: Department of Medical Genomics, Graduate School of Medicine,  University of Tokyo, Tokyo 113-0033,  Japan.
authors: Masahito
authors: M
authors: Kawazu
authors: Toshihide
authors: T
authors: Ueno
authors: Kenji
authors: K
authors: Kontani
authors: Yoshitaka
authors: Y
authors: Ogita
authors: Mizuo
authors: M
authors: Ando
authors: Kazutaka
authors: K
authors: Fukumura
authors: Azusa
authors: A
authors: Yamato
authors: Manabu
authors: M
authors: Soda
authors: Kengo
authors: K
authors: Takeuchi
authors: Yoshio
authors: Y
authors: Miki
authors: Hiroyuki
authors: H
authors: Yamaguchi
authors: Takahiko
authors: T
authors: Yasuda
authors: Tomoki
authors: T
authors: Naoe
authors: Yoshihiro
authors: Y
authors: Yamashita
authors: Toshiaki
authors: T
authors: Katada
authors: Young Lim
authors: YL
authors: Choi
authors: Hiroyuki
authors: H
authors: Mano
mesh_terms: D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins
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