BACKGROUND: The kinase Tor is the target of the immunosuppressive drug rapamycin and is a member of the phosphatidylinositol kinase (PIK)-related kinase family. It plays an essential role in progression through the G1 phase of the cell cycle. The molecular details of Tor signaling remain obscure, however. RESULTS: We isolated two Saccharomyces cerevisiae genes, BMH1 and BMH2, as multicopy suppressors of the growth-inhibitory phenotype caused by rapamycin in budding yeast. BMH1 and BMH2 encode homologs of the 14-3-3 signal transduction proteins. Deletion of one or both BMH genes caused hypersensitivity to rapamycin in a manner that was dependent on gene dosage. In addition, alterations in the phosphopeptide-binding pocket of the 14-3-3 proteins had dramatically different effects on their ability to relieve the growth-arresting rapamycin phenotype. Mutations that prevented 14-3-3 from binding to a phosphoserine motif abolished its ability to confer rapamycin resistance. In contrast, substitution of two residues in 14-3-3 that surround these phosphoserine-binding sites conferred a dominant rapamycin-resistant phenotype. CONCLUSIONS: Our studies reveal 14-3-3 as an important component in rapamycin-sensitive signaling and provide significant new insights into the structure and function of 14-3-3 proteins.
BACKGROUND: The kinase Tor is the target of the immunosuppressive drug rapamycin and is a member of the phosphatidylinositol kinase (PIK)-related kinase family. It plays an essential role in progression through the G1 phase of the cell cycle. The molecular details of Tor signaling remain obscure, however. RESULTS: We isolated two Saccharomyces cerevisiae genes, BMH1 and BMH2, as multicopy suppressors of the growth-inhibitory phenotype caused by rapamycin in budding yeast. BMH1 and BMH2 encode homologs of the 14-3-3 signal transduction proteins. Deletion of one or both BMH genes caused hypersensitivity to rapamycin in a manner that was dependent on gene dosage. In addition, alterations in the phosphopeptide-binding pocket of the 14-3-3 proteins had dramatically different effects on their ability to relieve the growth-arresting rapamycin phenotype. Mutations that prevented 14-3-3 from binding to a phosphoserine motif abolished its ability to confer rapamycin resistance. In contrast, substitution of two residues in 14-3-3 that surround these phosphoserine-binding sites conferred a dominant rapamycin-resistant phenotype. CONCLUSIONS: Our studies reveal 14-3-3 as an important component in rapamycin-sensitive signaling and provide significant new insights into the structure and function of 14-3-3 proteins.
Authors: Timothy R Lezon; Jayanth R Banavar; Marek Cieplak; Amos Maritan; Nina V Fedoroff Journal: Proc Natl Acad Sci U S A Date: 2006-11-30 Impact factor: 11.205
Authors: Paula G Bertram; Jae H Choi; John Carvalho; Ting-Fung Chan; Wandong Ai; X F Steven Zheng Journal: Mol Cell Biol Date: 2002-02 Impact factor: 4.272
Authors: Bruno D Fonseca; Chadi Zakaria; Jian-Jun Jia; Tyson E Graber; Yuri Svitkin; Soroush Tahmasebi; Danielle Healy; Huy-Dung Hoang; Jacob M Jensen; Ilo T Diao; Alexandre Lussier; Christopher Dajadian; Niranjan Padmanabhan; Walter Wang; Edna Matta-Camacho; Jaclyn Hearnden; Ewan M Smith; Yoshinori Tsukumo; Akiko Yanagiya; Masahiro Morita; Emmanuel Petroulakis; Jose L González; Greco Hernández; Tommy Alain; Christian K Damgaard Journal: J Biol Chem Date: 2015-05-04 Impact factor: 5.157