The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
The FKBP12-Rapamycin-binding Domain Is Required for FKBP12-Rapamycin-associated Protein Kinase Activity and G1 Progression
Open accessAbstract
The immunosuppressant rapamycin, in complex with its cellular receptor FKBP12, targets the cellular protein FKBP12-rapamycin-associated protein/mammalian target of rapamycin/rapamycin and FKBP12 target 1 (FRAP/mTOR/RAFT1) and inhibits/delays G1 cell cycle progression in mammalian cells. As a member of the novel phosphatidylinositol kinase-related kinase family, FRAP's kinase activity is essential for its signaling function. The FKBP12-rapamycin binding (FRB) domain in FRAP is also speculated to play an important role in FRAP function and signaling. However, the biochemical and physiological functions of FRB, as well as the mechanism for rapamycin inhibition, have been unclear. The present study focuses on investigation of FRB's role and the functional relationship between FRB domain and kinase domain in FRAP. Microinjection of purified FRB protein into human osteosarcoma MG63 cells results in a drastic blockage of the G1 to S cell cycle progression; such a dominant negative effect is reversed by a point mutation (Trp2027 --> Phe). The same mutation also abolishes kinase activity of FRAP without affecting ATP binding, and truncation studies suggest that upstream sequences including FRB are required for kinase activity in vitro. Given these data, we propose a model for FRAP function, in which the FRB domain is required for activation of the kinase domain, possibly through the interaction with an upstream activator. In addition, our observations provide direct evidence linking FRAP function to G1 cell cycle progression.
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“Notably, however, the kinase N-lobe features a large insertion corresponding to the FKBP12-rapamycin binding (FRB) domain (Chen et al., 1995; Chiu et al., 1994; Vilella-Bach et al., 1999) specific to mTORC1 among the PIKKs.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Vilella-Bach et al., 1999
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Osmotic Stress Signaling and Osmoadaptation in Yeasts
Hohmann, S. (2002) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.66.2.300-372.2002 · Cited by 1,773
Fingar, D. C., & Blenis, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207542 · Cited by 1,264
mTOR kinase structure, mechanism and regulation
Yang, H., Rudge, D. G., Koos, J. D., Vaidialingam, B., Yang, H. J., & Pavletich, N. P. (2013) · Nature · doi:10.1038/nature12122 · Cited by 1,075
Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling
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Metadata
- Authors
- Vilella-Bach, M., Nuzzi, P., Fang, Y., & Chen, J.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Chen, Jie
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-02
- Volume
- 274
- Issue
- 7
- Pages
- 4266-4272
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2000281583
- Cited by
- 154
- References
- 48
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 8 · 2014: 3 · 2013: 9 · 2012: 3
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- FRAP, mTOR, G1 cell cycle progression, rapamycin, immunosuppressants, dominant negative effect, osteosarcoma cells, ATP binding
- MeSH terms
- Amino Acid Sequence, Binding Sites, Carrier Proteins, Catalysis, Cell Line, Humans, Immunosuppressive Agents, Microinjections, Molecular Sequence Data, Protein Kinases, Serine, Tryptophan, Tumor Cells, Cultured, G1 Phase, S Phase, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, Amino Acid Substitution, Immunophilins, Sirolimus, Tacrolimus Binding Proteins, TOR Serine-Threonine Kinases
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