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Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells
Open accessAbstract
The immunosuppressive drug, rapamycin, interferes with an undefined signaling pathway required for the progression of G1-phase T-cells into S phase. Genetic analyses in yeast indicate that binding of rapamycin to its intracellular receptor, FKBP12, generates a toxic complex that inhibits cell growth in G1 phase. These analyses implicated two related proteins, TOR1 and TOR2, as targets of the FKBP12-rapamycin complex in yeast. In this study, we have used a glutathione S-transferase (GST)-FKBP12-rapamycin affinity matrix to isolate putative mammalian targets of rapamycin (mTOR) from tissue extracts. In the presence of rapamycin, immobilized GST-FKBP12 specifically precipitates similar high molecular mass proteins from both rat brain and murine T-lymphoma cell extracts. Binding experiments performed with rapamycin-sensitive and -resistant mutant clones derived from the YAC-1 T-lymphoma cell line demonstrate that the GST-FKBP12-rapamycin complex recovers significantly lower amounts of the candidate mTOR from rapamycin-resistant cell lines. The latter results suggest that mTOR is a relevant target of rapamycin in these cells. Finally, we report the isolation of a full-length mTOR cDNA that encodes a direct ligand for the FKBP12-rapamycin complex. The deduced amino acid sequence of mTOR displays 42 and 45% identity to those of yeast TOR1 and TOR2, respectively. These results strongly suggest that the FKBP12-rapamycin complex interacts with homologous ligands in yeast and mammalian cells and that the loss of mTOR function is directly related to the inhibitory effect of rapamycin on G1- to S-phase progression in T-lymphocytes and other sensitive cell types.
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“Another example of an MG is Cyclosporin A, which forms a binary complex with cyclophilin able to bind and inhibit calcineurin.80,81”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [81]
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mTOR Signaling in Growth, Metabolism, and Disease
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Metadata
- Authors
- Sabers, C. J., Martin, M. M., Brunn, G. J., Williams, J. M., Dumont, F. J., Wiederrecht, G., & Abraham, R. T.
- Affiliations
- Mayo Clinic (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Abraham, Robert T.
- ORCID
- Abraham, Robert T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-01
- Volume
- 270
- Issue
- 2
- Pages
- 815-822
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2158612356
- Cited by
- 887
- References
- 29
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 28 · 2023: 37 · 2022: 38 · 2021: 37 · 2020: 39 · 2019: 31 · 2018: 25 · 2017: 38 · 2016: 25 · 2015: 31 · 2014: 26 · 2013: 31 · 2012: 29
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM047286, GM47286)
- 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 › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- rapamycin, FKBP12, mTOR, TOR1, TOR2, G1/S transition, T cells, immunosuppressants, rapamycin resistance, YAC-1 cells, cDNA cloning
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, DNA-Binding Proteins, Fungal Proteins, Heat-Shock Proteins, Humans, Molecular Sequence Data, Polyenes, Protein Kinases, Tumor Cells, Cultured, Lymphoma, T-Cell, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Phosphotransferases (Alcohol Group Acceptor), DNA Primers, DNA, Complementary, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Sirolimus, Tacrolimus Binding Proteins, Saccharomyces cerevisiae Proteins, Rats, TOR Serine-Threonine Kinases
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