Cited by 887PI3K/AKT/mTOR signaling in cancerSignaling Pathways in DiseaseAutophagy in Disease and Therapy

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Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells

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Sabers, Candace J., Martin, Mary M., Brunn, Gregory J., Williams, Josie M., Dumont, Francis J., Wiederrecht, Gregory, Abraham, Robert T.·1995·Journal of Biological Chemistry

DOI 10.1074/jbc.270.2.815

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Abstract

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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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)
DOI: 10.1074/jbc.270.2.815
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 9442 d)
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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Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells

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