A mammalian protein targeted by G1-arresting rapamycin–receptor complex

Brown, Eric J.; Albers, Mark W.; Bum Shin, Tae; ichikawa, Kazuo; Keith, Curtis T.; Lane, William S.; Schreiber, Stuart L.

doi:10.1038/369756a0

Cited by 2,053PI3K/AKT/mTOR signaling in cancerSignaling Pathways in DiseaseProtein Kinase Regulation and GTPase Signaling

A mammalian protein targeted by G1-arresting rapamycin–receptor complex

Brown, Eric J., Albers, Mark W., Bum Shin, Tae, ichikawa, Kazuo, Keith, Curtis T., Lane, William S., Schreiber, Stuart L.·1994·Nature

DOI 10.1038/369756a0

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Abstract

The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.

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These natural products remodeled their target proteins (immunophilins), recruiting novel interacting proteins to form entirely new ternary complexes.
“their combined research revealed that these natural products remodeled their target proteins, a group of proteins named the immunophilins, recruiting novel interacting proteins to form entirely new ternary complexes (liu et al. 1991;Brown et al. 1994;Sabatini et al. 1994).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Brown et al. 1994
FK506 and rapamycin bind FKPB12, and these binary complexes induce inhibitory interactions with calcineurin and FRAP/mTOR, respectively.
“The former two bind to FKPB12 and these binary complexes induce inhibitory interactions with calcineurin and FRAP (later mTOR, mammalian Target of Rapamycin), respectively.78,79”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [78]

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[New aspects of research upon the yeast Saccharomyces cerevisiae [PSI+] prion].
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Authors: Brown, E. J., Albers, M. W., Bum Shin, T., ichikawa, K., Keith, C. T., Lane, W. S., & Schreiber, S. L.
Affiliations: Howard Hughes Medical Institute (US)
Harvard University (US)
ORCID: Brown, Eric J.
Albers, Mark W.
Schreiber, Stuart L.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1994-06
Volume: 369
Issue: 6483
Pages: 756-758
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/369756a0
OpenAlex: W2057106513
Cited by: 2,053
References: 28
Citations by year: 2026: 35 · 2025: 51 · 2024: 60 · 2023: 70 · 2022: 66 · 2021: 80 · 2020: 61 · 2019: 67 · 2018: 70 · 2017: 75 · 2016: 73 · 2015: 97 · 2014: 85 · 2013: 91 · 2012: 83
FWCI: 27.59
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
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: rapamycin, FKBP12, FRAP, TOR1, TOR2, G1 cell cycle arrest, p70 S6 kinase, cyclin-dependent kinases, mitogenic signaling, lipid kinase, protein binding, cDNA cloning
MeSH terms: Amino Acid Sequence, Animals, Carrier Proteins, Cattle, Cell Line, Cloning, Molecular, Fungal Proteins, Heat-Shock Proteins, Humans, Molecular Sequence Data, Polyenes, Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae, G1 Phase, Sequence Homology, Amino Acid, Phosphotransferases (Alcohol Group Acceptor), DNA, Complementary, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Immunophilins, Sirolimus, Tacrolimus Binding Proteins, Saccharomyces cerevisiae Proteins, TOR Serine-Threonine Kinases

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