Cited by 155PI3K/AKT/mTOR signaling in cancerSignaling Pathways in DiseaseProtein Kinase Regulation and GTPase Signaling

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 access

Vilella-Bach, Montserrat, Nuzzi, Paul, Fang, Yimin, Chen, Jie·1999·Journal of Biological Chemistry

DOI 10.1074/jbc.274.7.4266

Open this paper in CoChat — free account

Abstract

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.

Integrity signals

Registry

Crossref · 10.1074/jbc.274.7.4266

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

A mammalian protein targeted by G1-arresting rapamycin–receptor complex
Brown, E. J., Albers, M. W., Bum Shin, T., ichikawa, K., Keith, C. T., Lane, W. S., & Schreiber, S. L. (1994) · Nature · doi:10.1038/369756a0 · Cited by 2,053
Targets for Cell Cycle Arrest by the Immunosuppressant Rapamycin in Yeast
Heitman, J., Movva, N. R., & Hall, M. N. (1991) · Science · doi:10.1126/science.1715094 · Cited by 2,010
RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P., & Snyder, S. H. (1994) · Cell · doi:10.1016/0092-8674(94)90570-3 · Cited by 1,509
Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism
Hara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370
Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function
Pause, A., Belsham, G. J., Gingras, A., Donzé, O., Lin, T.-A., Lawrence, J. C., & Sonenberg, N. (1994) · Nature · doi:10.1038/371762a0 · Cited by 1,242
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1432 · Cited by 1,130
Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP
Choi, J., Chen, J., Schreiber, S. L., & Clardy, J. (1996) · Science · doi:10.1126/science.273.5272.239 · Cited by 933
Self-citation
Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells
Sabers, C. J., Martin, M. M., Brunn, G. J., Williams, J. M., Dumont, F. J., Wiederrecht, G., & Abraham, R. T. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.2.815 · Cited by 887
4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathwayPreprint
Gingras, A., Kennedy, S. G., O'Leary, M., Sonenberg, N., & Hay, N. (1998) · Genes & Development · doi:10.1101/gad.12.4.502 · Cited by 885
Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin
Brunn, G. J., Hudson, C. C., Sekulić, A., Williams, J. M., Hosoi, H., Houghton, P. J., Lawrence, J. C., & Abraham, R. T. (1997) · Science · doi:10.1126/science.277.5322.99 · Cited by 846

Flagged first, then by citations

Show all 48 references

Research works printed but not linked: 2

Koltin, 1991, Mol. Cell. Biol., 11, 1718
Cafferkey, 1993, Mol. Cell. Biol., 13, 6012

Sorted by citations

Items 101–155 of 155

Sirt4 Modulates Oxidative Metabolism and Sensitivity to Rapamycin Through Species-Dependent Phenotypes in Drosophila mtDNA Haplotypes
Sejour, R., Sanguino, R. A., Mikolajczak, M., Ahmadi, W., & Villa-Cuesta, E. (2020) · G3 Genes Genomes Genetics · doi:10.1534/g3.120.401174 · Cited by 14
Rapamycin and Torin2 inhibit Candida auris TOR: Insights through growth profiling, docking, and MD simulations
Biswas, B., Gangwar, G., Nain, V., Gupta, I., Thakur, A., & Puria, R. (2022) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2134927 · Cited by 13
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12
Novel classification based on immunohistochemistry combined with hierarchical clustering analysis in non‐functioning neuroendocrine tumor patients
Iida, S., Miki, Y., Ono, K., Akahira, J., Suzuki, T., Ishida, K., Watanabe, M., & Sasano, H. (2010) · Cancer Science · doi:10.1111/j.1349-7006.2010.01657.x · Cited by 12
An integrated genetic analysis of epileptogenic brain malformed lesions
Fujita, A., Kato, M., Sugano, H., Iimura, Y., Suzuki, H., Tohyama, J., Fukuda, M., Ito, Y., Baba, S., Okanishi, T., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01532-x · Cited by 11
Overexpression of TOR (target of rapamycin) inhibits cell proliferation in Dictyostelium discoideum
Swer, P. B., Mishra, H., Lohia, R., & Saran, S. (2015) · Journal of Basic Microbiology · doi:10.1002/jobm.201500313 · Cited by 11
Improving analytical methods for protein-protein interaction through implementation of chemically inducible dimerization
Andersen, T. G., Nintemann, S. J., Marek, M., Halkier, B. A., Schulz, A., & Burow, M. (2016) · Scientific Reports · doi:10.1038/srep27766 · Cited by 11
Oncolytic Virus-Induced Autophagy in Glioblastoma
Kamynina, М., Tskhovrebova, S., Fares, J., Timashev, P. S., Laevskaya, A., & Ulasov, I. V. (2021) · Cancers · doi:10.3390/cancers13143482 · Cited by 9
In silico identification of novel ligands targeting stress-related human FKBP5 protein in mental disorders
Ejiohuo, O., Bajia, D., Pawlak, J., & Szczepankiewicz, A. (2025) · PLoS ONE · doi:10.1371/journal.pone.0320017 · Cited by 9
Nanoparticle-eluting stents for coronary intervention: formulation, characterization, and in vitro evaluation
Agrawal, A. A., Raval, A., Velhal, S., Patel, V. V., & Patravale, V. B. (2021) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2021-0245 · Cited by 7
Nutrient Signaling to Muscle and Adipose Tissue by Leucine
Vary, T. C., & Lynch, C. J. (2005) · Oxidative stress and disease · doi:10.1201/9781420028362.pt2 · Cited by 7
Everolimus in liver and lung transplantation
Koch, M. (2009) · Drugs of today · doi:10.1358/dot.2009.45.1.1313982 · Cited by 6
p62/SQSTM1 signaling nexus and orchestration of ERK and mTOR pathways are crucial for Bacoside A- induced autophagy-mediated apoptosis in chronic myelogenous leukemia
Kundu, S., Saha, S., Ghosh, S., Sarkar, S., Kotal, A., & Chowdhury, A. A. (2025) · Archives of Pharmacal Research · doi:10.1007/s12272-025-01565-x · Cited by 5
Monitorización y efectos secundarios de los inmunosupresores en el trasplante
Sádaba, B. (2006) · Anales del Sistema Sanitario de Navarra · doi:10.4321/s1137-66272006000400017 · Cited by 5
Molecular treatment trajectories within psoriatic T lymphocytes: a mini review
Kuczyńska, M., Gabig‐Cimińska, M., & Moskot, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1170273 · Cited by 4
Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment
Lv, J., Wang, Y., Lv, J., Zheng, C., Zhang, X., Wan, L., Zhang, J., Liu, F., & Zhang, H. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07332-6 · Cited by 4
Probing the Topological Tolerance of Multimeric Protein Interactions: Evaluation of an Estrogen/Synthetic Ligand for FK506 Binding Protein Conjugate
Moore, T. W., Gunther, J. R., & Katzenellenbogen, J. A. (2010) · Bioconjugate Chemistry · doi:10.1021/bc100266v · Cited by 4
Mode of Action of FK506 and Rapamycin
Takahashi, N. (2003) · Elsevier eBooks · doi:10.1016/b978-012526451-8/50015-1 · Cited by 4
Protective Effect and Mechanism of Autophagy in Endothelial Cell Injury Induced by Hyperoxia
Zhu, X., He, S., Zhang, R., Kang, L., Lei, X., & Dong, W. (2023) · American Journal of Perinatology · doi:10.1055/s-0043-1771258 · Cited by 3
Pharmacological Characterization of Purified Recombinant mTOR FRB-Kinase Domain Using Fluorescence-Based Assays
Reichling, L. J., Lebakken, C. S., Riddle, S. M., Vedvik, K. L., Robers, M. B., Kopp, L. M., Bruinsma, R., & Vogel, K. W. (2008) · SLAS DISCOVERY · doi:10.1177/1087057108314609 · Cited by 3
Physiological functions of protein kinase inhibitors
Turchi, J. J., & Ho, M. (2000) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-0348-8393-1_7 · Cited by 3
Monitorización y efectos secundarios de los inmunosupresores en el tras- plante Monitoring and secondary effects of immunosuppressants in the transplant
Sádaba, B. (2006) · Cited by 2
Structure and Function of the mTOR Activator Rheb
Marshall, C. B., Mazhab‐Jafari, M. T., Stambolic, V., & Ikura, M. (2014) · Springer eBooks · doi:10.1007/978-3-7091-1806-1_13 · Cited by 2
Antitumor activity and safety of sirolimus for solid tumors with PIK3CA mutations: A multicenter, open-label, prospective single-arm study (KM 02-01, KCSG UN17-16)
Byeon, S., Kang, M. J., Choi, Y. J., Kim, Y. J., Kim, M., Yun, J., Yi, S. Y., Kim, J. Y., Kim, S. T., & Lee, J. (2020) · Translational Cancer Research · doi:10.21037/tcr.2020.04.07 · Cited by 2
Hedgehog signaling in cutaneous squamous cell carcinoma
Pyczek, J. (2018) · doi:10.53846/goediss-6687 · Cited by 2
Pimecrolimus increases the expression of interferon-inducible genes that modulate human coronary artery cells proliferation
Hußner, J., Sünwoldt, J., Seibert, I., Gliesche, D. G., & zu Schwabedissen, H. E. M. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.05.020 · Cited by 1
Mechanism by which a linoleic acid metabolite suppresses cancer cell growth by inhibiting mTOR
Park, S. J., Kim, S., Kwon, H., Choi, J., Kim, J. K., Jung, I., Lim, S.-W., Kim, Y. R., Yang, A., Lee, B., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.04.004 · Cited by 3
New insights into mTOR structure and regulation
Wang, N., Wu, R., Cheng, X., Jin, J., Jia, Z., & Zheng, J. (2014) · Chinese Science Bulletin · doi:10.1007/s11434-014-0417-0 · Cited by 1
[New perspectives in immunosuppression].
Sádaba, B., Azanza, Muñoz, M. J., & Gil, I. (2005) · PubMed · Cited by 1
FRB domain of human TOR protein induces compromised proliferation and mitochondrial dysfunction in Leishmaniadonovani promastigotes
Chakraborty, S., Mukherjee, S., Biswas, P., Ghosh, A., & Siddhanta, A. (2022) · Parasitology International · doi:10.1016/j.parint.2022.102591 · Cited by 2
Molecularly Targeted Therapy for Osteosarcoma: Where Do We Go from Here?
Ricafort, R. J., & Gorlick, R. G. (2010) · Springer eBooks · doi:10.1007/978-0-387-69062-9_21 · Cited by 1
Regulation of Cell Growth and Proliferation in Metazoans by mTOR and the p70 S6 Kinase
Avruch, J. (2003) · Elsevier eBooks · doi:10.1016/b978-012124546-7/50448-4 · Cited by 1
Etude par génétique inverse du gène codant la protéine TARGET OF RAPAMYCIN d'Arabidopsis thaliana (AtTOR), l'homologue d'une kinase contrôlant la croissance cellulaire chez les eucaryotes
Menand, B. (2002) · OpenGrey (Institut de l'Information Scientifique et Technique) · Cited by 1
Amino Acid-Sensing mTOR Signaling
Kim, J. E., Chen, J., & Erbay, E. (2005) · Oxidative stress and disease · doi:10.1201/9781420028362.ch12 · Cited by 1
Self-citation
The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activityPreprint
Fernandes, S., Pan, J., Terziyska, D. S., Koyuncu, S., Ding, X., Németh, I. B., Wilhelm, S., Nüchel, J., Al-Gburi, S., Gonidas, C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.01.673523 · Cited by 1
Yeast as a Model to Study the Immunosuppressive and Chemotherapeutic Drug Rapamycin
Rohde, J. R., Zurita-Martinez, S. A., & Cardenas, M. E. (2007) · Springer eBooks · doi:10.1007/978-1-4020-5963-6_13
Chemokine receptors CXCR4 and CCR5: Cell surface expression, signaling and modulation by β-arrestin 2
Liebick, M. (2015) · doi:10.53846/goediss-4939
New Medical/Biologic Paradigms in the Treatment of Bone Tumors
Choong, P. (2014) · Current Surgery Reports · doi:10.1007/s40137-014-0055-0
New Antiproliferative Immunosuppressive Agents
Sievers, T. M. (2003) · Journal of Pharmacy Practice · doi:10.1177/0897190003259383
Clinical Pharmacologic Principles and Immunosuppression
West‐Thielke, P. M., & Kaplan, B. E. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-642-9_4
Molecular signaling programs underlying neutrophil polarity and chemotaxis
Cook, S. L. (2013) · Illinois Digital Environment for Access to Learning and Scholarship (University of Illinois at Urbana-Champaign)
Identification of biomarkers for development of NF1-associated malignant peripheral nerve sheath tumours
Rad, E. (2015) · ORCA Online Research @Cardiff (Cardiff University)
Relação entre o perfil de expressão de genes envolvidos na farmacodinâmica de imunossupressores e de microRNAs reguladores, com a resposta terapêutica em transplantados renais
Bonezi, V. (2015) · doi:10.11606/d.9.2015.tde-23092015-153223
Natural compound rhein suppresses colorectal cancer cells growth through mTOR/p70S6 kinase pathway in vitro and in vivoPreprint
Zhang, H., Park, S., Huang, H., Yi, J. K., Park, S., Kwon, W., Kim, E.-K., Jang, S., Kim, S., Choi, S., et al. (2020) · doi:10.21203/rs.3.rs-41306/v1
Faculty Opinions recommendation of mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state.
Teleman, A. A., & Demetriades, C. (2013) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.717988236.793472501
Protein Function | Allostery in Proteins: Canonical Models and New Insights
Kim, E. D., Kim, C. D., Chaney, J., & Kim, S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00259-0
Faculty Opinions recommendation of Cap-independent translation ensures mTOR expression and function upon protein synthesis inhibition.
Bazzini, A., & Wu, Q. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.728776990.793560399
Caffeine and Rapamycin Impair Growth and Morphogenesis by Affecting Both TOR-Dependent Pathways in DictyosteliumPreprint
Jaiswal, P. (2024) · Preprints.org · doi:10.20944/preprints202407.0276.v1
Changes in Plasma Aβ42/40 Ratio and p-Tau181 in Amyloid-Positive Patients Treated with Sirolimus
Leibowitz, J., Kumi, F., Naseif, A., Leibowitz, E. J., & Baumeister, C. (2025) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-025-00323-1
Additional file 1 of An integrated genetic analysis of epileptogenic brain malformed lesions
Fujita, A., Kato, M., Sugano, H., Iimura, Y., Suzuki, H., Tohyama, J., Fukuda, M., Ito, Y., Baba, S., Okanishi, T., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26572534
Etude de la signalisation intracellulaire de la cardioprotection vis-à-vis des lésions d'ischémie-reperfusion : implication de GSK-3β, de la voie WNT et de la voie mTOR
Vigneron, F. (2010) · theses.fr (ABES) · doi:10.70675/dc85dc1azbcc2z4311zb705z678accc1150b
Régulation de cohésine par le complexe TORC1 chez la levure Schizosaccharomyces pombe
Besson, D. (2024) · theses.fr (ABES) · doi:10.70675/9a8af873zd99dz4045z9287zb276eb60d7d4
Phosphoinositides and inositol phosphates as molecular glues
Seaton‐Terry, A., Cutright, A. J., Loi, M. N. C., Martin, J., Gilligan, J. W., Kubina, J. N., Arambula, M. J., Palmu, S. T., Zhou, D., & Blind, R. D. (2026) · FEBS Letters · doi:10.1002/1873-3468.70388
BindingDB Entry 50038590: The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain.
BindingDB (2012) · UC San Diego · doi:10.7270/q2j1042g
Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.
Üstünel, B. E. (2012) · Deep Blue (University of Michigan)

Authors: Vilella-Bach, M., Nuzzi, P., Fang, Y., & Chen, J.
Affiliations: University of Illinois Urbana-Champaign (US)
Corresponding author: Chen, Jie
ORCID: Fang, Yimin
Chen, Jie
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1999-02
Volume: 274
Issue: 7
Pages: 4266-4272
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.274.7.4266
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7919 d)
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The FKBP12-Rapamycin-binding Domain Is Required for FKBP12-Rapamycin-associated Protein Kinase Activity and G1 Progression

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks