Cited by 4,116Signaling Pathways in DiseaseCalpain Protease Function and RegulationS100 Proteins and Annexins

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Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

Liu, Jun, Farmer, Jesse D., Lane, Willam S., Friedman, Jeff, Weissman, Irving, Schreiber, Stuart L.·1991·Cell

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Abstract

Although the immediate receptors (immunophilins) of the immunosuppressants cyclosporin A (CsA) and FK506 are distinct, their similar mechanisms of inhibition of cell signaling suggest that their associated immunophilin complexes interact with a common target. We report here that the complexes cyclophilin-CsA and FKBP-FK506 (but not cyclophilin, FKBP, FKBP-rapamycin, or FKBP-506BD) competitively bind to and inhibit the Ca(2+)- and calmodulin-dependent phosphatase calcineurin, although the binding and inhibition of calcineurin do not require calmodulin. These results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and FK506, respectively, by forming drug-dependent complexes with and altering the activity of calcineurin-calmodulin.

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Authors: Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I., & Schreiber, S. L.
Affiliations: Harvard University (US)
Howard Hughes Medical Institute (US)
ORCID: Weissman, Irving
Schreiber, Stuart L.
Venue: Cell
Publisher: Elsevier BV
Published: 1991-08
Volume: 66
Issue: 4
Pages: 807-815
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/0092-8674(91)90124-h
OpenAlex: W1984754431
Cited by: 4,116
References: 46
Citations by year: 2026: 61 · 2025: 90 · 2024: 68 · 2023: 104 · 2022: 78 · 2021: 84 · 2020: 96 · 2019: 77 · 2018: 76 · 2017: 74 · 2016: 95 · 2015: 101 · 2014: 106 · 2013: 111 · 2012: 115
FWCI: 63.40
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Funders: American Cancer Society
Damon Runyon Cancer Research Foundation
National Institutes of Health (5p01gm040660-02)
National Cancer Institute (T32CA009302)
National Institute of General Medical Sciences (GM-40660, GM38627)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
Keywords: calcineurin, cyclophilin, cyclosporine, FKBP, FK506, immunophilins, immunosuppressants, T cell receptor signaling, IgE receptor signaling
MeSH terms: Amino Acid Isomerases, Amino Acid Sequence, Animals, Anti-Bacterial Agents, Base Sequence, Calmodulin, Calmodulin-Binding Proteins, Carrier Proteins, Cations, Divalent, Cloning, Molecular, Cyclosporins, Humans, Immunosuppressive Agents, Molecular Sequence Data, Molecular Weight, Oligonucleotides, Oligopeptides, Phosphoprotein Phosphatases, Polyenes, Protein Binding, Tacrolimus, Peptidylprolyl Isomerase, Calcineurin, Sirolimus, Tacrolimus Binding Proteins, Macromolecular Substances, Mice, In Vitro Techniques

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Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

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