title: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.
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.
authors.affiliation: Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: J D
authors.initials: JD
authors.lastname: Farmer
authors.forename: W S
authors.initials: WS
authors.lastname: Lane
authors.forename: J
authors.initials: J
authors.lastname: Friedman
authors.forename: I
authors.initials: I
authors.lastname: Weissman
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000591:Amino Acid Isomerases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001483:Base Sequence; D019703:Calcineurin; D002147:Calmodulin / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002413:Cations, Divalent; D003001:Cloning, Molecular; D003524:Cyclosporins / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009841:Oligonucleotides / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011090:Polyenes / Q000378:metabolism; D011485:Protein Binding; D020123:Sirolimus; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins
chemical_list: D000900:Anti-Bacterial Agents; D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D002413:Cations, Divalent; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D046911:Macromolecular Substances; D009841:Oligonucleotides; D009842:Oligopeptides; D011090:Polyenes; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus