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

Cell. 1991 Aug 23;66(4):807-15. doi: 10.1016/0092-8674(91)90124-h.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Isomerases / metabolism*
  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / metabolism*
  • Base Sequence
  • Calcineurin
  • Calmodulin / metabolism
  • Calmodulin-Binding Proteins / antagonists & inhibitors
  • Calmodulin-Binding Proteins / metabolism*
  • Carrier Proteins / metabolism*
  • Cations, Divalent
  • Cloning, Molecular
  • Cyclosporins / metabolism*
  • Humans
  • Immunosuppressive Agents / metabolism*
  • In Vitro Techniques
  • Macromolecular Substances
  • Mice
  • Molecular Sequence Data
  • Molecular Weight
  • Oligonucleotides / chemistry
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Peptidylprolyl Isomerase
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism*
  • Polyenes / metabolism
  • Protein Binding
  • Sirolimus
  • Tacrolimus
  • Tacrolimus Binding Proteins

Substances

  • Anti-Bacterial Agents
  • Calmodulin
  • Calmodulin-Binding Proteins
  • Carrier Proteins
  • Cations, Divalent
  • Cyclosporins
  • Immunosuppressive Agents
  • Macromolecular Substances
  • Oligonucleotides
  • Oligopeptides
  • Polyenes
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Amino Acid Isomerases
  • Tacrolimus Binding Proteins
  • Peptidylprolyl Isomerase
  • Sirolimus
  • Tacrolimus