Identification of the Immunophilins Capable of Mediating Inhibition of Signal Transduction by Cyclosporin a and FK506: Roles of Calcineurin Binding and Cellular Location

Richard J Bram, Deborah T. Hung, Patrick K. Martin, Stuart L. Schreiber, Gerald R. Crabtree

Research output: Contribution to journalArticle

228 Citations (Scopus)

Abstract

The immunosuppressants cyclosporin A (CsA) and FK506 appear to block T-cell function by inhibiting the calcium-regulated phosphatase calcineurin. While multiple distinct intracellular receptors for these drugs (cyclophilins and FKBPs, collectively immunophilins) have been characterized, the functionally active ones have not been discerned. We found that overexpression of cyclophilin A or B or FKBP12 increased T-cell sensitivity to CsA or FK506, respectively, demonstrating that they are able to mediate the inhibitory effects of their respective immunosuppressants in vivo. In contrast, cyclophilin C, FKBP13, and FKBP25 had no effect. Direct comparison of the Ki of each drug-immunophilin complex for calcineurin in vitro revealed that although calcineurin binding was clearly necessary, it was not sufficient to explain the in vivo activity of the immunophilin. Subcellular localization was shown also to play a role, since gene deletions of cyclophilins B and C which changed their intracellular locations altered their activities significantly. Cyclophilin B has been shown previously to be located within calcium-containing intracellular vesicles; its ability to mediate CsA inhibition implies that certain components of the signal transduction machinery are also spatially restricted within the cell.

Original languageEnglish (US)
Pages (from-to)4760-4769
Number of pages10
JournalMolecular and Cellular Biology
Volume13
Issue number8
StatePublished - Aug 1993
Externally publishedYes

Fingerprint

Immunophilins
Calcineurin
Tacrolimus
Cyclosporine
Signal Transduction
Immunosuppressive Agents
Tacrolimus Binding Protein 1A
Cyclophilin A
Tacrolimus Binding Proteins
Cyclophilins
Calcium
T-Lymphocytes
Drug Receptors
Gene Deletion
Pharmaceutical Preparations
cyclophilin B
Cyclophilin C

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Identification of the Immunophilins Capable of Mediating Inhibition of Signal Transduction by Cyclosporin a and FK506 : Roles of Calcineurin Binding and Cellular Location. / Bram, Richard J; Hung, Deborah T.; Martin, Patrick K.; Schreiber, Stuart L.; Crabtree, Gerald R.

In: Molecular and Cellular Biology, Vol. 13, No. 8, 08.1993, p. 4760-4769.

Research output: Contribution to journalArticle

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