NF-AT activation requires suppression of Crm1-dependent export by calcineurin

Nature. 1999 Mar 18;398(6724):256-60. doi: 10.1038/18473.

Abstract

Nuclear import of the NF-AT transcription factors during T-cell activation requires the calcium-activated phosphatase calcineurin, which unmasks nuclear-location signals on NF-AT. We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1. Calcineurin suppresses this futile cycling by a non-catalytic mechanism involving the masking of nuclear export signals on NF-AT targeted by Crm1. This clustering of binding sites for calcineurin and Crml on NF-AT establishes an inherent competition between these molecules that imparts exquisite calcium sensitivity to the shuttling dynamics of the NF-AT transcription factors. Such a balance between nuclear import and export may regulate the action of other transcription factors.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • Calcineurin / metabolism*
  • Calcium / metabolism
  • Calcium Signaling
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Cricetinae
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Hybrid Cells
  • Karyopherins*
  • Mutation
  • NFATC Transcription Factors
  • Nuclear Localization Signals
  • Nuclear Proteins*
  • Precipitin Tests
  • Receptors, Cytoplasmic and Nuclear*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Karyopherins
  • NFATC Transcription Factors
  • Nuclear Localization Signals
  • Nuclear Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • exportin 1 protein
  • Calcineurin
  • Calcium