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Mol Cell. 2015 Apr 16;58(2):232-43. doi: 10.1016/j.molcel.2015.02.027. Epub 2015 Mar 26.

Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms.

Author information

1
Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
2
Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Electronic address: anant.parekh@dpag.ox.ac.uk.

Abstract

Protein isoforms are widely expressed in biological systems. How isoforms that co-exist within the same sub-cellular domain are differentially activated remains unclear. Here, we compare the regulatory mechanism of two closely related transcription factor isoforms, NFAT1 and NFAT4, that migrate from the cytoplasm to the nucleus following the increase in intracellular Ca(2+) that accompanies the opening of store-operated Orai1/CRAC channels. We demonstrate that NFAT1 has a private line of communication with Orai1, activating in response to Ca(2+) microdomains near the open channels. By contrast, NFAT4 stimulation requires both local Ca(2+) entry and a nuclear Ca(2+) rise. We mapped differences in nuclear location to amino acids within the SP-3 motif of the NFAT regulatory domain. The different Ca(2+) dependencies enable agonists to recruit different isoform combinations as stimulus strength increases. Our study uncovers a mechanism whereby co-existing cytoplasmic transcription factor isoforms are differentially activated by distinct sub-cellular Ca(2+) signals.

PMID:
25818645
PMCID:
PMC4405353
DOI:
10.1016/j.molcel.2015.02.027
[Indexed for MEDLINE]
Free PMC Article

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