title: Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms.
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.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Pulak
authors.initials: P
authors.lastname: Kar
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Electronic address: anant.parekh@dpag.ox.ac.uk.
authors.forename: Anant B
authors.initials: AB
authors.lastname: Parekh
mesh_terms: D020816:Amino Acid Motifs; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000071740:ORAI1 Protein; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494008:NFATC3 protein, human; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D020033:Protein Isoforms; D002118:Calcium
references.citation: Mol Cell. 2000 Sep;6(3):539-50
references.pmid: 11030334
references.citation: J Invest Dermatol. 2002 May;118(5):779-88
references.pmid: 11982754
references.citation: J Biol Chem. 2002 Jul 26;277(30):27517-27
references.pmid: 11971908
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2975-80
references.pmid: 12606721
references.citation: Genes Dev. 2003 Sep 15;17(18):2205-32
references.pmid: 12975316
references.citation: Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2873-7
references.pmid: 8146203
references.citation: Nature. 1996 Jul 25;382(6589):370-3
references.pmid: 8684469
references.citation: FASEB J. 1998 Jan;12(1):35-42
references.pmid: 9438408
references.citation: Neuron. 1998 Mar;20(3):389-99
references.pmid: 9539117
references.citation: Nature. 1998 Apr 30;392(6679):933-6
references.pmid: 9582075
references.citation: J Physiol. 2005 Feb 1;562(Pt 3):697-706
references.pmid: 15513935
references.citation: Physiol Rev. 2005 Apr;85(2):757-810
references.pmid: 15788710
references.citation: Curr Biol. 2005 Jul 12;15(13):1235-41
references.pmid: 16005298
references.citation: Nature. 2006 May 11;441(7090):179-85
references.pmid: 16582901
references.citation: Nature. 2006 Jun 1;441(7093):646-50
references.pmid: 16511445
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9357-62
references.pmid: 16751269
references.citation: Nature. 2006 Sep 14;443(7108):230-3
references.pmid: 16921383
references.citation: Nature. 2006 Sep 14;443(7108):226-9
references.pmid: 16921385
references.citation: Curr Biol. 2006 Oct 24;16(20):2073-9
references.pmid: 16978865
references.citation: FASEB J. 2006 Nov;20(13):2381-3
references.pmid: 17023391
references.citation: Nature. 2007 Mar 15;446(7133):284-7
references.pmid: 17361175
references.citation: Trends Cell Biol. 2007 Jun;17(6):251-60
references.pmid: 17493814
references.citation: J Physiol. 2008 Jul 1;586(13):3043-54
references.pmid: 18467365
references.citation: FEBS J. 2008 Dec;275(24):6268-80
references.pmid: 19016842
references.citation: Curr Biol. 2009 May 26;19(10):853-8
references.pmid: 19375314
references.citation: FEBS J. 2009 Nov;276(21):6324-37
references.pmid: 19796173
references.citation: Annu Rev Immunol. 2010;28:491-533
references.pmid: 20307213
references.citation: Nat Rev Drug Discov. 2010 May;9(5):399-410
references.pmid: 20395953
references.citation: Nat Rev Immunol. 2010 Sep;10(9):645-56
references.pmid: 20725108
references.citation: J Biol Chem. 2011 Apr 29;286(17):14795-803
references.pmid: 21325277
references.citation: Curr Biol. 2012 Feb 7;22(3):242-7
references.pmid: 22245003
references.citation: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6969-74
references.pmid: 22509043
references.citation: Mol Cell. 2013 Jan 24;49(2):322-30
references.pmid: 23219532
references.citation: Curr Biol. 2014 Jun 16;24(12):1361-8
references.pmid: 24909327
references.citation: J Neurosci. 2014 Jul 2;34(27):9107-23
references.pmid: 24990931
references.citation: Physiology (Bethesda). 2014 Sep;29(5):361-8
references.pmid: 25180265