1、See online version for legend and references.SnapShot:Ca2+-Calcineurin-NFAT SignalingGerald R.Crabtree1 and Stuart L.Schreiber21Stanford University School of Medicine,Stanford,CA 94305,USA;2Broad Institute of Harvard and MIT,Cambridge,MA 02142,USA210 Cell 138,July 10,2009 2009 Elsevier Inc.DOI 10.10
2、16/j.cell.2009.06.026210.e1 Cell 138,July 10,2009 2009 Elsevier Inc.DOI 10.1016/j.cell.2009.06.026SnapShot:Ca2+-Calcineurin-NFAT SignalingGerald R.Crabtree1 and Stuart L.Schreiber21Stanford University School of Medicine,Stanford,CA 94305,USA;2Broad Institute of Harvard and MIT,Cambridge,MA 02142,USA
3、Ca2+-calcineurin-NFAT signaling transmits signals to the nucleus from a wide variety of receptors and is required for developmental events as diverse as axon out-growth,cardiac morphogenesis,lung morphogenesis,neural crest diversification,epithelial stem cell maintenance,and immune responses.The pat
4、hway appears to be particularly dedicated to vertebrate-specific morphogenic events,perhaps reflecting its first evolutionary appearance in vertebrates.Calcineurin-NFAT signaling is the target of the drugs cyclosporin A and FK506 and several viral immune modulators.In addition,its malfunction is imp
5、licated in Downs syndrome,diabetes,and cardiac hypertrophy.Receptors that induce the entry of Ca2+into the cell resulting in the activation of calcineurin phosphatase are shown in the lower left.Ca2+binds to the regulatory subunit of calcineurin as well as to calmodulin to activate the phosphatase a
6、ctivity of calcineurin(Stemmer and Klee,1994).The immunosuppressive drugs FK506 and cyclosporin A inhibit calcineurin by binding first to the abundant intracellular proteins,FKBP and cyclophilin,respectively.These protein complexes then bind to calcineurin,preventing substrate access(Liu et al.,1991
7、).The specificity of these calcineurin inhibitors is due to the large composite surface arising from FKBP bound to FK506(see inset structure)(Griffith et al.,1995)or cyclosporin A bound to cyclophilin.FK506 and cyclosporin A are highly specific probes of the NFAT signaling path-way in tissues where
8、the concentration of calcineurin is less than the concentration of FKBP or cyclophilin(Graef et al.,2001).Calcineurin removes several phosphate residues from the N terminus of NFATc proteins,the Ca2+-calcineurin-sensitive subunits of NFAT transcription complexes.Removal of the phosphates exposes nuc
9、lear localization sequences in NFATc proteins leading to their rapid entry into the nucleus(Beals et al.,1997a).Once in the nucleus,the NFATc proteins assemble on DNA with partner proteins generically termed NFATn(lower right)that are often the endpoints of other signaling pathways(Crabtree and Olso
10、n,2002).In most cases,NFAT-depen-dent transcription requires that the Ca2+signaling be coincident with MAP kinase signaling,providing a mechanism for signal integration and coincidence detection.The targets of NFAT signaling(panel,upper right)are largely cytokines,growth factors and their receptors,
11、proteins involved in cell-cell interactions,as well as many microRNAs.Of particular importance are positive feedback loops initiated by direct binding of NFATc1 and NFATc4 to their promoters as well as the regulation of Ca2+channels,such as the IP3 receptor,responsible for the release of intracellul
12、ar Ca2+stores(Genazzani et al.,1999).This positive feedback loop appears to be important in committing cells to specific fates.A negative feedback loop mediated by the NFAT-dependent activation of RCAN(DSCR1)gene expression appears to constrain the pathway(Arron et al.,2006).NFATc proteins are activ
13、ely removed from the nucleus by first priming with Dyrk1a or protein kinase A(PKA)followed by phosphorylation by GSK3(Arron et al.,2006;Beals et al.,1997b;Gwack et al.,2006).The inhibition of GSK3 by AKT and PI3 kinase(PI3K)signaling increases the level of NFATc proteins in the nucleus and hence pro
14、vides a second means of coincidence detection and signal integration.Many of the phenotypes of Downs syndrome are thought to be due to the duplication of the DSCR and Dyrk1a genes on chromosome 21.Increased gene dosage both reduces NFATc import into the nucleus and also facilitates export leading to
15、 a reduction in NFATc function and compromised positive feedback(Arron et al.,2006).AbbreviationsAKT,the cellular homolog of the acute transforming oncogene v-AKT;BCR,B cell receptor;CRAC,Ca2+release-activated Ca2+channel;DSCR1/RCAN,Downs syn-drome critical region 1,now called regulator of calcineur
16、in;Dyrk1a,dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A;FKBP,FK506-binding protein;GSK3,glycogen synthease kinase 3;IP3R1,inositol 1,4,5-triphosphate receptor 1;NFAT,nuclear factor of activated T cells;NMDA,N-methyl-D-aspartate recep-tor;NFATc,Ca2+-calcineurin-dependent subunits
17、of NFAT complexes,also cyclosporin-sensitive subunit of NFAT complexes;NFATn,generic name for nuclear sub-units of NFAT-transcription complexes;NF-B,nuclear factor binding to the immunoglobulin kappa locus in B cells;PI3K,phosphatidylinositol 3-kinase;IP3,inositol 1,4,5-triphosphate;PLC,phospholipas
18、e gamma;STIM,stromal interaction molecule;Sox2,sex determination-box containing gene;TRP,transient receptor potential channel;TCR,T cell receptor;VEGF,vascular endothelial growth factorRefeRencesArron,J.R.,Winslow,M.M.,Polleri,A.,Chang,C.P.,Wu,H.,Gao,X.,Neilson,J.R.,Chen,L.,Heit,J.J.,Kim,S.K.,et al.
19、(2006).NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.Nature 441,595600.Beals,C.R.,Clipstone,N.A.,Ho,S.N.,and Crabtree,G.R.(1997a).Nuclear localization of NF-ATc by a calcineurin-dependent,cyclosporin-sensitive Intramolecular interac-tion.Genes Dev.11,824834.Beals,C.R.,S
20、heridan,C.M.,Turck,C.W.,Gardner,P.,and Crabtree,G.R.(1997b).Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.Science 275,19301934.Crabtree,G.R.,and Olson,E.N.(2002).NFAT signaling:choreographing the social lives of cells.Cell 109(Suppl),S67S79.Genazzani,A.A.,Carafoli,E.,and Guerini,D.
21、(1999).Calcineurin controls inositol 1,4,5-trisphosphate type 1 receptor expression in neurons.Proc.Natl.Acad.Sci.USA 96,57975801.Graef,I.A.,Chen,F.,Chen,L.,Kuo,A.,and Crabtree,G.R.(2001).Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature.Cell 105,863875.Griffi
22、th,J.P.,Kim,J.L.,Kim,E.E.,Sintchak,M.D.,Thomson,J.A.,Fitzgibbon,M.J.,Fleming,M.A.,Caron,P.R.,Hsiao,K.,and Navia,M.A.(1995).X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12FK506 complex.Cell 82,507522.Gwack,Y.,Sharma,S.,Nardone,J.,Tanasa,B.,Iuga,A.,Srikanth,S.,Oka
23、mura,H.,Bolton,D.,Feske,S.,Hogan,P.G.,et al.(2006).A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.Nature 441,646650.Liu,J.,Farmer,J.D.,Jr.,Lane,W.S.,Friedman,J.,Weissman,I.,and Schreiber,S.L.(1991).Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.Cell 66,807815.Stemmer,P.M.,and Klee,C.B.(1994).Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B.Biochemistry 33,68596866.
