Regulation of the Calmodulin-stimulated Protein Phosphatase, Calcineurin

The role of protein phosphatases in the regulation of cellular processes is now well established (1Shenolikar S. Annu. Rev. Cell Biol. 1994; 10: 55-86Crossref PubMed Scopus (403) Google Scholar, 2Cohen P.T. Chen M.X. Armstrong C.G. Adv. Pharmacol. 1996; 36: 67-89Crossref PubMed Scopus (37) Google Scholar). Calcineurin (also called protein phosphatase 2B), a major calmodulin-binding protein in brain and the only serine/threonine protein phosphatase under the control of Ca2+/calmodulin, plays a critical role in the coupling of Ca2+ signals to cellular responses (3Klee C.B. Crouch T.H. Krinks M.H. Proc. Natl. Acad. Sci. U. S. A. 1980; 76: 6270-6273Crossref Scopus (610) Google Scholar, 4Stewart A.A. Ingebritsen T.S. Manalan A. Klee C.B. Cohen P. FEBS Lett. 1982; 137: 80-84Crossref PubMed Scopus (339) Google Scholar, 5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google Scholar, 6Kincaid R.L. Adv. Second Messenger Phosphoprotein Res. 1993; 27: 1-25PubMed Google Scholar). Its stimulation by the multifunctional protein, calmodulin, ensures the coordinated regulation of its protein phosphatase activity with the activities of the many other enzymes, including a large number of protein kinases, under Ca2+ and calmodulin control. Despite its special abundance in neural tissues, calcineurin is broadly distributed, and its structure is highly conserved from yeast to man (6Kincaid R.L. Adv. Second Messenger Phosphoprotein Res. 1993; 27: 1-25PubMed Google Scholar). Its resistance to the endogenous phosphatase inhibitor 1 and inhibitor 2 and to the potent inhibitors of protein phosphatase 1 and 2A, okadaic acid, calyculin, and microcystin (1Shenolikar S. Annu. Rev. Cell Biol. 1994; 10: 55-86Crossref PubMed Scopus (403) Google Scholar, 2Cohen P.T. Chen M.X. Armstrong C.G. Adv. Pharmacol. 1996; 36: 67-89Crossref PubMed Scopus (37) Google Scholar) made it difficult to identify its functions until it was identified as the target of the immunosuppressive drugs, FK506 and cyclosporin A (CsA). 1The abbreviations used are: CsA, cyclosporin A; IP3, inositol trisphosphate; FKBP, FK506-binding protein; NMDA, N-methyl-d-aspartate.Calcineurin was thus shown to play an essential role in T cell activation (7Liu J. Farmer J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3620) Google Scholar). The demonstration that FK506 and CsA, when bound to their respective binding proteins, FKBP12 and cyclophilin A, are specific inhibitors of calcineurin provided the tools needed to reveal its many other roles in the transduction of Ca2+ signals (8Liu J. Albers M.W. Wandless T.J. Luan S. Alberg D.G. Belshaw P.J. Cohen P. MacKintosh C. Klee C.B. Schreiber S.L. Biochemistry. 1992; 31: 3896-3901Crossref PubMed Scopus (502) Google Scholar). Its calmodulin dependence distinguishes it from two other known Ca2+-regulated protein phosphatases, the insulin-sensitive pyruvate dehydrogenase phosphatase of mitochondria (9Denton R.M. McCormack J.G. Rutter G.A. Burnett P. Edgell N.J. Moule S.K. Diggle T.A. Adv. Enzyme Regul. 1996; 36: 183-198Crossref PubMed Scopus (54) Google Scholar) and a family of protein phosphatases homologous to the product of the Drosophila retinal degeneration C (rdgC) gene (10Steele F.R. Washburn T. Rieger R. O'Tousa J.E. Cell. 1992; 69: 669-676Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 11Vinos J. Jalink K. Hardy R.W. Britt S.G. Zuker C.S. Science. 1997; 277: 687-690Crossref PubMed Scopus (103) Google Scholar, 12Sherman P.M. Sun H. Macke J.P. Williams J. Smallwood P.M. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11639-11644Crossref PubMed Scopus (50) Google Scholar). Calcineurin has a relatively narrow substrate specificity. Phosphoproteins listed in Table I are preferentially dephosphorylated by calcineurin whereas others such as casein, synapsin 1, and calmodulin kinase II are dephosphorylated at much slower rates or not at all (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google Scholar). Other potentially physiological substrates, whose kinetic characteristics have not been determined, include NO synthase, a GTPase involved in endocytosis (dynamin, previously called dephosphin), the transcription factor Elk-1, and the heat shock protein, hsp25 (13Dawson T.M. Steiner J.P. Dawson V.L. Dinerman J.L. Uhl G.R. Snyder S.H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9808-9812Crossref PubMed Scopus (512) Google Scholar, 14Herskovits J.S. Burgess C.C. Obar R.A. Vallee R.B. J. Cell Biol. 1993; 122: 565-578Crossref PubMed Scopus (398) Google Scholar, 15Sugimoto T. Stewart S. Guan K.-L. J. Biol. Chem. 1997; 272: 29415-29418Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 16Gaestel M. Benndorf R. Hayess K. Priemer E. Engel K. J. Biol. Chem. 1992; 267: 21607-21611Abstract Full Text PDF PubMed Google Scholar). The substrate specificity of calcineurin is not due only to a specific sequence but rather is determined by both primary and higher order structural features (17Blumenthal D.K. Takio K. Hansen R.S. Krebs E.G. J. Biol. Chem. 1985; 261: 8140-8145Abstract Full Text PDF Google Scholar,18Donella-Deana A. Krinks M.H. Ruzzene M. Klee C.B. Pinna L.A. Eur. J. Biochem. 1994; 219: 109-117Crossref PubMed Scopus (73) Google Scholar). The phosphorylation-independent tight binding of substrates, such as described for the transcription factor NF-ATp (nuclear factor-activated T cells), may allow calcineurin to dephosphorylate proteins whose intracellular concentration is very low (19Jain J. McCaffrey P.G. Miner Z. Kerppola T.K. Lambert J.N. Verdine G.L. Curran T. Rao A. Nature. 1993; 365: 352-355Crossref PubMed Scopus (679) Google Scholar, 20Wesselborg S. Fruman D.A. Sagoo J.K. Bierer B.E. Burakoff S.J. J. Biol. Chem. 1996; 271: 1274-1277Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Calcineurin also dephosphorylates phosphotyrosine, but theK cat, except when determined in the presence of Ni2+, is 2 orders of magnitude lower than that for phosphoserine (Table I).Table ISubstrate specificity of calcineurinSubstratesk catk mRef.s−1mmInhibitor 1aValues of k cat measured in the absence of added metal are underestimated.2.80.0035Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google ScholarRII subunit2.70.0217Blumenthal D.K. Takio K. Hansen R.S. Krebs E.G. J. Biol. Chem. 1985; 261: 8140-8145Abstract Full Text PDF Google ScholarNeurogranin1.80.01393Seki K. Chen H.C. Huang K.-P. Arch. Biochem. Biophys. 1995; 316: 673-679Crossref PubMed Scopus (68) Google ScholarPhosphorylase kinase (α subunit)aValues of k cat measured in the absence of added metal are underestimated.1.40.0065Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google ScholarNeuromodulin0.1–0.50.01593Seki K. Chen H.C. Huang K.-P. Arch. Biochem. Biophys. 1995; 316: 673-679Crossref PubMed Scopus (68) Google ScholarMicrotubule-associated proteinsMAP-20.6–2.20.0025Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google ScholarTau factor0.6–0.80.0025Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google ScholarDARPP-32aValues of k cat measured in the absence of added metal are underestimated.0.20.0145Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google ScholarDLDVPIPGRFDRRVSVAAEbSynthetic peptide routinely used for calcineurin assays. Values of 12 s−1 and 0.1 mm have been reported recently (62, 95). For comparison at pH 7.5 in the absence of added metal the k cat value for the dephosphorylation of the peptide substrate by crude calcineurin is 40 s−1.2.20.02694Blumenthal D.K. Chan C.P. Takio K. Gallis B. Hansen R.S. Krebs E.G. Adv. Protein Phosphatases. 1985; 1: 163-171Google Scholar5.9cAssayed in the presence of 1 mmNi2+.0.02394Blumenthal D.K. Chan C.P. Takio K. Gallis B. Hansen R.S. Krebs E.G. Adv. Protein Phosphatases. 1985; 1: 163-171Google ScholarDLDVPIPGRFDRRVYVAAE<0.0294Blumenthal D.K. Chan C.P. Takio K. Gallis B. Hansen R.S. Krebs E.G. Adv. Protein Phosphatases. 1985; 1: 163-171Google Scholar0.3cAssayed in the presence of 1 mmNi2+.0.00394Blumenthal D.K. Chan C.P. Takio K. Gallis B. Hansen R.S. Krebs E.G. Adv. Protein Phosphatases. 1985; 1: 163-171Google Scholarp-Nitrophenyl phosphate2623.095Mertz P. Yu L. Sikkink R. Rusnak F. J. Biol. Chem. 1997; 272: 21296-21302Abstract Full Text Full Text PDF PubMed Scopus (63) Google ScholarExcept when indicated kinetic constants were measured in the presence of Mn2+ or Mg2+.a Values of k cat measured in the absence of added metal are underestimated.b Synthetic peptide routinely used for calcineurin assays. Values of 12 s−1 and 0.1 mm have been reported recently (62Etzkorn F.A. Chang Z.Y. L.A. Biochemistry. 1994; PubMed Scopus Google Scholar, P. Yu L. Sikkink R. Rusnak F. J. Biol. Chem. 1997; 272: 21296-21302Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). For comparison at pH 7.5 in the absence of added metal the k cat value for the dephosphorylation of the peptide substrate by crude calcineurin is 40 in the presence of 1 in a when indicated kinetic constants were measured in the presence of Mn2+ or The peptide to of the of protein kinase (Table is used to calcineurin phosphatase activity (17Blumenthal D.K. Takio K. Hansen R.S. Krebs E.G. J. Biol. Chem. 1985; 261: 8140-8145Abstract Full Text PDF Google Scholar). it is a substrate for protein phosphatases 1, 2A, and it is well to the okadaic calcineurin activity in crude provided that the is to to calcineurin M.J. Klee C.B. J. H. A Scholar, P.M. Krinks M.H. Klee C.B. FEBS Lett. 1995; PubMed Scopus (37) Google Scholar, Klee C.B. Nature. 1996; PubMed Scopus Google Scholar, D.A. Klee C.B. Burakoff S.J. Bierer B.E. A to Enzymol. 1996; Scopus Google Scholar). The activity has been to its and to a the of the by a by the of the by a the of a Biophys. 1994; PubMed Scopus (50) Google Scholar). is with the metal for calcineurin activity (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google the of calcineurin as an Huang J. Biol. Chem. Full Text PDF PubMed Google and the demonstration that calcineurin a metal L. A. Rusnak F. J. Chem. 1995; Scopus Google Scholar). the recently of calcineurin J.P. J.L. M.J. K. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, L.A. A. Chen F. J.E. R. J.E. Nature. 1995; PubMed Scopus Google two metal are the structure of the The specific activity of calcineurin in crude in the absence of added that the crude has its P.M. Krinks M.H. Klee C.B. FEBS Lett. 1995; PubMed Scopus (37) Google Scholar). of crude calcineurin by the and its and by that is for activity Klee C.B. Nature. 1996; PubMed Scopus Google Scholar). of its calcineurin is a of a and calmodulin-binding calcineurin A, bound in the presence of only of to a calcineurin (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google Scholar). the protein phosphatases, is conserved from yeast to man and is essential for highly conserved are the of the and of calcineurin A from P.T. Chen M.X. Armstrong C.G. Adv. Pharmacol. 1996; 36: 67-89Crossref PubMed Scopus (37) Google Scholar, 6Kincaid R.L. Adv. Second Messenger Phosphoprotein Res. 1993; 27: 1-25PubMed Google Scholar). The primary structure of the and of calcineurin A, of gene are and for calcineurin calcineurin calcineurin and calcineurin is shown in the of and whose functions are not the the of their is a conserved of the whereas in the are for the of the as to of and for the neural and the broadly (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google Scholar, 6Kincaid R.L. Adv. Second Messenger Phosphoprotein Res. 1993; 27: 1-25PubMed Google Scholar, S. E. PubMed Scopus Google Scholar, T. H. A. Chang K. C. J. 1992; PubMed Scopus Google Scholar). Calcineurin is a highly conserved protein identified as an protein the of its sequence A. Klee C.B. Cohen P. Eur. J. Biochem. PubMed Scopus Google Scholar). Its determined by is to that of calmodulin with two of two by a J. S. H. Klee C.B. A. Biochemistry. 1994; PubMed Scopus Google Scholar). from its it of with and with in the M. Sikkink R. Rusnak F. FEBS Lett. 1995; PubMed Scopus (50) Google Scholar). conserved from yeast to man is the of the A. Cohen P. S. Williams A. Klee C.B. FEBS Lett. 1982; PubMed Scopus Google Scholar, J. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar). are two of calcineurin with calcineurin and and is only in only has been reported in and the yeast (6Kincaid R.L. Adv. Second Messenger Phosphoprotein Res. 1993; 27: 1-25PubMed Google Scholar). The highly conserved structure of calcineurin A, in 1, was by M.J. Klee C.B. Biochemistry. PubMed Scopus Google Scholar). The of calcineurin by the calcineurin by and binding of to calcineurin and is to M.J. Klee C.B. Biochemistry. PubMed Scopus Google Scholar, H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, G.R. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, J. M. E. F. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, J. H. Klee C.B. A. FEBS Lett. 1995; PubMed Scopus Google Scholar, R. A. S. P. R. Rusnak F. Biochemistry. 1995; PubMed Scopus Google Scholar, Chang J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). with calcineurin are to as the of The activity of calcineurin is in the protein, but it when by from the The to in the absence of calmodulin, two a calmodulin-binding and an M.J. Klee C.B. Biochemistry. PubMed Scopus Google Scholar, R.L. Adv. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of the of calcineurin and of its with in the structure of the calcineurin were with L.A. A. Chen F. J.E. R. J.E. Nature. 1995; PubMed Scopus Google Scholar). L.A. A. Chen F. J.E. R. J.E. Nature. 1995; PubMed Scopus Google Scholar) and that of the with J.P. J.L. M.J. K. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar) of the of the and the have been determined at and the of the and the of calcineurin A, in the protein, the structure of the of the calcineurin shown in 2 is to that of the The to that of protein phosphatase 1 Biochem. Sci. 1996; Full Text PDF PubMed Scopus Google of a of a of by and and a of by an all The two metal and bound to provided by the two of the the The a whose is by a by the and and the of calcineurin B. The the two are in with the of calcineurin involved in the with calcineurin A 1 and the 1, and the and the determined in J. M. E. F. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, J. H. Klee C.B. A. FEBS Lett. 1995; PubMed Scopus Google Scholar). of of calcineurin A with the of calcineurin may the binding to for the very of calcineurin for calcineurin A and C. as to the relatively low of the calcineurin of calcineurin A for calcineurin J. H. Klee C.B. A. FEBS Lett. 1995; PubMed Scopus Google Scholar, Chang J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the protein, acid, to the of calcineurin to the of the of calcineurin whereas the of the protein is conserved of calcineurin not involved in is not for activity but may as a structural J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Rusnak F. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). the protein, with the of two to the that the the is not in the L.A. A. Chen F. J.E. R. J.E. Nature. 1995; PubMed Scopus Google Scholar). The structure of is with its to M.J. Klee C.B. Biochemistry. PubMed Scopus Google Scholar). The of the calcineurin of calcineurin A, to with calcineurin the binding of the FKBP12 with calcineurin the and the calcineurin of calcineurin A, whereas the of the calcineurin of calcineurin A and calcineurin the binding of FK506 of the and calcineurin from the identified as the major of of calcineurin with J. M. E. F. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar). by calcineurin binding to calcineurin A may by of the two immunosuppressive their binding to calcineurin (7Liu J. Farmer J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3620) Google Scholar). the conserved structural features of calcineurin are for the of calcineurin to with two of immunosuppressive drugs, and with their respective binding proteins in S.L. G.R. 1992; Full Text PDF PubMed Scopus Google Scholar). The Ca2+ dependence of the phosphatase activity of calcineurin is by two but proteins, calmodulin and calcineurin (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google Scholar). than calcineurin with its bound to calcineurin A, but the is of the low and 1 in a The activity is than by the of an of calmodulin and is the of an with the that activation is the of the binding of calmodulin to the concentration of Ca2+ needed for activation with of calmodulin, and the calmodulin concentration needed for activation with Ca2+ P.M. Klee C.B. Biochemistry. 1994; PubMed Scopus Google Scholar). The highly Ca2+ dependence of the calmodulin stimulation of calcineurin of the to to narrow Ca2+ cell with enzymes, the of calmodulin activation is to binding to the calmodulin-binding in a of an (5Klee C.B. Draetta G.F. Hubbard M.J. Adv. Enzymol. Relat. Areas Mol. Biol. 1988; 61: 149-200PubMed Google A. M. Annu. Rev. Biophys. 1995; PubMed Scopus Google Scholar). The structure of the calmodulin-binding in the structure of calcineurin and the of the by the is with but of the of the structure of the The of the calmodulin binding also the role of calmodulin in the of crude calcineurin a phosphatase activity that is calmodulin and not added for activity but is to a and by P.M. Krinks M.H. Klee C.B. FEBS Lett. 1995; PubMed Scopus (37) Google Scholar). The for for the phosphatase activity and of crude calcineurin to the in crude calcineurin is by Klee C.B. Nature. 1996; PubMed Scopus Google Scholar). The of the binding of may the metal in the of the to the of The of calcineurin by that it is the of the of at the of calcineurin activity by has also been in yeast and in Ca2+ stimulation Klee C.B. Nature. 1996; PubMed Scopus Google Scholar, H. K. R.W. Cell. 1997; Full Text Full Text PDF Scopus Google Scholar). The of calcineurin activity by the of a to the and to protein dephosphorylation to the of the The of the role of calcineurin in the of calcineurin has been Calcineurin is for the of an from its under Z.Y. J. Biol. Chem. 1985; Full Text PDF PubMed Google Scholar) or and J. M. E. F. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, R. A. S. P. R. Rusnak F. Biochemistry. 1995; PubMed Scopus Google Scholar, Chang J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S.K. Rusnak F. FEBS Lett. 1992; PubMed Scopus Google Scholar). The and of the two the of calcineurin that Ca2+ binding to the of calcineurin plays a structural rather than a role P.M. Klee C.B. Biochemistry. 1994; PubMed Scopus Google Scholar). to the low is not only for the activation but also for calmodulin activation P.M. Klee C.B. Biochemistry. 1994; PubMed Scopus Google Scholar). The of calcineurin activation has not been is not the of whose structure is to the of other protein phosphatases, is or the of calcineurin but the calmodulin-binding and has an for Ca2+ than that of the P.M. Klee C.B. Biochemistry. 1994; PubMed Scopus Google Scholar). The structure of the identified the calcineurin and calcineurin A as the binding of the an for the of both for the of J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar) and by and H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, G.R. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, J. M. E. F. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, B. M. B. Biochem. Biophys. Res. 1993; PubMed Scopus Google Scholar, R.S. T. J. J. 1995; PubMed Scopus Google Scholar, A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). also the of the of FK506 the of the structural and FK506 and and the binding of the FKBP12 FK506-binding proteins S.L. G.R. 1992; Full Text PDF PubMed Scopus Google Scholar). of FKBP12 and cyclophilin A involved in with calcineurin are from the and in with the of activity and calcineurin R.A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, F.A. Chang L.A. Protein Sci. 1992; 1: PubMed Scopus Google Scholar, Schreiber S.L. J. Chem. 1993; Scopus Google Scholar, F.A. Chang Z.Y. L.A. Biochemistry. 1994; PubMed Scopus Google Scholar). The binding of two and to the calcineurin a until the of calcineurin A that are to FK506 or CsA, that the are but not R.S. T. J. J. 1995; PubMed Scopus Google Scholar, A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The from yeast to man of the of calcineurin the that with endogenous of FK506 and have been the of the of calcineurin to the and by FK506 that may such T. S. H. P. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, Steiner J.P. Snyder S.H. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). The of calcineurin to the may a of Ca2+ from by protein dephosphorylation K. A. E. E. T. M. B.E. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, R.A. Snyder S.H. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). potentially of calcineurin is a of the family of proteins whose is to or phosphatases to their M. J.D. Science. 1995; 267: PubMed Scopus Google Scholar). the and FK506 Ca2+ to The phosphorylation-independent binding of the transcription factor to calcineurin may of calcineurin by the substrate S. Fruman D.A. Sagoo J.K. Bierer B.E. Burakoff S.J. J. Biol. Chem. 1996; 271: 1274-1277Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). to shown the binding for target proteins with the The regulation of calcineurin is from an has now been shown to a major in the regulation of cellular is than the regulation of transcription of the T cell S.L. G.R. 1992; Full Text PDF PubMed Scopus Google G.R. Annu. Rev. Biochem. 1994; PubMed Scopus Google Scholar, A. C. P.G. Annu. Rev. 1997; PubMed Scopus Google Scholar, J. A. M. A to Enzymol. 1993; Scopus Google Scholar). The of the transcription in to an of intracellular Ca2+ by the of the T cell is its dephosphorylation by was the of the transduction of a at the to the (7Liu J. Farmer J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3620) Google Scholar, J. McCaffrey P.G. Miner Z. Kerppola T.K. Lambert J.N. Verdine G.L. Curran T. Rao A. Nature. 1993; 365: 352-355Crossref PubMed Scopus (679) Google Scholar). A Ca2+ and the of calcineurin and NF-ATp to the the activation of gene is by the a of intracellular Ca2+ L.A. J.P. G.R. Nature. 1996; PubMed Scopus Google Scholar, F. E. F. Nature. 1996; PubMed Scopus Google Scholar, P. G.R. Science. 1997; PubMed Scopus Google Scholar). The of calcineurin in the regulation of the of an of and is in G.R. Annu. Rev. Biochem. 1994; PubMed Scopus Google Scholar, A. C. P.G. Annu. Rev. 1997; PubMed Scopus Google Scholar, J. A. M. A to Enzymol. 1993; Scopus Google and A. U. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google it in T calcineurin plays an role in the regulation of gene in to Ca2+ signals in yeast J. A. M. A to Enzymol. 1993; Scopus Google Scholar, T. H. S. T. T. J. 1992; Scopus Google Scholar, Scopus Google Scholar, T.J. Scopus Google Scholar, I. A. H. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. M. J. Cell Sci. 1994; PubMed Google Scholar). major of of calcineurin in are the J. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar) and the to T. H. S. T. T. J. 1992; Scopus Google Scholar). The of involved in two has now been shown to by the and of a transcription factor also with calcineurin Scopus Google Scholar, T.J. Scopus Google Scholar). Other processes under calcineurin control include Ca2+ and I. A. H. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. M. J. Cell Sci. 1994; PubMed Google Scholar, C. C. S. R.L. R.L. J. 1994; PubMed Scopus Google Scholar). the of of calcineurin in and are in to a major The dephosphorylation of by calcineurin in was the for a protein phosphatase calcineurin for the of and S. P. Nature. PubMed Scopus Google Scholar). activation of calcineurin not only in of the of the and R.A. G.R. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, A. Rev. 1992; PubMed Scopus Google but is also involved in the of the Ca2+ I. Nature. 1994; PubMed Scopus Google Scholar). The regulation of the of the may the for the role of calcineurin in and and 1994; PubMed Scopus Google Scholar, M. B. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). activation of has also been to S.H. 1995; 1: PubMed Scopus Google Scholar). A role for calcineurin has also been in K. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar) and in the of for the of in to Ca2+ F.R. Nature. 1995; PubMed Scopus Google Scholar, P. P. Biochemistry. 1995; PubMed Scopus Google Scholar). The of the regulation of the by the immunosuppressive in the A. F. Klee C.B. P. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar) may for their whereas in the calcineurin activation of the is to of by binding to E. S. 1996; 66: PubMed Scopus Google Scholar). of two intracellular Ca2+ involved in coupling in and other and the involved in Ca2+ by and potentially all cellular processes under for and the of many of