From the Department of Developmental Biology and Department of Pathology, Stanford University Medical School, Stanford, California 94305
Calcineurin (PP2B), a serine/threonine
phosphatase controlled by cellular calcium, was originally identified
in extracts of mammalian brain. Within the past few years this
phosphatase has been implicated in a wide variety of biological
responses including lymphocyte activation, neuronal and muscle
development, neurite outgrowth, and morphogenesis of vertebrate heart
valves. Progress in this area has been greatly accelerated by the drugs
cyclosporin A and FK506, which use a unique mechanism of action to
achieve near genome-specific nanomolar inhibition of calcineurin. This minireview will focus on the role of calcineurin in regulating transcription during development, primarily through its
dephosphorylation of downstream targets such as the
calcineurin-dependent, cytoplasmic subunits of the NF-AT
transcription complex.
The Ca2+, calcineurin/NF-AT signaling pathway was
defined about 10 years ago (1-4) and was one of the first signaling
pathways to bridge the cell membrane with the nucleus. Although the
pathway is simple (Fig. 1), multiple
levels of regulation impinge upon it, making it adaptable for many
functions in a wide variety of cell types. The pathway was defined by a
strategy of working backward from the nucleus to the cell membrane
Ca2+ channels in T lymphocytes. The regulatory regions of
the IL-21 gene were
identified and found to bind a cyclosporin-sensitive transcription
complex called NF-AT1 (1, 5-7). This transcription complex was shown
to be made up of cytoplasmic (NFATc) and nuclear (NFATn) components
(2). The cytoplasmic component translocated into the nucleus with a
calcium signal, and the import was blocked by the drugs FK506 and
cyclosporin A (2). Identification of calcineurin as the in
vitro and in vivo target of FK506 and cyclosporin A (3,
4) established that calcineurin was required for the nuclear import of
NF-ATc (8). Finally, a screen for somatic cell mutations that prevented
NF-AT transcriptional activation yielded many mutations that abolished
the activity of the capacitance-regulated activation channels (CRAC)
and hence identified it as the source of Ca2+ that
regulated NF-AT import (9-11).
INTRODUCTION
Calcineurin and Regulation of Nuclear Import of NF-ATc Family
Members
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Fig. 1.
Signaling through calcium, calcineurin, and
NF-AT in different cell types. The Ca2+,
calcineurin/NFATc signaling cassette (light blue)
is used in several different tissues for quite different outcomes. In
lymphocytes, NF-ATc1, -c2, and -c3 are expressed, and the genes
activated include those encoding cytokines and cell surface molecules
involved in cell-cell communication and cell death. In cardiac
endocardial cells, the same signaling pathway uses NF-ATc1 to regulate
the expression of genes essential for heart valve morphogenesis. In
hippocampal cells, L-type Ca2+ channels and
N-methyl-D-aspartate receptors activate
the NF-ATc4 protein and lead to activation of the IP3R1
gene, which may participate in a positive feedback loop reinforcing
synaptic connections. The nomenclature used for the different
cytoplasmic, calcium-sensitive subunits of the NF-AT is the genome data
base nomenclature as per the original definition of the cytoplasmic and
nuclear subunits of the complex (2). TCR, T cell receptor;
GMCSF, granulocyte-macrophage colony-stimulating
factor.
Calcineurin functions in this pathway by directly dephosphorylating the cytoplasmic subunits of the NF-AT1 transcription complex (12-14), which are encoded by four genes (NF-ATc1-4) (15) and which undergo cytoplasmic to nuclear translocation as originally described (2). Calcineurin binds directly to NF-ATc family members through a conserved motif in the N terminus of the protein, which functions as an effective dominant negative (16-18). This unconventional direct interaction between the phosphatase and its substrate outside of the enzymatic site results in a surprisingly specific relationship between the phosphatase and its substrate. Calcineurin dephosphorylates serines within the SP repeats (SP1 to SP3) and the serine-rich region of NF-ATc family members (13, 19). When phosphorylated, these residues appear to obscure the two nuclear localization sequences required for nuclear import, perhaps by forming salt bridges between the basic nuclear localization sequence and the acidic phosphoserines of NF-ATc family members (13, 20).
Once dephosphorylated by calcineurin, NF-ATc family members move into
the nucleus where they are maintained by persistent elevation of
intracellular Ca2+ and the continuous activity of
calcineurin (11). Persistent activation of calcineurin is required
because NFATc proteins are rapidly exported from the nucleus.
Export of NF-ATc1 and -c4 was found to be caused by the phosphorylation
of the same residues that are dephosphorylated by calcineurin to bring
about nuclear import. Biochemical purification of the nuclear kinase
that phosphorylated these residues identified GSK3 as a potential
export kinase (19). The persistent activation of calcineurin necessary
to maintain NF-ATc family members in the nucleus requires the CRAC
channel, which is known to provide a sustained high level of
Ca2+ (21). Indeed overexpression of constitutively active
calcineurin or a NF-ATc1 mutant that is constitutively nuclear
suppresses mutations in the CRAC channel allowing the activation of
immune response genes such as IL-2 with only a PKC signal (11).
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NFAT Complexes as Coincidence Detectors and Integrators of Ras and Ca2+ Signaling |
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Early studies indicated that NF-AT integrated Ca2+
signals with signals transduced by mitogen-activated protein kinase
and/or protein kinase C (1, 22, 23). Thus, the NF-AT1 transcription complex acts as a coincidence detector in that it requires that both
Ras/PKC and Ca2+/calcineurin signaling be coincident to
achieve activation (Fig. 2). In fact, DNA
binding by NF-ATc proteins is quite weak because of the unusual
structural features of its Rel-like DNA binding domain (24), and as a
consequence the protein requires a partner for tight association with
DNA. Thus, Ca2+ signaling becomes dependent on coincident
Ras/PKC signaling and vice versa. In nearly all cell types studied,
activation of Rac, Ras, or PKC must accompany a Ca2+ signal
for activation of NF-AT-dependent transcription (Fig. 2).
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In addition to the effects of GSK3 on NF-ATc1, the movement of NF-ATc3
into the nucleus appears to be opposed by the actions of either JNK
kinase (25) or perhaps the combination of MEKK1 and CK1 (20). Although
the evidence is conflicting, these two kinases have both been reported
to provide opposition to the cytoplasmic dephosphorylation by
calcineurin in cell lines. However, because the transcriptional
activity of NF-AT complexes is enhanced rather than blocked by agents
that activate MEKK1 and JNK (1, 23, 26-28) the physiological roles of
these kinases remain to be understood.
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Signaling through Ca2+, Calcineurin, and NF-ATc Family Members in Neurons |
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Calcineurin has been shown to have important roles in axonal
guidance (29) as well as memory and learning (30, 31). In general,
these functions in neurons have been thought to be independent of
transcription. However, recent evidence indicates that the NF-ATc
family members may have critical roles in the development of synaptic
connections. NF-ATc4 is expressed in hippocampal neurons and undergoes
translocation to the nucleus with brief depolarization or even with
physiological 5-Hz stimulation (32). The latter is significant in that
it implies that normal synaptic activity is sufficient to send NF-ATc4
into the nucleus, i.e. when you think about it NF-ATc4
enters the nucleus. A potential downstream gene appears to be
IP3R1, which encodes a Ca2+ channel and
is activated shortly after birth in response to the neural activity of
the newborn animal (33). The promoter region of this gene has a cluster
of NF-ATc sites and appears to be dependent on the activity of the
NF-ATc4 protein, which is expressed in neurons (32). In
addition, the activation of this gene after birth or in cultured
hippocampal neurons is blocked by FK506 or cyclosporin A (33). These
studies suggest that signaling by Ca2+, calcineurin, and
NF-ATc4 regulates a positive feedback pathway that could reinforce
synaptic connections (Fig. 1). However, additional studies with null
mutations of NF-ATc4 and possibly other redundant family members will
be necessary to confirm this hypothesis.
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The Morphogenesis of Heart Valves and the Calcium, Calcineurin, NFAT Pathway |
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Null mutations in the NF-ATc1 gene result in a failure
of heart valve development and abnormalities of the cardiac septum that
recall the common cardiac abnormalities that occur in nearly 1% of all
live births (34, 35). Although calcineurin is expressed ubiquitously,
at embryonic days 8.5-13, NF-ATc1 is expressed only in the cells that
are destined to contribute to heart valves. Remarkably, the protein is
nuclear in the endocardial cells that are adjacent to the cardiac
jelly, suggesting that a local signal results in its nuclear
localization (Fig. 1). Either cyclosporin or FK506 blocks this
translocation and results in an arrest in valve development, indicating
that an as yet uncharacterized signal (presumably a cytokine or growth
factor) activates calcineurin leading to nuclear localization of
NF-ATc1 and activation of genes that orchestrate the formation
of a cardiac valve (Fig. 1). Much needs to be learned about this
extremely important pathway including the nature of the signal, the
downstream genes, and the role of this pathway in the cardiac valve
abnormalities that affect nearly 50 million individuals worldwide.
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The Role of Signaling through Ca2+, Calcineurin, and NF-ATc4 in Myocardial Hypertrophy |
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The heart responds to stress with the hypertrophy of
cardiomyocytes. This response is probably normal during development but becomes damaging in hypertension or after multiple myocardial infarctions. The signals for the stress-induced hypertrophy of cardiac
muscle have long been known to be dependent on calcium, and recently it
was discovered that severe cardiac hypertrophy could be induced by the
overexpression of a truncated constitutively active calcineurin A (36).
In addition, a similar pathology could be induced in animals in which a
truncated NF-ATc4 was overexpressed (36). Furthermore, cyclosporin A
prevents the development of cardiac hypertrophy in response to certain
(but apparently not all) stimuli (37, 38). Additional studies with mice
bearing mutations in calcineurin genes or the NF-ATc4 gene
will be necessary to confirm these pharmacologic and overexpression
studies, but the present results indicate that calcineurin and NF-ATc4
represent new targets for development of antihypertrophic agents.
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Calcineurin and Control of Transcription in Yeast |
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In yeast, signals initiated by pheromone or other agents that
increase intracellular Ca2+ lead to the activation of
transcription of FKS2, PMR2, PMC1, PMR1, and other genes (39-41). This transcriptional
response requires the Crz1/Tcn1 gene and plays an important
role in controlling ion homeostasis (40). The mechanism of control of
Crz1p/Tcn1p is remarkably similar to the control of NF-ATc
proteins in mammalian cells (Fig. 3).
Like NF-ATc proteins that translocate from cytoplasm to nucleus upon
activation of calcineurin, Crz1p/Tcn1p also translocates and
furthermore is dephosphorylated at critical serines similar to NF-ATc
family members (42). Despite these mechanistic similarities, there is
relatively little sequence similarity in the two proteins other than a
conserved group of serines in the N-terminal translocation domain, and
whereas Crz1/Tcn1 use a zinc finger for DNA binding the
NFATc family uses a Rel domain.
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Calcineurin Inhibitors |
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In recent years, five different classes of calcineurin inhibitors have been discovered (Table I) raising questions regarding their various roles in Ca2+/calcineurin signaling. Each of these inhibits calcineurin by binding to the protein and inhibiting its ability to dephosphorylate substrates, such as NFATc family members, thereby preventing their nuclear localization. Perhaps the most interesting of these is the DSCR1 gene and its relatives, DSCR2 and ZAK14 (43). DSRC1 is located on chromosome 21 in the so-called critical region (hence its name, Down's Syndrome critical region 1 gene). One possibility is that overexpression of DSCR1 as a result of trisomy leads to inhibition of calcineurin and subsequent effects on the development of the brain, immune system, heart, and skeleton. However, the Down's Syndrome critical region includes a number of genes, and it is possible that the syndrome could arise from overexpression of several of these. Two pieces of evidence indicate that overexpression of DSCR1 might underlie the pathogenesis of Down's Syndrome. First, Estivill, Luna, and co-workers (43) have shown that DSCR1 protein is actually overexpressed in the brains of Down's Syndrome patients. Second, some of the symptoms of Down's Syndrome appear in mice with mutations of the different calcineurin-dependent (NF-ATc) subunits of the transcription complex. Recently, yeast have been shown to have a related protein, Pcn1p, that binds and inactivates calcineurin (44, 45) (Fig. 3).
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Two additional interesting classes of calcineurin inhibitors are Cabin/Cain (46, 47), which are novel proteins, and the CHP protein that has similarity to calcineurin B (48, 49). The CHP proteins appear to compete with calcineurin B for binding to the A protein and thereby inhibit the Ca2+-dependent activation of calcineurin A. On the other hand, the DSCR1, -2, and -3 proteins act as competitive inhibitors of phosphatase activity with nanomolar binding constants. Cabin (also called Cain) is a noncompetitive inhibitor of calcineurin phosphatase activity with a Ki of 440 nM. A physiologic role of these proteins is still unclear, but they do antagonize NF-ATc translocation.
A fourth class of calcineurin inhibitors is found in the genome of certain viruses, most notably African swine fever virus. Here the A238L protein encoded by the virus binds tightly to calcineurin and blocks NF-ATc translocation and function (50). A238L shares sequence similarity with NF-ATc family members throughout the calcineurin interaction domain; hence it is likely that A238L induces cyclosporin-like immunosuppression in the host, allowing the virus to invade the host.
Finally, the AKAP79 protein (51) was the first calcineurin inhibitor to
be found and is also a scaffolding protein. AKAP79 binds both
calcineurin and protein kinase A and may anchor calcineurin at specific
sites that allow the protein to engage the proper substrates when activated.
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Calcineurin and Regulation of NF-![]() |
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NF-B and other Rel proteins play critical roles in the
development of the liver, skin, inflammatory responses, and in some as-pects of the recombinational immune response. Unlike NF-AT, which
absolutely requires a calcium stimulus, NF-
B can be fully activated
by PKC activators in the absence of calcium (55). However, suboptimal
stimuli can be augmented with a calcium signal (7, 56). This calcium
facilitation of NF-
B activity can be mimicked with overexpression of
a constitutively active calcineurin and can be partially (about
40-70%) blocked with cyclosporin A or FK506, indicating that
calcineurin is likely to be required for full induction of NF-
B
activity in certain circumstances (57). The reduction in NF-
B
activity by CsA or FK506 appears to result from an inhibition of the
transcriptional induction of the p50 subunit and the c-Rel protein (58)
as well as reduced degradation of I
B (57). However, the mechanism
underlying the latter effect is not known.
The AP-1 transcription complex consists of Fos and Jun proteins that
are encoded by families of genes including c-jun,
junB, junD, as well as c-fos,
fra, and others. Transcription controlled by most AP-1 sites
is not sensitive to inhibition by CsA or FK506 (7, 56). However, a site
in the IL-2 promoter that binds junD and perhaps
c-jun requires the actions of calcineurin for full function
(59, 60). In addition, an apparent AP-1 site in the collagenase
promoter is sensitive to FK506 (61) and hence likely to be
calcineurin-dependent. The activity of JNK is partially inhibited by CsA or FK506 and is also partially
calcium-dependent. The mechanism underlying the effect of
calcineurin on JNK activity has not been elucidated.
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Calcineurin and Regulation of MEF2 Transcription Factors |
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Muscle cells respond to Ca2+ signals by differentiation and the conversion from fast fibers to slow fibers (62). Calcineurin appears to mediate the later transition by controlling the activity of NF-AT and Mef2 (myocyte enhancer binding factor 2) transcription factors that in turn control genes essential for muscle differentiation. The Mef2 proteins are encoded by at least four genes, Mef2A-D, which are related in their DNA binding domain to MCM-1, Agamous, ARG80, deficiens, and serum response factors (63) and hence are referred to as MAD box proteins. The mechanism of the control of Mef2 proteins by calcineurin appears to involve the Ca2+-dependent dissociation of histone deacetylase 4 (HDAC) (64). In addition, Ca2+ activates calmodulin kinase, which in turn phosphorylates and exports HDAC4 from the nucleus.2
The calcium-dependent control of Mef2 might have
important roles in regulating programmed cell death. Greenberg and
colleagues (65) recently found that Ca2+ stimuli that
protected neurons from cell death activated MEF2-dependent transcription in a calcineurin-dependent fashion.
Presumably, the genes that are activated by MEF2 in neurons protect
them from cell death. In lymphocytes, the
Ca2+-dependent activation of MEF2 appears to
lead to programmed cell death by activating the Nur77 transcription
factor (66). Why neurons and lymphocytes would have opposite responses
to the calcium/calcineurin-dependent activation of MEF2 is
not clear but probably relates to the cellular context in which the
Ca2+ signal is delivered (15).
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ACKNOWLEDGEMENTS |
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I thank Scott Stewart and other members of my laboratory for helpful suggestions and Jeanie Oberlindacher for preparation of the manuscript. I am also grateful to Kyle Cunningham for unpublished data.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the first article of four in the "Ca2+-dependent Cell Signaling through Calmodulin-activated Protein Phosphatase and Protein Kinases Minireview Series."
To whom correspondence should be addressed. Tel.: 650-723-8391;
Fax: 650-723-5158; E-mail: crabtree@cmgm.stanford.edu.
Published, JBC Papers in Press, November 28, 2000, DOI 10.1074/jbc.R000024200
2 E. Olson, personal communication.
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ABBREVIATIONS |
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The abbreviations used are: IL, interleukin; CRAC, capacitance-regulated activation channels; PKC, protein kinase C; JNK, c-Jun NH2-terminal kinase; MEKK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase.
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