Regulation of Cell Proliferation by Calcineurin: Comparison
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Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. 

  • cancer
  • cell cycle
  • intracellular calcium ions
  • calcineurin
  • dephosphorylation

1. Introduction

Intracellular calcium ions (Ca2+) act as pleiotropic secondary messengers in key signaling pathways involving a variety of cellular functions. While the extracellular Ca2+ concentration is 11.5 mM, the steady-state intracellular Ca2+ concentration is kept very low at several tens of nanomoles. It is well known that the concentration of Ca2+ varies greatly in different cellular compartments, for example, intracellular calcium, 100 nM; endoplasmic reticulum (ER), 0.5–1 mM; and mitochondria, 100–200 nM [1].
The binding of a hormone or growth factor to a G protein coupled receptor (GPR) or a tyrosine kinase receptor (RTK) initiates the Ca2+ signaling cascade. The activation of such receptors transmits the signals to phospholipase C (PLC), which cleaves phosphatidylinositol 4,5-biphosphate (PIP2) to produce diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3). InsP3 then binds to the InsP3 receptor (InsP3R) and stimulates the release of Ca2+ from intracellular stores, such as ER [2], and allows for the entry of Ca2+ [3,4][3][4] from the extracellular space. Spatially and temporally coordinated Ca2+ release via InsP3R is regulated by complex feedback mechanisms [1].
Changes in Ca2+ concentration trigger signal transduction, which regulates a wide range of cellular events such as gene expression, cell cycle, cell motility, autophagy, and apoptosis [1,5][1][5]. Local changes in intracellular Ca2+ diffuse through the cell and have effects on the distal sites [6]. Long-term intracellular Ca2+ increases in the mitochondria and causes the release of cytochrome c and subsequently triggers apoptosis [7]. Due to the diverse roles of Ca2+, the dysregulation of calcium homeostasis can impair cell function and trigger cell death, and by doing so, may contribute to heart disease, cancer, and mental disorders. As a result, Ca2+ signals must be tightly regulated during the cell cycle. Indeed, previous studies have characterized Ca2+ transients during the cell cycle [8,9][8][9].  Ca2+ oscillations are narrow in the sense of periodic rise and fall, while Ca2+ concentration alterations are broad in the sense of simple Ca2+ concentration changes. To facilitate different cellular processes, intracellular downstream effectors decode the frequency, amplitude, and duration of intracellular Ca2+ oscillations [11][10]. The most widely known family of calcium downstream effectors is calmodulin (CaM). CaM is highly conserved among eukaryotes with four EF-hand Ca2+ binding sites. CaM is involved in the regulation of cell proliferation and cell cycle through CaM-dependent phosphorylation/dephosphorylation events [12][11]. When Ca2+ binds to CaM, the Ca2+/CaM complex can interact with and control target proteins such as serine/threonine phosphatase calcineurin (CaN) and the family of Ca2+/CaM-dependent protein kinases (CaMK). The molecular mechanisms through which Ca2+/CaM regulates cell cycle progression, especially through the activation state of the cyclin-dependent kinase (CDK) complex, is of great interest, and therefore has been studied intensively. It has been shown that although all eukaryotic cells require Ca2+ signaling for cell proliferation, some transformed cells and tumor cell lines are less dependent on Ca2+ for cell growth [13,14][12][13]. Ca2+-mediated signaling pathways, therefore, play important roles in tumorigenesis, tumor progression, metastasis, and invasion [6].

2. Cell Cycle and CDK

Cell division is precisely regulated by a series of CDKs, whose activity is dependent on the binding to different cell cycle-specific cyclins [15][14]. Cyclins confer substrate specificity and form CDK/cyclin complexes, which activate or inactivate target proteins by phosphorylation, and orchestrate coordinated cell cycle progression. In addition to CDK association with cyclins, the activity of CDKs is tightly regulated by several mechanisms, including phosphorylation, binding of CDK inhibitors (CKIs), and subcellular localization of CDK/cyclin complexes [16][15]. One of the critical targets of the CDK-cyclin complex in the G1 phase is the retinoblastoma protein (Rb). In the early G1 phase, CDK4/6-cyclin D initiates the phosphorylation of Rb, and, subsequently, CDK2-cyclin E phosphorylates Rb [17,18,19,20][16][17][18][19]. Phosphorylation of Rb releases the E2F transcription factor, and promotes the expression of the genes required for cell cycle progression [21,22][20][21]. This enables cells to pass through the restriction point at the G1/S boundary and to commence the S phase. CDK2-cyclin A plays an important role in S phase progression through the phosphorylation of proteins involved in DNA replication [23,24][22][23]. As cells enter the S phase, the CDK2-cyclin A complex is activated and remains activated throughout the G2 phase [25,26][24][25]. In the late G2 phase, CDK1-cyclin B is activated, allowing for the entry of cells into mitosis [27][26]. During G2/M transition, CDK1-cyclin A activity is necessary for prophase initiation [28][27].

3. Calcium, Calmodulin, and Calmodulin-Dependent Protein Kinases in Cell Proliferation

In mammalian cells, Ca2+ is required at several different points during the cell cycle. Cells are most sensitive to the depletion of extracellular Ca2+ at early G1 and near the G1/S boundary [12,29][11][28]. In early G1, Ca2+ regulates the expression of immediate-early genes, such as FOS, JUN, and MYC. Ca2+ is also required for Rb phosphorylation at the G1/S boundary. Spontaneous Ca2+ oscillations at the G1/S phase transition have been described in synchronized immortalized cell lines. These Ca2+ oscillations are accompanied by DNA replication [30][29]. Once hormone receptors are activated, intracellular Ca2+ levels increase. Ca2+ regulates certain targets directly and others indirectly through Ca2+-binding proteins, such as CaM. Ca2+/CaM activates various pathways involved in the regulation of cellular processes, such as secretion, cell motility, ion homeostasis, and gene transcription. CaM also modulates a large number of intracellular enzymes, including protein kinases, protein phosphatases, phosphodiesterases, adenylyl cyclases, and ion channels [31][30]. CaM is required for cell cycle progression through G1, specifically the G1/S transition. Consistent with this notion, CaM antagonists block cell cycle progression in early or late G1 phases [32][31]. Furthermore, the exit from mitosis is sensitive to changes in the concentration of CaM [33][32]. Upon binding with Ca2+, CaM undergoes a major conformational change, and forms a Ca2+/CaM complex to interact with a variety of target proteins such as cellular kinases [34][33]. The best-studied kinases involved in Ca2+/CaM signaling are the CaMKs [35,36][34][35]. CaN and CaMK play important roles in cell cycle progression by activating or inhibiting key cell cycle regulators (Figure 1). The CaN/NFAT pathway contributes to inducing the transcription of cyclin D1 [37][36] and CDK4, and stabilizes cyclin D1 by dephosphorylating Thr286 of cyclin D [38][37]. 
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Figure 1. Regulation of cell cycle progression by calcineurin and CaMK. CaN dephosphorylates the NFAT transcription factor, which in turn activates p21, cyclin D1, CDK4, c-myc, and cyclin A. CaN also stabilizes cyclin D1 by dephosphorylation. Furthermore, the CaN/NFAT pathway and its downstream target c-myc regulate p21. p21 is a well-known inhibitor of CDK2-cyclin E and CDK4/6-cyclin D. CaMK negatively regulates the expression of p27, which is an inhibitor of CDK4-cyclin D and CDK2-cyclin E. CDK2-cyclin E and CDK4/6-cyclin D complexes phosphorylate Rb, leading to the activation of E2F1 and the subsequent G1/S progression. In G2/M, CaMK phosphorylates and activates cdc25, leading to downstream dephosphorylation and the activation of CDK1. Solid red lines indicate phosphorylation, red dotted lines indicate dephosphorylation, and green dotted lines indicate transcriptional activation.

4. Characteristics of Calcineurin

CaN, also known as protein phosphatase 2 B (PP2B), is a serine/threonine protein phosphatase that is conserved in all eukaryotes [54,55,56,57][38][39][40][41]. CaN is a heterodimer composed of a catalytic subunit, calcineurin A (CnA), and a Ca2+-binding regulatory subunit, calcineurin B (CnB). In mammals, three independent genes, PPP3CA, PPP3CB, and PPP3CC, encode CnAα, CnAβ, and CnAγ, respectively. CnAα and CnAβ exhibit ubiquitous expression patterns, whereas the CnAγ expression is restricted to the testis and brain [58,59,60,61][42][43][44][45]. The CaN regulatory subunits CnB1 and CnB2 are encoded by two genes (PPP3R1 and PPP3R2, respectively). The CnB1 protein is expressed ubiquitously, whereas the CnB2 protein is specifically expressed in the testes. CnA contains an amino-terminal catalytic domain followed by a CnB-binding domain, a CaM-binding domain, and an autoinhibitory domain. CaN also contains a nuclear localization signal (NLS) in the catalytic domain and a nuclear export signal (NES) in the carboxyl terminus. The autoinhibitory domain of CnA blocks the catalytic site and the NLS [56,62][40][46]. CnB contains four EF-hand Ca2+-binding motifs and an amino-terminal myristylation site. CaN is activated by the increased intracellular Ca2+ concentration in the cell and plays essential roles in multiple signaling processes [63][47]. The binding of Ca2+/CaM to the regulatory domain leads to the attenuation of autoinhibition, followed by dramatic enzymatic activation. Of note, although there are multiple kinases that are regulated by CaM, and CaN is the only phosphatase directly regulated by Ca2+/CaM.

5. Mechanisms Regulating Calcineurin Activity

Several proteins have been reported to inhibit CaN, including AKAP79 (A-kinase anchoring protein-79) [69][48], PMCA2 (plasma membrane calcium ATPase 2) [70][49], CHP (calcineurin homologous protein) [71,72][50][51], Cabin/Cain [73[52][53],74], calcipressin/RCAN/DSCR/CSP [75[54][55][56],76,77], and FK506-binding protein (FKBP) 38 [78][57]. Subcellular localization of CaN is regulated by its interaction with AKAP79, a scaffold protein that anchors CaN at distinct subcellular locations, leading to the inhibition of CaN [67,69,79][58][48][59]. In breast cancer cells, PMCA2 interacts with and sequesters CaN in the membrane, and suppresses the activation of the CaN-NFAT pathway [70][49]. CHP competes with CnB to bind to CnA, and inhibits CaN activity [71,72][50][51]. While Cabin1/cain inhibits CaN by interacting with CaN in a phosphorylation-dependent manner through a binding site on CaN, which is distinct from that of the drug–immunophilin complex [73,74][52][53]. Calcipressin/RCAN/DSCR/CSP has also been identified as a CnA-binding protein that inhibits CaN activity [77,80][56][60]. A conserved peptide (FLISPPxSPP) of the calcipressin family is phosphorylated and functions as a binding site for CaN. As the expression of calcipressin is induced by CaN, it functions as a feedback inhibitor of CaN signaling. Calcipressin/RCAN/DSCR/CSP binds CaN at the same site as NFAT and other substrates, with competition for binding between these molecules being a possible regulatory mechanism [81][61]. FKBP38 targets BCL-2 to the mitochondria and inhibits apoptosis. The same protein also binds to and inhibits CaN, even in the absence of FK506 [78][57]. Furthermore, histone H1 inhibits CaMKII and CaN by blocking CaM autophsophorylation [82][62]. CaN is also inactivated by the oxidation of key methionine residues [83,84,85,86][63][64][65][66]. Conversely, CaN is activated by the intramolecular cleavage by two different proteases, caspase 3 and Ca2+-dependent protease calpain [87,88,89][67][68][69].

6. Functions of Calcineurin/NFAT

Cyclosporine A and FK506 are well-characterized immunosuppressive agents that prevent organ transplant rejection [93,94,95][70][71][72]. These compounds bind tightly to endogenous cytoplasmic cyclophilin A or FKBP12, respectively. Interestingly, cyclophilin A or FKBP12, in complex with cyclosporine A or FK506, bind to CaN and block the access of the CaN substrate to the active site of the CaN [96][73]. This indicates the possibility that the immunosuppressive effects of these drugs could be, in part, caused by the disruption of CaN functions. Consistent with this view, it has been show that CaN inhibition by cyclosporine A or FK506 delays G1/S progression in various cell types [97,98,99,100][74][75][76][77]. Mechanistically, cyclosporin A induces the expression of the cyclin inhibitor p21 and a reciprocal reduction in cyclins A and E, leading to CDK2 inactivation [101,102][78][79].

7. A Therapeutic Perspective for Cancer

Owing to the high frequency of CaN/NFAT activation in cancer and the contribution of these molecules in cancer progression, the CaN/NFAT pathway could be a potential therapeutic target. Indeed, the anticancer effects of CaN inhibitors have been studied extensively in the past. For instance, cyclosporine A or FK506 induced apoptosis and rapid tumor clearance, resulting in the regression of leukemia [160][80]. Cyclosporine A or FK506 also inhibits tumor growth in the bladder and prostate xenografts in vivo [174,178,179][81][82][83]. In addition, cyclosporine A itself is also directly involved in tumor growth, as it increases TGFβ production [180][84], activates Ras [181][85], suppresses PTEN expression, and increases AKT activation [182][86].

8. Conclusions

Nuclear Ca2+ is involved in tumor growth and alters the expression of the genes involved in cell proliferation. Furthermore, previous studies have suggested that the modulation of nuclear Ca2+ signaling may be effective in cancer therapy. Activation of CaN and its downstream dephosphorylation has been identified as a mechanism by which nuclear Ca2+ regulates cell proliferation and cell cycle progression. As discussed above, dephosphorylation of proteins by CaN plays an important role in tumor formation and progression. Therefore, in the future, it will be necessary to identify the molecular mechanism of CaN activation and the substrates that promote cancer cell growth. Targeting the interactions of activated CaN with specific substrates in cancer cells, without affecting the normal immune function of CaN, may effectively inhibit the growth of cancer cells, leading to the establishment of new tumor-specific therapies.

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