12.1. Introduction

Ca²⁺ is a ubiquitous intracellular messenger that transduces a variety of cellular responses downstream of the activation of G-protein-coupled or tyrosine kinase receptors. Depending on the agonist and cellular context, Ca²⁺ can mediate different responses in the same cell [1]. The specific cellular response transduced downstream of the particular Ca²⁺ transient is encoded in the spatial and temporal dynamics of the Ca²⁺ signal, leading to the activation of a subset of Ca²⁺-dependent effectors and the ensuing cellular response. As such, the duration, amplitude, frequency, and spatial localization of Ca²⁺ signals encode targeted signals that activate Ca²⁺-sensitive effectors to define a particular cellular response. To generate and fine-tune those Ca²⁺ signals, cells use two main Ca²⁺ sources: entry of extracellular Ca²⁺ and Ca²⁺ release from intracellular stores. The primary intracellular Ca²⁺ store is the endoplasmic reticulum (ER), which can concentrate Ca²⁺ in the hundreds of μM range [2]. In contrast, cytoplasmic Ca²⁺ concentration is kept at rest at extremely low levels (∼100 nM or lower), thus providing a low-noise background for detection of complex Ca²⁺ dynamics [3].

The Ca²⁺-signaling machinery includes Ca²⁺ entry and extrusion pathways in the plasma membrane (PM), ER membrane Ca²⁺ release channels, and Ca²⁺ reuptake ATPases within the ER membrane [4]. These Ca²⁺ transport pathways, in addition to intracellular Ca²⁺ buffers and Ca²⁺ uptake and release through other intracellular organelles, primarily the mitochondria, combine to shape highly tuned and dynamic Ca²⁺ transients that regulate cellular functions [5].

Under physiological conditions in non-excitable cells, Ca²⁺ transients are typically initiated downstream of agonist stimulation through the activation of the PLC-IP₃ signal transduction cascade, which leads to the opening of intracellular Ca²⁺ channel inositol 1,4,5-trisphosphate receptors (IP₃Rs) to release Ca²⁺ from intracellular stores [6]. Ca²⁺ release depletes the stores and activates a Ca²⁺ influx pathway in the PM termed store-operated Ca²⁺ entry (SOCE). SOCE is mediated by two key players: ER transmembrane Ca²⁺ sensors represented by the STIM family of proteins and PM Ca²⁺ channels of the Orai family that link directly to STIMs (see Chapters 1 through 3). The N-terminus of STIM1 faces the ER lumen and consists of two EF-hand domains that detect luminal Ca²⁺ concentration. The loss of STIM1 Ca²⁺ binding upon store depletion leads to conformational changes in the protein and its aggregation into clusters that translocate and stabilize into ER-PM junctions with very close apposition (∼20 nm) [7]. STIM1 within these ER-PM junctions binds to and recruits Orai1 through a diffusional trap mechanism, resulting in opening Orai1 channels and Ca²⁺ entry [8]. As such, the STIM-Orai clusters at ER-PM junctions define a specific microdomain at ER-PM junctions that also include the ER Ca-ATPase (SERCA) [9,10].

The tightly regulated remodeling of the Ca²⁺-signaling machinery upon store depletion allows for specific Ca²⁺ signaling in the midrange between Ca²⁺ microdomains and global Ca²⁺ waves [10] (see Chapter 5). Spatially, Ca²⁺ signaling can occur in localized spatially restricted elementary Ca²⁺ release events that activate effectors located in the immediate proximity of the Ca²⁺ channel. Alternatively, Ca²⁺ signals/waves occur/spread through the entire cell resulting in a global spatially unrestricted signal.

We have recently described a SOCE-dependent Ca²⁺-signaling modularity that signals in the midrange between these two spatial extremes [10]. Store depletion downstream of receptor activation and IP₃ generation results in a localized Ca²⁺ entry point source at the SOCE clusters that induces Ca²⁺ entry into the cytoplasm, which is readily taken up into the ER lumen through SERCA activity only to be released again through open IP₃Rs distally to the SOCE entry site and gate Ca²⁺-activated Cl^- channels as downstream Ca²⁺ effectors. This mechanism, referred to as “Ca²⁺ teleporting,” allows for specific activation of Ca²⁺ effectors that are distant from the point source Ca²⁺ channel without inducing a global Ca²⁺ wave, thus providing a novel module in the Ca²⁺-signaling repertoire. A cartoon summary of Ca²⁺ teleporting is found in Figure 12.1.

Figure 12.1

Cartoon illustrating Ca²⁺ teleporting that mediates midrange Ca²⁺ signaling. Receptor activation generates IP₃ that releases Ca²⁺ from stores. Following store depletion, the SOCE machinery forms spatially localized clusters that support Ca²⁺ entry. Ca (more...)

The relationship between Ca²⁺ signaling and cellular proliferation is complex with Ca²⁺ transients detected at various stages of the cell cycle [2]. These transients are thought to activate a multitude of Ca²⁺ effectors downstream of the initial Ca²⁺ signal, which were shown to be important for cellular proliferation, including, for example, calmodulin (CaM) and Ca²⁺-CaM-dependent protein kinase II (CaMKII).

However, there are a few cases where Ca²⁺ signals have been shown directly to be critical for cell cycle progression, including in mitosis for nuclear envelope breakdown and for chromosome disjunction [11]. In contrast, nuclear envelope breakdown during meiosis in vertebrate oocytes occurs independently of Ca²⁺, but Ca²⁺ is required for the completion of meiosis I in vertebrate oocytes [12–14]. Interestingly, multiple Ca²⁺ signaling pathways are modified during M-phase of the cell cycle, with the best defined example being Xenopus oocyte maturation [15].

Several Ca²⁺ influx pathways have been implicated in cell proliferation and cell cycle progression, including TRP channels, voltage-gated Ca²⁺ channels (Ca_V), purinergic P2X receptors, ionotropic glutamate receptors, and SOCE [16]. Blockers of voltage-gated Ca²⁺ channels were shown to slow down cell growth, arguing for a role for these channels in cell cycle progression [16–18]. Experimental manipulation of the expression levels of members of the TRPC, TRPV, and TRPM families of cation channels, which are Ca²⁺ permeable, was linked to cell proliferation with differential effects depending on the particular channel studied [16]. However, some of these studies are difficult to interpret because channel knockdown or overexpression could have significantly broader effects on Ca²⁺ signaling than affecting Ca²⁺ influx through the specific channel in question, as it may lead to changes in expression of other Ca²⁺-signaling pathways as a compensatory mechanism. Furthermore, the majority of TRP channels conduct cations with some Ca²⁺ permeability and are not Ca²⁺ selective like Orai1 or Ca_V channels, with the exception of TRPV5 and TRPV6 (see Chapter 13). Hence, changes in their expression is likely to affect the ionic balance across the cell membrane with effects on resting membrane potential, which may in turn affect cell proliferation.

The relationship between SOCE and cell proliferation is an intimate one that goes beyond the well-recognized roles of Ca²⁺ signaling in cellular growth and proliferation. SOCE is dramatically downregulated during the division phase of the cell cycle through mechanisms that have not been fully elucidated. This is in line with the significant remodeling of the Ca²⁺-signaling machinery during M-phase, which has been well characterized during oocyte meiosis. Furthermore, there is mounting evidence from multiple neoplasms for an important role for SOCE in metastasis.

This chapter presents a brief overview of our current knowledge as to the mechanisms regulating SOCE during cell cycle from cellular proliferation to metastasis with an emphasis on SOCE regulation during cell division (mitosis and meiosis).

12.2. Role of Ca²⁺ Signals in Cellular Proliferation

The requirement for Ca²⁺ in cell proliferation has been known for decades with the optimum extracellular Ca²⁺ concentration to support proliferation being in the 0.5–1 mM range [16]. However, the requirement for Ca²⁺ during cell growth and proliferation is vague and difficult to define given the broad involvement of Ca²⁺ signaling in many aspects of cellular physiology and signaling. Also, bifurcating signaling pathways such as G-protein-coupled receptor activation can induce cell proliferation together with a Ca²⁺ signal without any direct link between Ca²⁺ and cell growth. Nonetheless, Ca²⁺ influx appears to support cellular proliferation since immortalized/neoplastic cells do not require as much Ca²⁺ in the extracellular medium as primary cells, and this is of importance for cell cycle studies and in the design of anticancer drugs.

Ca²⁺ release from intracellular stores through IP₃Rs or ryanodine receptors (RyR) has been implicated in proliferation. IP₃R activation is involved in stimulating the proliferation of stem cells, kidney cells, pancreatic beta cells, breast cancer, and vascular smooth muscle cells [19–26]. RyR are more likely to be involved in the regulation of cellular differentiation [25]. The activation of IP₃Rs also stimulates the proliferation of breast cancer cells [26]. Interestingly, breast cancer cells rely for their survival and proliferation on Ca²⁺ released via IP₃Rs to fuel mitochondrial respiration, making this Ca²⁺-dependent cross talk between the ER and mitochondria a potential target for drug development [27].

Further strengthening a role for Ca²⁺ in proliferation, several Ca²⁺-dependent downstream effectors have been implicated in cellular proliferation. A primary intracellular Ca²⁺-binding effector, the ubiquitous cellular Ca²⁺-sensing protein CaM, is required for cell cycle progression and proliferation [28,29]. Furthermore, CaM levels are highly regulated during the cell cycle with an increase at the G₁/S transition [30]. Several effectors downstream of CaM have been identified, including CaM kinases I and II that interfere with various steps of the cell cycle, and CaM-dependent protein phosphatase calcineurin [31–33]. In T cells, calcineurin dephosphorylates and activates the nuclear factor of activated T cells (NFAT), inducing its nuclear translocation, where it stimulates gene transcription in support of cell proliferation [34] (see Chapter 5). Several other effectors have been identified downstream of Ca²⁺ signals and the activation of CaM-dependent phosphorylation/dephosphorylation processes such as NF-κB and the cAMP response element [33].

Ca²⁺ influx through multiple pathways has also been implicated in cell proliferation. Ca_V channels, particularly T-type channels, have been described as regulating the proliferation of several cancer cells [35], and in the case of TRP channels, most knockdown experiments revealed that they are also required for cell proliferation [16]. SOCE is now probably the most extensively studied Ca²⁺ pathway involved in cell proliferation. Beyond the immune response, NFAT stimulation by SOCE is involved in the proliferation of other cell types such as neural progenitor cells [36,37], osteoblasts [38], kidney cells [39], and endothelial and endothelial progenitor cells involved in angiogenesis in cancer patients [40,41].

12.3. Remodeling of the Ca²⁺-Signaling Machinery during Meiosis

As discussed earlier, not only are Ca²⁺ signals important for cellular proliferation and cell cycle progression, but Ca²⁺ transport pathways are themselves modulated during the cell cycle. This regulation of Ca²⁺ signaling during the cell cycle is presumed to support its progression although direct evidence for this remains scarce. An important case study is the remodeling of Ca²⁺-signaling pathways during Xenopus oocyte meiosis, where multiple Ca²⁺-signaling modules are modified to prepare the egg for fertilization and the egg-to-embryo transition.

Vertebrate oocytes arrest at prophase of meiosis I for prolonged periods of time [42,43]. Before oocytes acquire the competency to be fertilized, they undergo a maturation period during which they progress to metaphase of meiosis II in a process termed “oocyte maturation.” Mature oocytes, typically referred to as eggs, complete meiosis at fertilization and transition to the mitotic cell cycle. Egg activation is highly Ca²⁺ dependent as Ca²⁺ mediates critical steps to initiate development, including the block of polyspermy and the completion of meiosis II to ensure a proper egg-to-embryo transition. In order to be effective, these events need to occur in a chronological fashion since polyspermy needs to be prevented before the completion of meiosis to ensure zygote viability. Throughout phylogeny in all sexually reproducing species investigated to date, Ca²⁺ has been shown to encode the egg-to-embryo transition through a species-specific Ca²⁺ transient at fertilization with well-defined spatial, temporal, and amplitude dynamics [44–47]. Eggs acquire the ability to produce this fertilization-specific Ca²⁺ transient only after oocyte maturation, owing to dramatic remodeling of the Ca²⁺-signaling machinery during oocyte maturation that affects multiple Ca²⁺ transport proteins such as IP₃R, PMCA, and Orai/STIM [15].

The fertilization-specific Ca²⁺ signal in Xenopus is distinguished by a sustained elevated Ca²⁺ plateau that lasts for several minutes following a local Ca²⁺ rise at the site of sperm entry that spreads slowly (∼9 μm/s), in the form of a Ca²⁺ wave, across the entire egg [48–51]. In contrast, Ca²⁺ transients in oocytes tend to have a saltatory mode of propagation with a more rapid wave speed (∼20 μm/s) [52–54]. Given that the frog oocytes express only the type 1 IP₃R isoform and no RyR [55], these changes in Ca²⁺ release during oocyte maturation are thus due to changes in the regulation of the IP₃R during maturation as discussed in more detail in the following text. IP₃-dependent Ca²⁺ release plays a central role in mediating the Ca²⁺ transient at fertilization in vertebrate eggs.

In mammals, the slow oscillations that are maintained for long periods of time depend on Ca²⁺ influx from the extracellular space, presumably through the SOCE pathway [56–58]. Fertilization activates phospholipase Cγ (PLCγ) in Xenopus or delivers PLCζ in mammalian eggs, which increases IP₃ production and gates IP₃Rs to release Ca²⁺ from the ER [59–62]. It is clear that IP₃-dependent Ca²⁺ release properties are modulated during oocyte maturation when an increase in IP₃-dependent Ca²⁺-release sensitivity is noted and conserved among different species [54,63–67].

IP₃-dependent Ca²⁺ release is sensitized during Xenopus oocyte maturation [54]. Threshold IP₃ concentrations lead to small and spatially separate elementary Ca²⁺ release events (puffs) in oocytes [68]; whereas in eggs, similar IP₃ concentrations lead to larger consolidated events referred to as single release events (SREs) (Figure 12.2b) [54]. These larger release events are likely due to the clustering of the smaller elementary Ca²⁺ puffs [54,69–71]. The ER remodels during oocyte maturation forming large patches that are enriched in IP₃Rs as compared to the neighboring reticular ER (Figure 12.2a) [72]. Interestingly, we found that this clustering sensitizes IP₃Rs within ER patches, to respond to lower IP₃ concentrations as compared to IP₃Rs that localize to the reticular ER [72]. This sensitization appears to be due to increased Ca²⁺-dependent cooperativity at subthreshold IP₃ concentrations due to the physical clustering of IP₃Rs within ER patches, because IP₃Rs freely exchange between the two ER compartments (i.e., patches and reticular ER) [72]. A similar sensitization of the IP₃R is observed during mitosis [73] and has been suggested to depend on cdk1 phosphorylation of IP₃R [74].

Figure 12.2

Clustering of elementary Ca²⁺ release events during oocyte maturation.

Sensitization of IP₃-dependent Ca²⁺ release during oocyte maturation takes place simultaneously with the activation of multiple kinase cascades that drive this differentiation pathway. This argued for a potential role for phosphorylation of IP₃R in modulating its sensitivity in both Xenopus and mouse eggs, especially that IP₃R was found to be phosphorylated specifically during oocyte maturation at maturation-promoting factor (MPF)/mitogen-activated protein kinase (MAPK) conserved sites [54,75,76]. However, direct evidence showing that phosphorylation at these residues modulates IP₃ sensitivity of the channels is lacking. Furthermore, IP₃R sensitization could also be related to the number of functional IP₃Rs, given their gating cooperativity. In that context, the number of functional IP₃Rs increases during Xenopus oocyte maturation (without a significant change in total IP₃R protein pool) as they translocate from annulate lamellae to the ER [77,78]. Annulate lamellae represent an oocyte-specific vesicular compartment to which IP₃Rs localize but are silenced presumably through protein-protein interactions [77,78].

Two additional transport pathways important in defining Ca²⁺ transient in the frog oocyte are the PM Ca²⁺ ATPase (PMCA) that possesses high affinity for Ca²⁺ and functions to decrease Ca²⁺ levels back to the resting state [79,80] and the SERCA pump that ensures Ca²⁺ sequestration into the ER lumen [81]. PMCA, which localizes to the cell membrane in immature Xenopus oocytes, is internalized into an intracellular vesicular pool during oocyte maturation [71]. Coupled to the continuous and constant SERCA-dependent Ca²⁺ reuptake and the increased sensitivity of IP₃-dependent Ca²⁺ release, PMCA internalization contributes to the sustained Ca²⁺ plateau after the slow rising Ca²⁺ phase at fertilization [15,71].

Finally, SOCE completely inactivates in the mature Xenopus egg compared to immature oocytes [82,83]. The regulation of SOCE during meiosis is covered in more detail in the next section.

12.4. SOCE Inactivation during M-Phase

Immature Xenopus oocytes possess a robust SOC current that has similar biophysical properties to CRAC, the prototypical SOC channel activity originally characterized in immune cells [82,84,85] (see Chapter 1). However, during oocyte maturation, SOCE is inactivated completely: in mature eggs, SOCE is no longer activated when stores are depleted [82]. The inhibition of SOCE requires the activation of maturation-promoting factor (MPF, composed of CDK1 and cyclin B) [83]. This was shown by measuring both the SOC current and the levels of activation of multiple kinases that drive oocyte maturation at the single-oocyte level, to allow for direct correlation between the activity of various kinases and SOCE at the single-cell level [83]. Therefore, the fertilization-specific Ca²⁺ transient in Xenopus eggs is generated without contribution from SOCE. Xenopus eggs respond to sperm entry with a single sweeping Ca²⁺ transient that lasts several minutes [49,86]. This Ca²⁺ signal encodes subsequent events associated with egg activation in the following order: (1) fast block to polyspermy due to gating of Ca²⁺-activated Cl^- channels that depolarize the cell membrane; (2) slow block to polyspermy due to cortical granule fusion; and (3) completion of meiosis due to calcineurin and CaMKII activation [15,87,88]. SOCE inactivation is likely to contribute to shaping the dynamics of the fertilization-specific Ca²⁺ signal and therefore promote the egg-to-embryo transition.

Interestingly, SOCE is downregulated but not completely inactivated during mammalian oocyte meiosis as store depletion in metaphase II eggs induces Ca²⁺ entry, which supports Ca²⁺ oscillations following fertilization [89]. In contrast to Xenopus eggs, mammalian oocytes respond at fertilization with multiple Ca²⁺ oscillations that can last for hours [57]. Maintenance of these Ca²⁺ oscillations depends on Ca²⁺ influx through SOCE, presumably to refill Ca²⁺ stores and provide a continuous Ca²⁺ source for the Ca²⁺ release waves. There is, hence, a correlation between the occurrence of SOCE during meiosis and the ability of the oocyte to support Ca²⁺ oscillations at fertilization. Some reports have argued that SOCE amplitude increases during oocyte maturation in both mouse and pig [90,91]. In contrast, we and others have shown that SOCE is downregulated but not completely inhibited during mouse oocyte meiosis, and that downregulated SOCE is required for the egg-to-embryo transition [92,93]. The reasons for these discrepancies remain unclear. Nonetheless, collectively the data suggest that SOCE downregulation during vertebrate oocyte maturation represents an important determinant of the remodeling of Ca²⁺ signaling in preparation for fertilization.

Furthermore, similar to what is observed in meiosis of frog oocytes, SOCE is also inhibited during mitosis of mammalian cells. In the late 1980s, Volpi and Berlin showed that histamine stimulation during interphase in HeLa cells produced an initial Ca²⁺ rise owing to Ca²⁺ release from internal stores, followed by an elevated plateau due to Ca²⁺ influx from the extracellular space [94]. By contrast, histamine stimulation in mitotic cells resulted only in the Ca²⁺ release phase, arguing that Ca²⁺ influx is inhibited during mitosis. This observation was made around the time when the initial ideas regarding SOCE were being formulated. The same group later argued that SOCE inhibition during mitosis occurs due to uncoupling of store depletion from SOCE, as thapsigargin (an agent that causes store depletion by blocking SERCA) activated SOCE in interphase but not mitotic cells [95]. More recent studies confirmed that SOCE is inactivated during mitosis in RBL-2H3, HeLa, and HEK293 cells [96–98].

Investigating SOCE levels throughout the cell cycle showed that there is a slight enhancement of SOCE during the G₁ and S phases, and dramatic downregulation during M-phase [98]. Consistent with this cell cycle-dependent modulation of SOCE activity, SOCE has been shown to control the G₁/S transition but is not necessary during S-phase or the G₂/M transition [99]. Furthermore, SOCE has emerged as an important player in cell proliferation, yet the mechanisms by which it controls distinct phases of the cell cycle remain elusive. Recent studies show that inactivation of SOCE by silencing STIM1 in smooth muscle cells, cervical and breast cancer cells significantly inhibited proliferation by slowing down cell cycle progression [21,100]. This is discussed in more detail in Section 12.6.

Collectively, most current evidence argues that SOCE downregulation during M-phase is conserved and as such could be physiologically significant. Although this has not been directly addressed experimentally, one can speculate that tight regulation of Ca²⁺ signaling is required during M-phase owing to its important functional role at multiple steps throughout the process including nuclear-envelope breakdown, anaphase onset, and cell cleavage. Hence, SOCE inactivation might represent a safety mechanism that prevents sporadic Ca²⁺ signals from occurring during cell division, which may disrupt its normal progression.

12.5. Mechanisms Regulating SOCE Inactivation during M-Phase

Aside from the role of Maturation Promoting Factor (MPF, Cdk1) in SOCE inhibition, very little was known regarding the mechanistic regulation of SOCE inactivation during M-phase. It has also been argued that SOCE inhibition during mitosis in COS-7 cells is the result of the microtubule-network remodeling that accompanies mitosis [101]. Laser scanning confocal microscopy to monitor cytosolic Ca²⁺ dynamics revealed that SOCE was progressively inhibited in mitosis and became virtually absent during metaphase [101]. Russa and colleagues used various cytoskeletal modifying drugs and immunofluorescence to assess the contribution of microtubule and actin filaments to SOCE. Nocodazole treatment caused microtubule reorganization and retraction from the cell periphery that mimicked the natural mitotic microtubule remodeling that was also accompanied by SOCE inhibition. Short exposure to paclitaxel, a microtubule-stabilizing drug, strengthened SOCE, whereas long exposure resulted in microtubule disruption and SOCE inhibition. Actin-modifying drugs (cytochalasin D, calyculin A) did not affect SOCE. These findings indicate that mitotic microtubule remodeling plays a significant role in the inhibition of SOCE during mitosis. However, recent studies investigating the behavior of STIM1 and Orai1 during M-phase have provided additional insights [96,97,102–104].

STIM1 is a phosphoprotein, as revealed in large-scale mass spectrometry studies with different findings as to the specific phosphorylated residues from immunoprecipitated STIM1, presumably due to the different cell types used with lack of careful control of the cell cycle stage [105]. Smyth and colleagues reported that during mitosis of HeLa and HEK293 cells, which were treated with 1.67 μM nocodazole for 12–16 h, STIM1 fails to move to peripheral junctions to form puncta and interact with Orai1[97]. Furthermore, during mitosis, STIM1 becomes phosphorylated at multiple sites identified by mass spectrometry. Phosphorylation of STIM1 could also be detected by an anti-phospho-Ser/Thr-Pro MPM-2 antibody [106] in this study. STIM1 contains 10 minimal MPF-MAPK consensus sites (S/T-P), all located in the far C-terminus (Figure 12.3). Removal of these 10 residues by truncation at amino acid 482 abolished MPM-2 recognition of mitotic STIM1 [97]. The resulting truncated protein, when coexpressed with Orai1 in mitotic cells, partially rescues SOCE as measured by Ca²⁺ imaging and SOC current recording by whole-cell patch-clamp technique. In addition, alanine substitution at two residues (Ser486 and Ser668) was sufficient to partially rescue SOCE, although to a lesser extent than the 482 deletion mutant [97]. Cotransfection with an Orai1 construct was necessary in these experiments because truncated STIM1 was not able to rescue SOCE in mitotic cells unless Orai1 was coexpressed. In fact, Smyth and colleagues reported that HEK293 cells expressing the truncated STIM1 did expand at a slightly but significantly slower rate, but no other significant alterations to the mitotic process were observed [97].

Figure 12.3

The molecular domains of human STIM1. ER STIM1 contains a luminal and a cytosolic domain. Indicated are the locations in the sequence of the N-terminal signal peptide (SP), a Ca²⁺-binding canonical EF-hand domain (cEF), a non-Ca²⁺-binding hidden EF-hand (more...)

In a subsequent study, a STIM1 mutant retaining the full-length C-terminus, but lacking the 10 putative phosphorylation sites by alanine substitution (STIM1-10A), was able to rescue SOCE in mitotic cells expressing only endogenous Orai1 [96]. This would suggest that phosphorylation of STIM1 is the major underlying mechanism for shutting down SOCE during mitosis. When the cellular localization of STIM1-10A was examined by confocal microscopy in mitotic cells, the results were striking. STIM1-10A was incapable of dissociating from EB1 and accumulated in the spindle area. Mutation of the TRIP EB1-binding domain to TRNN rescued appropriate partitioning of STIM1 to the cell periphery. However, STIM1-10A supported SOCE in mitosis is likely not due to restoration of the EB1 interaction by STIM1-10A, because STIM1 activation of SOCE is independent of its EB1 interaction [107]. However, ER mislocalization driven by STIM-10A did not cause obvious mitotic defects. In addition, the phosphomimetic STIM1-10E mutant failed to inhibit SOCE activation in interphase cells [96].

Our group studied the mechanisms regulating SOCE inactivation during Xenopus oocyte meiosis with disparate results from what is observed in mitosis [103]. SOCE inactivation during meiosis is dependent on the kinase cascade that drives oocyte maturation, where activation of MPF was shown to be necessary and sufficient to inactivate SOCE in Xenopus oocytes [82,83]. Overexpression of human STIM1 and Orai1 by injection of in vitro transcribed mRNA into Xenopus oocytes greatly enhances SOCE, yet even this current induced by exogenous expression is inactivated during meiosis (Figure 12.4c) [103]. Associated with this inhibition of SOCE, STIM1 fails to cluster following Ca²⁺ store depletion (Figure 12.4b). Furthermore, meiosis was associated with inhibition of SOCE mediated by constitutively active STIM1 mutants [103], arguing that this inhibition is an active process. STIM1 is phosphorylated at multiple sites during meiosis as shown by a mobility shift on SDS-PAGE and by mass spectrometry. However, mutagenesis of all possible phosphorylation sites to alanines failed to rescue either STIM1 clustering or SOCE activation [103]. Interestingly, STIM1 clustering inhibition during meiosis required activation of MPF and was independent of the activity of the MAPK cascade, consistent with the requirement for MPF activation to inhibit endogenous SOCE during meiosis [83,103]. Our data suggest that STIM1 phosphorylation is not responsible for STIM1 clustering inhibition or SOCE inactivation during M-phase. Thus, while there are similarities between the regulation of STIM1 in meiosis and mitosis, there appear to be some differences as well. Indeed, it is likely that there is much more to be learned about the causes and consequences of STIM1 phosphorylation. More complex and sophisticated assays or models may be necessary to fully understand STIM1 phosphorylation.

Figure 12.4

Meiosis is associated with inhibition of STIM1 clustering and Orai1 internalization. Oocyte were injected with mCherry-STIM1 and GFP-Orai1 (a) and matured into eggs (meiosis) (b). Images show the distribution of Orai1 and STIM1 before and after store (more...)

In a follow-up study, substitution of the regulatory region of STIM1, which contains the 10 MPF-MAPK putative phosphorylation sites, with GFP-rescued clustering of STIM1 into puncta during meiosis, but still did not rescue SOCE [102]. These data argue that SOCE inactivation during meiosis is not only due to inhibition of STIM1 clustering in response to store depletion. Indeed, SOCE inactivation during meiosis is also associated with the removal of Orai1 from the cell membrane into an endosomal compartment (Figure 12.4b) [103,104]. Orai1 is enriched in the cell membrane of immature oocytes (Figure 12.4a) and continuously recycles between the cell membrane and an endosomal compartment through a Rho- and Rab5-dependent pathway [104]. However, in eggs, Orai1 is internalized into an endosomal compartment, which requires the activities of dynamin and caveolin in addition to Rab5. Orai1 possesses a consensus caveolin-binding domain in its N-terminal cytoplasmic region that when mutated inhibits the ability of Orai1 to be internalized during meiosis, supporting the role of caveolin-mediated endocytosis in Orai1 internalization [104]. Whether Orai1 trafficking is regulated during mitosis in a similar fashion to meiosis remains unclear (Figure 12.5). Nonetheless, even without the regulation of STIM1 by phosphorylation, Orai1 internalization would be sufficient to inhibit SOCE during M-phase, thus bringing into question the role of STIM1 phosphorylation.

Figure 12.5

Working model of SOCE inactivation during M-phase. (a) Events mediating STIM1Orai1 coupling during interphase. Orai1 has been shown to recycle between an endosomal compartment (Endo) and the cell membrane in Xenopus oocytes; however, it is not known whether (more...)

An important difference between mitosis and meiosis studies is the experimental approaches used as they may affect both the results and interpretations. Xenopus oocyte meiosis provides an important advantage in that oocytes are physiologically arrested at prophase I and eggs at metaphase II of meiosis, as discussed earlier. This removes the need for pharmacological or other experimental interventions to arrest cells in M-phase. M-phase is a transient phase that involves dramatic remodeling of multiple aspects of cellular physiology as the cell prepares to divide. Interventions such as nocodazole treatment may modify physiological processes in ways that are not always predictable. Such treatments, however, are necessary to allow cell synchronization in mitosis. Hence, future research should focus on the regulation of SOCE and STIM1 phosphorylation in mitosis under more physiological conditions, ideally in primary cells. Nonetheless, understanding SOCE inhibition during M-phase will undoubtedly provide important clues regarding the basic mechanisms controlling SOCE activation and regulation.

12.6. SOCE and Cancer

The level of Ca²⁺-signaling remodeling in cancer cells is remarkable and is associated with dysregulation of several Ca²⁺ channels and pumps [108,109]. The expression levels of essential components of SOCE, including members of the STIM and Orai families (Orai1, Orai3, STIM1, and STIM2), are modulated in several types of tumors. SOCE affects hallmarks of cancer progression, including cell cycle progression, escaping apoptosis, tumorigenesis, metastasis, angiogenesis, and tumor immunity. The differential expression of these components seems to depend on the cancer type and tumor stage (reviewed in [110–116]).

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Rawad Hodeify

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Fang Yu

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Raphael Courjaret

Department of Physiology and Biophysics

Weill-Cornell Medical College

Doha, Qatar

Nancy Nader

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Maya Dib

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Lu Sun

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Ethel Adap

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Satanay Hubrack

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar

Khaled Machaca

Department of Physiology and Biophysics

Weill Cornell Medicine Qatar

Doha, Qatar