Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Stromal Interaction Molecule

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101840

Synonyms

 GOK;  STIM1;  STIM2

Historical Background

STIM1 is a key protein in initiation of calcium flux. STIM1 senses and reacts to changes in the levels of stored calcium ions (Ca+2) in a cell. Cells keep tight control on many important intracellular calcium-dependent processes by controlling the availability of free Ca+2, maintaining low levels of free Ca+2 in the cytosol relative to extracellular and stored intracellular Ca+2 levels. In calcium flux, intracellular release of stored Ca+2 ions, primarily stored in the endoplasmic reticulum (ER) of non-muscle cells or in the sarcoplasmic reticulum in muscle cells, can initiate specific calcium-dependent activities in the cell, such as enzyme activation. The release of stored Ca+2 into the cytosol then triggers an influx of extracellular Ca+2 through cell membrane channels to amplify the calcium-dependent activities. This is referred to as SOCE (storage-operated calcium entry). The extracellular Ca+2 ions enter through CRAC channels (calcium release-activated channels) as well as through nonspecific cation channels. An additional part of calcium flux is the subsequent reestablishment of homeostasis with low levels of intracellular free Ca+2 in the cytosol by pumping Ca+2 ions back into storage in the ER using SERCA (sarco/endoplasmic reticulum calcium ATPase) pumps.

STIM1 was identified as a unique gene (initially called GOK) located at p15.5 in chromosome 11 in humans (Parker et al. 1996). This is in a region of the short arm of chromosome 11 named “multiple tumor-associated chromosome region 1” which is suspected of involvement in many different tumors, including pediatric malignancies (Richard et al. 1993). The human gene is approximately 4 kb long and encodes a single protein of an estimated 84 kDa that includes a transmembrane section. The gene is highly conserved with 90% identity between the mouse and human for both the DNA and amino acid sequences (Parker et al. 1996).

The involvement of STIM1 in calcium flux was first proposed by Zhang and colleagues (Zhang et al. 2005) based on their research with STIM1 EF-hand mutants that activated calcium release-activated calcium (CRAC) channels without there being a decrease of stored Ca+2. They also reported movement of wild-type STIM1 to the plasma membrane with depletion of stored Ca+2. This suggested that STIM1 is important in sensing changes in stored Ca+2 levels and in the activation of CRAC channels. Subsequently, STIM2 was identified as a STIM1 homologue with two STIM2 isoforms of 105 kDa and 115 kDa based on differential phosphorylation (Williams et al. 2001). STIM2, like STIM1, contains EF-hand and SAM domains and coprecipitates with STIM1 as oligomeric complexes. Although STIM1 and STIM2 show possible hetero-oligomeric associations, more recently, differences in the roles of STIM1 and STIM2 have emerged (Shalygin et al. 2014). In rat neurons, activation of SOCE to allow rapid influx of Ca+2 appears to be a primary function of STIM1, whereas STIM2 is involved in maintaining levels of intracellular Ca+2 in resting cells (Gruszczynska-Biegala et al. 2011).

Structure, Biosynthesis, and Metabolism

STIM1 is a single-pass transmembrane protein located primarily in the ER membrane, but it has been observed to a lesser extent in the cell membrane. Upon activation, STIM1 localizes to the puncta of the ER membrane where the ER and cell membranes are in close proximity (Baba et al. 2006). The N-terminal portion of STIM1 extends into the ER lumen and consists of an EF-hand domain and a SAM (sterile alpha motif) domain (Figs. 1 and 2). The EF hand domain is a known calcium binding motif, and, in inactive STIM1, the EF hand has a bound Ca+2 ion. Loss of this bound Ca+2 ion leads to activation of STIM1 (Stathopulos et al. 2008). The SAM domain is a known protein-protein interaction motif and is believed to facilitate STIM1-STIM1 homodimerization and STIM1-STIM2 heterodimerization. The cytoplasmic portion of inactive STIM1 appears as a folded structure with three alpha helical coiled regions (C1, C2, C3) referred to as the SOAR (STIM1-ORAI1-activating region) (Feske and Prakriya 2013). Further toward the C-terminal of STIM1 is a region of proline-serine residues that provide flexibility to the STIM1 tail which contains an enrichment of lysine residues with a high cationic charge (Fig. 1). The STIM1 gene is approximately 250 kb and contains 12 exons. STIM2, located at p15.1 on chromosome 4, is approximately 71 kb and contains ten exons. Intron/exon junctures are highly conserved between STIM1 and STIM2 (Williams et al. 2001). STIM1 is 685 amino acids in length, whereas STIM2 is approximately 748 amino acids, varying from STIM1 primarily in the C-terminus, suggesting differing interactions with CRAC channels. Ca+2 binding residues in the EF hand vary slightly between STIM1 and STIM2 suggesting a slower release by STIM2 during stored Ca+2 depletion, and this could contribute to their differing contributions in calcium flux and homeostasis. Expression of STIM1 and STIM2 can vary among cell types with STIM2 being more dominant in nerve cells.
Stromal Interaction Molecule, Fig. 1

STIM1: Inactive (left) and active (right) forms. STIM1 is a single-pass transmembrane protein with its C-terminus in the cytosol and the N-terminus in the ER lumen. The cytosolic portion contains the SOAR (STIM1-ORAI1-activating region), also referred to as the CAD (CRAC channel activating domain), which, in its active form, extends toward the cell membrane where the C-terminus interacts with ORAI1 components in a CRAC (calcium release-activated channel) complex. This STIM1-ORAI1 opens the CRAC channel for inflow of Ca+2. The cytosolic portion of STIM1 contains three coiled sections, a flexible proline-serine section and a lysine-rich region. The ER lumen portion of STIM1 has an EF-hand domain which binds a Ca+2 ion when STIM1 is inactive and a SAM (sterile alpha motif) domain which participates in protein-protein interactions when STIM1 is active

Stromal Interaction Molecule, Fig. 2

STIM1: SAM and EF-hand domains. The ER lumen portion of STIM1 has a SAM (sterile alpha motif) domain that is frequently found in proteins that undergo protein-protein interactions. It is believed to provide the interface in STIM1-STIM1 and STIM1-STIM2 interactions during oligomerization. The EF-hand domain is a frequently observed calcium binding motif. In inactive STIM1, a single calcium ion is bound. Upon depletion of stored Ca+2 in the ER, STIM1 becomes active, and this leads to conformational changes in the SAM domain to allow further protein-protein interactions, and it allows conformational changes in the cytosolic portion of STIM1, extending the SOAR section toward the cell membrane

De novo synthesis of STIM1 and ORAI1 is under the control of NF-κB (nuclear factor-kappa B) which binds in the gene promoter regions to stimulate expression (Lang et al. 2012). Further control of STIM1 and ORAI1 is provided by SGK1 (serum and glucocorticoid inducible kinase 1) which suppresses ubiquitination to reduce protein turnover and by AMPK (AMP activated kinase) which downregulates NF-κB. In addition, oligomerization of STIM1 and ORAI1 in CRAC channel activation further reduces their turnover.

The most important posttranslational modifications identified for STIM1 and STIM2 so far are phosphorylation and glycosylation. There are multiple phosphorylation sites on STIM1 and STIM2 that can alter protein-protein interactions. Multiple pathways are suspected for the variations of STIM phosphorylation. For example, phosphorylation of STIM1 at ERK1/ERK2 sites (SER575, Ser608, and Ser621) leads to release of STIM1 from EB1 during Ca+2 store depletion followed by return of STIM1 phosphorylation to basal levels (Pozo-Guisado et al. 2013). This suggests a means by which STIM1 activation of CRAC channels can be turned off following calcium influx. N-linked glycosylation at two asparagine sites within the STIM1 SAM domain, at N131 and N171, establishes STIM1 in the ER and assists in recognition and recycling of STIM1 (Williams et al. 2002). O-linked N-acetylglucosamine (O-GlcNAc) of STIM1 attenuates activation of SOCE in neonatal cardiomyocytes suggesting a role in early development of muscle tissue (Zhu-Mauldin et al. 2012).

Mechanism of Action

Calcium ions (Ca+2) are involved in important functions in cells such as enzyme activation, assisting in protein folding, initiating programmed cell death, controlled chromatin modification in NETosis or ETosis, conveyance of secondary signals within the cell, bone formation, and rapid depolarization of neurons and muscles (Mukherjee and Brooks 2014). Because of the broad range of involvement of calcium ions, intracellular levels and availability of Ca+2 must be tightly controlled. Whereas 99% of calcium in the body is tied up in bone, the level of free Ca+2 ions in the extracellular environment is typically around 1 mM. To avoid aberrant calcium-dependent intracellular activity, the cytosolic level of free Ca+2 is kept at 100 nM when the cell is at rest. In order to facilitate rapid calcium-dependent intracellular responses to extracellular signals, cells maintain stores of Ca+2 in the ER in non-muscle cells and the sarcoplasmic reticulum in muscle cells which can be released into the cytosol to initiate the intended intracellular calcium-dependent activity. Triggering of the different intracellular Ca+2 dependent activities typically initiates from extracellular signals that bind surface receptors which internalize the signal, transferring it to a secondary intracellular signal. The secondary signal then triggers release of stored Ca+2 from the ER. G protein-coupled receptors (GPCR) provide a typical example of such triggering (Mukherjee and Brooks 2014). When an extracellular ligand binds the GPCR, cytoplasmic phospholipase C (PLC) activity associated with the GPCR converts phosphatidylinositol 4,5-bisphosphate (PIP2) to a secondary signal, inositol 1,4,5-trisphosphate (IP3) (Fig. 3, 1). IP3 crosses the cytosol to activate IP3-responsive channels (IP3R) in the ER that allow an outflow of the stored Ca+2. The resulting drop in ER Ca+2 leads to loss of the bound Ca+2 ion in the STIM1 (or STIM2) EF-hand domain (Fig. 3, 2). The STIM1 without its bound Ca+2 then becomes active STIM1. Active STIM1 extends its cytoplasmic SOAR region and forms both cytosolic and ER dimerization interactions with other STIM1 or STIM2 molecules (Fig. 3, 3). These then move to the ER puncta, which are locations where the ER membrane is in close proximity to the cell membrane. The extended STIM1 (and STIM2) CAD (CRAC channel activating domains) interact with ORAI1 components of a CRAC channel opening the channel for inflow of Ca+2 to further effect the Ca+2-dependent activities (Fig. 3, 4). When the need for Ca+2 inflow subsides, the STIM1 interactions with the CRAC channel can end, possibly influenced by phosphorylation of STIM1 (Pozo-Guisado et al. 2013). The cell then reestablishes Ca+2 homeostasis by pumping Ca+2 ions back into ER storage (Fig. 3, 5). STIM can also activate other Ca+2 channels, such as the TRP channels, but most of our knowledge of STIM and CRAC channel activation was gained from STIM1-ORAI1 studies (Mukherjee and Brooks 2014). Numerous cell surface receptors can convey signals into the cell that trigger release of ER stored Ca+2. There are numerous intracellular Ca+2-dependent activities that can be induced from these triggers. Current research on calcium function and dysregulation is to understand the relation between specific receptors, secondary signals, and the resultant intracellular activities. This also involves analysis of the variations in STIM1 and STIM2 expression relative to each other in different cell types.
Stromal Interaction Molecule, Fig. 3

STIM1 activation. (1) When a cell surface receptor is stimulated by ligand binding, it can initiate a secondary signal, such as IP3 (inositol 1,4,5-triphosphate), which can activate release of ER-stored Ca+2 through IP3-responsive channels. The subsequent drop in the ER Ca+2 level leads to (2) activation of STIM1 when it loses its bound Ca+2 ion. Active STIM1 extends its cytosolic SOAR region and (3) undergoes further dimerization as it moves to the ER puncta. (4) STIM1 binds ORAI1 and opens the CRAC channel to allow additional Ca+2 to enter the cell. (5) Ca+2 is reestablished when SERCA (sarco/endoplasmic reticulum calcium ATPase) pumps Ca+2 ion back into storage in the ER

STIM in Health and Disease

Calcium dysregulation with STIM and SOCE involvement has been linked to some cancers, immunological diseases, neurological diseases, and numerous other diseases (Mukherjee and Brooks 2014). The key position of STIM molecules in initiating intracellular Ca+2-dependent actions indicates that STIM molecules and their partners are potential therapeutic targets.

Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder in which neurons are destroyed resulting in dementia and cognitive disorders due to synapse loss in the hippocampus and cortex. Plaque formation from accumulation of β-amyloid peptide (Aβ) can lead to neuron degeneration in AD. The Aβ occurs from cleavage of β-amyloid precursor protein (APP), a membrane protein. The enzymes that cleave the APP are β-secretase and γ-secretase. Accumulation of Aβ can induce oxidative stress and disrupt intracellular Ca+2 homeostasis in neurons. Mutations in the presenilin-1 (PS1) gene have been associated with some cases of familial AD. PS1, an aspartyl protease that is part of the γ-secretase complex, participates in the cleavage of APP. PS1 can affect ER C1+2 release channels as well as induce increased synthesis of STIM1 and STIM2. The resulting cellular stress can lead to Ca+2 dysregulation (Mukherjee and Brooks 2014).

Cancers

STIM molecules have shown involvement in cancers (reviewed in: Johnstone et al. 2010; Lang et al. 2012; Mukherjee and Brooks 2014). Disruption of Ca+2 homeostasis can lead to the abnormalities in metastasis, migration, motility, and transcription seen in cancer cells. In colorectal cancer, increased STIM2 expression is suspected of interfering with the tumor suppressor effects of STIM1-mediated apoptosis, leaving tumor cells capable of further progression (Aytes et al. 2012). In hepatocellular carcinomas, STIM1 has higher expression levels compared to the patient’s normal hepatocytes (Yang et al. 2013). And STIM1 overexpression is seen in a majority of early stage cervical cancers leading to Ca+2 dysregulation (Chen et al. 2013). These are just a few examples of the cancers with STIM-related Ca+2 dysregulation.

Immunology

The immune system has numerous vulnerabilities with regard to Ca+2 regulation from NETosis by neutrophils, as part of the early innate immune response to infections; to motility; and control of T cell and B cell proliferation in the adaptive immune response. SOCE involvement, including STIM1 and STIM2 expression, in different immune processes and immunodeficiencies has been described previously (Notarangela 2013; Robert et al. 2011; Baba and Kurosaki 2011).

Other Diseases and Abnormal States

SOCE with STIM1 involvement can be involved in other diseases and abnormal states such as stroke, infertility, tumor growth, hypertension, obesity, thrombosis, and diabetes. Many of these show abnormalities in SGK1 expression which affects SOCE and turnover rates of STIM1 and ORAI1 molecules.

Summary

STIM1 and STIM2 play important roles in calcium flux connecting the release of stored ER Ca+2 ions, triggered by cell surface receptors and intracellular secondary signals, to the opening of Ca+2 entry channels in the cell membrane by SOCE. Abnormalities in STIM expression and actions are involved in many varied diseases. However, we still need to identify and study all the components of calcium flux and homeostasis. There are other means of calcium entry besides the STIM1-ORAI1 CRAC channels, and these alternate routes need further definition. Also there is need to identify other binding partners of STIM1 and STIM2 when they are in their inactive states. The key roles of STIM1 and STIM2 in initiation of SOCE show that STIM molecules are promising targets for new therapeutics that will be effective in a broad variety of diseases. With regard to the STIM structures, further research is needed to determine how loss of the bound Ca+2 ion from the EF-hand domain in the ER lumen leads to conformational changes in the cytosolic portion of STIM as well as further protein-protein interactions during oligomerizations. In addition, the means by which different cell surface receptors using shared secondary signals to initiate release of stored Ca+2 from the ER can trigger different intracellular effects via STIMs and SOCE. Variations in location, duration, strength, and oscillations of the signals appear to have influence on the STIM1 and/or STIM2 responses and how intensely they affect CRAC channels and the subsequent return to Ca+2 homeostasis.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of South FloridaTampaUSA