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SOCE and cancer: Recent progress and new perspectives

View Article: PubMed Central - PubMed

ABSTRACT

Ca2+ acts as a universal and versatile second messenger in the regulation of a myriad of biological processes, including cell proliferation, differentiation, migration and apoptosis. Store‐operated Ca2+ entry (SOCE) mediated by ORAI and the stromal interaction molecule (STIM) constitutes one of the major routes of calcium entry in nonexcitable cells, in which the depletion of intracellular Ca2+ stores triggers activation of the endoplasmic reticulum (ER)‐resident Ca2+ sensor protein STIM to gate and open the ORAI Ca2+ channels in the plasma membrane (PM). Accumulating evidence indicates that SOCE plays critical roles in cancer cell proliferation, metastasis and tumor neovascularization, as well as in antitumor immunity. We summarize herein the recent advances in our understanding of the function of SOCE in various types of tumor cells, vascular endothelial cells and cells of the immune system. Finally, the therapeutic potential of SOCE inhibitors in the treatment of cancer is also discussed.

No MeSH data available.


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Schematic diagram of SOCE mediated by ORAI1 and STIM1. (a) STIM1 protein consists of a canonical EF hand, a hidden EF hand and a SAM domain in the ER luminal domain, and CCD, SOAR and ERM domains as well as serine‐ or proline‐ and lysine‐rich clusters on the cytosolic side. (b) The ORAI1 protein contains four membrane‐spanning regions and intracellular N‐ and C‐termini. It also has a unique R/P‐rich region in the N‐terminus and a putative coiled‐coil domain in its intracellular C‐terminus. (c) The stimulation of PM receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca2+ release from the ER lumen. STIM1 senses Ca2+ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca2+ influx through ORAI channels. The Ca2+ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other nonhematopoietic cells.
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ijc29840-fig-0001: Schematic diagram of SOCE mediated by ORAI1 and STIM1. (a) STIM1 protein consists of a canonical EF hand, a hidden EF hand and a SAM domain in the ER luminal domain, and CCD, SOAR and ERM domains as well as serine‐ or proline‐ and lysine‐rich clusters on the cytosolic side. (b) The ORAI1 protein contains four membrane‐spanning regions and intracellular N‐ and C‐termini. It also has a unique R/P‐rich region in the N‐terminus and a putative coiled‐coil domain in its intracellular C‐terminus. (c) The stimulation of PM receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca2+ release from the ER lumen. STIM1 senses Ca2+ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca2+ influx through ORAI channels. The Ca2+ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other nonhematopoietic cells.

Mentions: During the last decade, the two major protein families STIM and ORAI12, 17, 18, 19 were identified. STIM proteins (STIM1 and STIM2) are type I single‐pass transmembrane proteins that are located predominantly in the ER.23 As shown in Figure 1a, the domain structure of STIM1 includes the following: an N‐terminal signal peptide, a canonical EF hand Ca2+‐binding motif, a hidden non‐Ca2+‐binding EF hand and a sterile α‐motif (SAM) domain in the ER luminal region, a putative coiled‐coil domain (CCD), a STIM‐ORAI activating region (SOAR) or CRAC activation domain (CAD), a serine‐ or proline‐rich clusters and a polybasic C‐tail in the cytoplasmic region.24 The EF‐hand domain is responsible for sensing the Ca2+ fluctuation in the ER lumen, whereas the cytoplasmic domain, in particular the SOAR/CAD domain,25, 26 directly gates and opens the ORAI channels. At rest, STIM1 is evenly distributed throughout the ER membrane. On depletion of Ca2+ stores, STIM1 undergoes rapid dimerization/oligomerization and moves into regions at the ER–PM junctions (termed puncta) so that they can physically interact with ORAI channels and elicits Ca2+ influx within a few seconds.27 The STIM1 homologue STIM2 acts as a weaker activator of ORAI channels and is responsible for the maintenance of stable cytosolic and ER Ca2+ concentrations to prevent uncontrolled activation of SOCE.28, 29


SOCE and cancer: Recent progress and new perspectives
Schematic diagram of SOCE mediated by ORAI1 and STIM1. (a) STIM1 protein consists of a canonical EF hand, a hidden EF hand and a SAM domain in the ER luminal domain, and CCD, SOAR and ERM domains as well as serine‐ or proline‐ and lysine‐rich clusters on the cytosolic side. (b) The ORAI1 protein contains four membrane‐spanning regions and intracellular N‐ and C‐termini. It also has a unique R/P‐rich region in the N‐terminus and a putative coiled‐coil domain in its intracellular C‐terminus. (c) The stimulation of PM receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca2+ release from the ER lumen. STIM1 senses Ca2+ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca2+ influx through ORAI channels. The Ca2+ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other nonhematopoietic cells.
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ijc29840-fig-0001: Schematic diagram of SOCE mediated by ORAI1 and STIM1. (a) STIM1 protein consists of a canonical EF hand, a hidden EF hand and a SAM domain in the ER luminal domain, and CCD, SOAR and ERM domains as well as serine‐ or proline‐ and lysine‐rich clusters on the cytosolic side. (b) The ORAI1 protein contains four membrane‐spanning regions and intracellular N‐ and C‐termini. It also has a unique R/P‐rich region in the N‐terminus and a putative coiled‐coil domain in its intracellular C‐terminus. (c) The stimulation of PM receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca2+ release from the ER lumen. STIM1 senses Ca2+ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca2+ influx through ORAI channels. The Ca2+ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other nonhematopoietic cells.
Mentions: During the last decade, the two major protein families STIM and ORAI12, 17, 18, 19 were identified. STIM proteins (STIM1 and STIM2) are type I single‐pass transmembrane proteins that are located predominantly in the ER.23 As shown in Figure 1a, the domain structure of STIM1 includes the following: an N‐terminal signal peptide, a canonical EF hand Ca2+‐binding motif, a hidden non‐Ca2+‐binding EF hand and a sterile α‐motif (SAM) domain in the ER luminal region, a putative coiled‐coil domain (CCD), a STIM‐ORAI activating region (SOAR) or CRAC activation domain (CAD), a serine‐ or proline‐rich clusters and a polybasic C‐tail in the cytoplasmic region.24 The EF‐hand domain is responsible for sensing the Ca2+ fluctuation in the ER lumen, whereas the cytoplasmic domain, in particular the SOAR/CAD domain,25, 26 directly gates and opens the ORAI channels. At rest, STIM1 is evenly distributed throughout the ER membrane. On depletion of Ca2+ stores, STIM1 undergoes rapid dimerization/oligomerization and moves into regions at the ER–PM junctions (termed puncta) so that they can physically interact with ORAI channels and elicits Ca2+ influx within a few seconds.27 The STIM1 homologue STIM2 acts as a weaker activator of ORAI channels and is responsible for the maintenance of stable cytosolic and ER Ca2+ concentrations to prevent uncontrolled activation of SOCE.28, 29

View Article: PubMed Central - PubMed

ABSTRACT

Ca2+ acts as a universal and versatile second messenger in the regulation of a myriad of biological processes, including cell proliferation, differentiation, migration and apoptosis. Store‐operated Ca2+ entry (SOCE) mediated by ORAI and the stromal interaction molecule (STIM) constitutes one of the major routes of calcium entry in nonexcitable cells, in which the depletion of intracellular Ca2+ stores triggers activation of the endoplasmic reticulum (ER)‐resident Ca2+ sensor protein STIM to gate and open the ORAI Ca2+ channels in the plasma membrane (PM). Accumulating evidence indicates that SOCE plays critical roles in cancer cell proliferation, metastasis and tumor neovascularization, as well as in antitumor immunity. We summarize herein the recent advances in our understanding of the function of SOCE in various types of tumor cells, vascular endothelial cells and cells of the immune system. Finally, the therapeutic potential of SOCE inhibitors in the treatment of cancer is also discussed.

No MeSH data available.


Related in: MedlinePlus