| 2005 |
STIM1 (and its Drosophila ortholog Stim) is an essential and conserved component of store-operated Ca2+ (SOC)/CRAC channel function; RNAi-mediated knockdown of Stim in Drosophila S2 cells suppressed CRAC current, and knockdown of human STIM1 in Jurkat T cells similarly reduced CRAC channel activity and thapsigargin- or agonist-dependent Ca2+ entry. |
RNAi knockdown, patch-clamp electrophysiology, Ca2+ imaging in Drosophila S2 cells, Jurkat T cells, HEK293, and SH-SY5Y cells |
The Journal of cell biology |
High |
15866891
|
| 2006 |
The cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, ICRAC, and TRPC1 channels; the ERM domain mediates selective binding of STIM1 to TRPC1, 2, and 4 (but not TRPC3, 6, or 7), and a cationic lysine-rich region is essential for gating of TRPC1. |
Dominant-negative mutant overexpression, siRNA knockdown, Co-IP, Ca2+ imaging, patch-clamp in HEK293 and Jurkat cells |
Nature cell biology |
High |
16906149
|
| 2009 |
STIM1 amino acid fragment 344-442 (SOAR, STIM1-Orai activating region) is necessary and sufficient to fully activate all Orai channels; SOAR acts in combination with STIM1 (450-485) to regulate interaction strength with Orai1; the polybasic STIM1 (672-685) mediates characteristic inward rectification of Orai1 by interacting with a Pro-rich region in the Orai1 N-terminus; SOAR mutations prevent Orai1 activation but not co-clustering. |
Domain deletion/mutagenesis, Ca2+ imaging, patch-clamp electrophysiology, Co-IP in HEK293 cells |
Nature cell biology |
High |
19182790
|
| 2008 |
Store depletion triggers redistribution of STIM1 and co-clustering with Orai1, accompanied by a pronounced increase in FRET between STIM1 and Orai1, demonstrating physical interaction underlies CRAC channel activation; store depletion also induces STIM1-dependent conformational rearrangements within Orai1 (decrease in Orai1-Orai1 FRET). |
Live-cell FRET microscopy, patch-clamp, mutagenesis in HEK293 cells |
The Journal of physiology |
High |
18832420
|
| 2010 |
STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress, which evokes constitutive Ca2+ entry independent of intracellular Ca2+ stores; STIM1- and Orai1-deficient cells are resistant to oxidant stress-induced Ca2+ entry and cell death. |
S-glutathionylation assay, site-directed mutagenesis (C56), Ca2+ imaging, siRNA knockdown in multiple cell lines |
The Journal of cell biology |
High |
20679432
|
| 2010 |
STIM1 contains an intramolecular clamp: an acidic motif within the STIM1 coiled-coil region keeps the CAD/SOAR domain inactive; mutations in this acidic region render STIM1 constitutively active, while mutations in a short basic segment of CAD/SOAR prevent Orai1 activation, supporting a model where CAD/SOAR is released from an intramolecular clamp during STIM1 activation. |
Site-directed mutagenesis, Ca2+ imaging, FRET, co-immunoprecipitation in HEK293 cells |
Science signaling |
High |
21081754
|
| 2000 |
STIM1 protein is located at the cell surface (plasma membrane) in addition to intracellular compartments; it is a phosphoprotein (phosphorylated predominantly on serine residues) and is N-linked glycosylated; it is not secreted and does not undergo proteolytic processing. |
Immunofluorescence, cell surface biotinylation, Western blot, phosphorylation analysis in K562 cells |
Biochimica et biophysica acta |
Medium |
11004585
|
| 2008 |
Reversal of STIM1 puncta formation (from near-PM junctions back to tubular ER distribution) absolutely requires SOCE-dependent store refilling; ML-9, an MLCK inhibitor, causes rapid store-independent reversal of STIM1 puncta and inhibition of SOCE and ICRAC; STIM1 puncta form at specific predetermined cellular loci. |
Live-cell EYFP-STIM1 fluorescence imaging, patch-clamp, pharmacological inhibition in HEK293 cells |
Journal of cell science |
Medium |
18285445
|
| 2009 |
STIM1 gates TRPC channels by electrostatic interaction between STIM1 K684/K685 in the polybasic domain and conserved negative charges (aspartates/glutamates) in TRPC1 (D639/D640) and TRPC3 (D697/D698); charge mutants provide direct evidence for TRPC channels as STIM1-regulated SOCs. |
Charge-swap mutagenesis, Co-IP, Ca2+ imaging, patch-clamp in HEK293 cells |
Channels (Austin, Tex.) |
High |
19574740
|
| 2009 |
TRPC channels (TRPC1, 3, 5, 6, 7) function independently of STIM1 and Orai1 in HEK293 cells; STIM1 knockdown did not reduce TRPC5 activity and TRPC7-mediated entry was not dependent on STIM1 or Orai1; STIM1/Orai1 signaling and TRPC signaling occur in distinct plasma membrane domains (STIM1 puncta are distinct from lipid rafts). |
RNAi knockdown, constitutively active STIM1 mutant expression, Ca2+ imaging, lipid raft disruption in HEK293 and vascular smooth muscle cells |
The Journal of physiology |
Medium |
19332491
|
| 2011 |
STIM1 controls the magnitude of Ca2+ entry in B cells through SOCE, and its concentration sets a threshold for Ca2+-driven, PKC-δ- and RasGRP-dependent proapoptotic Erk activation that mediates negative selection; this pathway is biochemically distinct from DAG-driven Erk activation. |
Genetic overexpression/knockdown of STIM1, PKC-δ knockout mice, Ca2+ imaging, Erk activation assays in B cells |
Nature immunology |
High |
21441934
|
| 2013 |
STIM1 macrophages lacking STIM1 cannot activate FcγR-induced Ca2+ entry and phagocytosis; STIM1 deficiency results in resistance to experimental immune thrombocytopenia, anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis, establishing STIM1 as an essential component of FcγR activation. |
Conditional STIM1 knockout mice, Ca2+ imaging, phagocytosis assays, in vivo disease models |
Blood |
High |
18941110
|
| 2013 |
STIM1 controls endothelial barrier function by coupling the thrombin receptor to RhoA activation, myosin light chain phosphorylation, actin stress fiber formation, and loss of cell-cell adhesion, independently of Ca2+ entry and Orai1. |
siRNA knockdown, STIM1 overexpression, RhoA activity assay, transendothelial electric resistance measurement, myosin light chain phosphorylation assay in endothelial cells |
Science signaling |
High |
23512989
|
| 2014 |
STIM1 p.R304W gain-of-function mutation in the coiled-coil 1 domain causes constitutive activation of the CRAC channel in vitro; in zebrafish, this results in spontaneous bleeding and reduced thrombocytes, recapitulating Stormorken syndrome. |
Heterologous expression, Ca2+ imaging, patch-clamp, zebrafish model of Stormorken syndrome |
Proceedings of the National Academy of Sciences of the United States of America |
High |
24591628
|
| 2014 |
STIM1 co-clustering with Orai1 is controlled by a coiled-coil clamp: CC1-CC3 interaction regulates SOAR/CAD exposure and higher-order oligomerization; disrupting CC1-CC3 interactions leads to constitutive STIM1 activation and Orai1 channel opening. |
FRET-derived Interaction in a Restricted Environment (FIRE) assay, mutagenesis, Ca2+ imaging in HEK293 cells |
The Journal of biological chemistry |
High |
25342749
|
| 2014 |
STIM1 is polarized to the front of migrating endothelial leader cells via microtubule plus-end transport, where local ER Ca2+ depletion activates STIM1 to support pulsatile front retraction and adhesion during directed cell migration; diacylglycerol gradient from polarized PLC signaling further promotes persistent forward migration. |
Live-cell fluorescence imaging, STIM1 overexpression/knockdown, Ca2+ imaging in migrating endothelial cells |
Nature cell biology |
High |
24463606
|
| 2014 |
STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly (via Src activation) and extracellular matrix degradation; Orai1 blockade inhibited MT1-MMP recycling to the plasma membrane, trapping it in endocytic compartments. |
STIM1 knockdown, Ca2+ imaging, invadopodium assays, MT1-MMP trafficking assay, xenograft mouse model |
The Journal of cell biology |
High |
25404747
|
| 2015 |
STIM1 local rearrangement within its transmembrane domain (rather than change in oligomeric state) prompts conformational changes in the cytosolic juxtamembrane coiled-coil region; critical residues within the cytoplasmic domain mediate autoinhibition; STIM1-TM reorganization switches STIM1-CT into an extended conformation, projecting the ORAI-activating domain to gate ORAI1 channels. |
Gain-of-function TM domain mutation, FRET, Ca2+ imaging, mutagenesis in HEK293 cells |
Nature communications |
High |
26184105
|
| 2015 |
STIM1 and Orai1 form nanoclusters at ER-PM junctions; extended STIM1 molecules bridge a 12-nm ER-PM gap and rearrange into small clusters following store depletion; Orai1 channels aggregate into puncta on raised membrane subdomains upon store depletion; stoichiometry of Orai1 is unchanged by store depletion or STIM1 co-expression. |
Transmission electron microscopy, freeze-fracture electron microscopy of STIM1- and Orai1-transfected HEK293 cells |
Proceedings of the National Academy of Sciences of the United States of America |
High |
26351694
|
| 2016 |
In cardiomyocytes, STIM1 silencing impairs mTORC2 kinase activity and phosphorylation of Akt at S473, leading to enhanced GSK-3β activity and failure of adaptive hypertrophy; STIM1 directly interacts with Rictor, a specific component of mTOR complex 2, placing STIM1 upstream of mTORC2/Akt/GSK-3β signaling in cardiac hypertrophy. |
In vivo shRNA gene silencing in mice, Co-IP (STIM1-Rictor interaction), mTORC2 kinase assay, Akt phosphorylation assay, pressure overload models |
Circulation |
High |
26936863
|
| 2017 |
STIM1 phosphorylation at Y361 by Pyk2 kinase upon ER Ca2+ store depletion is required for Orai1 recruitment into STIM1 puncta and SOCE; phospho-defective STIM1-Y361F formed puncta but failed to recruit Orai1 and prevented thrombin-induced vascular permeability in mouse lungs. |
Site-directed mutagenesis, phospho-specific antibody, Ca2+ imaging, transendothelial resistance, in vivo mouse lung vascular permeability assay |
Scientific reports |
High |
28218251
|
| 2017 |
Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 at a site adjacent to the STIM1-Orai1 coupling region, disrupts the STIM1-Orai1 complex, disassembles STIM1 oligomers, and facilitates slow Ca2+-dependent inactivation of the CRAC channel. |
Co-IP, pulldown, mutagenesis of CaM-binding site, Ca2+ imaging, FRET in HEK293 cells |
Nature communications |
High |
29051492
|
| 2018 |
The STIM1 ER-luminal domain has 5-6 Ca2+-binding sites (not just the single EF-hand); binding at these sites is energetically coupled to the EF-hand site; Ca2+ dissociation controls a switch to a second structured conformation of the luminal domain rather than protein unfolding; other luminal-domain Ca2+-binding sites interact with the EF-hand to control physiological STIM1 activation in cells. |
In vitro Ca2+ binding assays, mutagenesis, structural characterization, functional Ca2+ imaging in cells |
Nature communications |
High |
30382093
|
| 2018 |
In unstimulated T cells, ORAI1, RYR1, and STIM1 form preformed nanoscale complexes (diameter ~300 nm) in the subplasmalemmal space confirmed by super-resolution microscopy and Co-IP/FRET; upon TCR stimulation, NAADP-evoked Ca2+ release through RYR1 in coordination with ORAI1 and STIM1/STIM2 rapidly increases Ca2+ microdomains. |
Super-resolution microscopy, Co-immunoprecipitation, FRET, Ca2+ microdomain imaging in primary T cells |
Science signaling |
High |
30563862
|
| 2019 |
The STIM1 α3 helical segment (aa 400-403) within CAD/SOAR does not mediate Orai1 binding but instead conveys STIM1 coupling into Orai1 channel gating; cysteine crosslinking revealed close proximity of STIM1 α3 to the cytosolic extension of Orai1 TM3, forming the STIM1-Orai1 gating interface (SOGI). |
Mutagenesis, cysteine crosslinking, FRET, patch-clamp in HEK293 cells |
Cell calcium |
High |
30831274
|
| 2019 |
Sequential Ca2+-dependent conformational changes of the luminal STIM1 domain upon activation were determined: Ca2+ dissociation destabilizes the two EF-hands, triggering disassembly of the hydrophobic cleft formed with the SAM domain; canonical EF-hand and hydrophobic cleft mutations associated with tubular aggregate myopathy or cancer yield constitutively clustered STIM1 with active Ca2+ entry through Orai1. |
Molecular dynamics simulations, site-directed mutagenesis, live-cell clustering assays, Ca2+ imaging |
Science signaling |
High |
31744929
|
| 2020 |
Optogenetic incorporation of photoreceptors into STIM1 modular domains revealed molecular determinants for STIM1 protein oligomerization, intramolecular conformational switch, and protein-target interactions; light-inducible STIM1 tools enabled reversible control of Ca2+ channel gating, dynamic protein-microtubule interactions, and ER-PM contact site assembly. |
Optogenetic engineering, FRET, Ca2+ imaging, live-cell microscopy in HEK293 cells |
Nature communications |
High |
32098964
|
| 2020 |
The NMR-derived solution structure of the STIM1 CC1 domain is a three-helix bundle; two interhelical sites between CC1α1 and CC1α2 helices control the CC1-CC3 clamp strength that governs the balance between tight (inactive) and extended (active) STIM1 conformations; these interactions are disrupted in the Stormorken disease-related STIM1 R304W mutant. |
Solution NMR structure determination, mutagenesis, FRET-based conformational assay, Ca2+ imaging |
Nature chemical biology |
High |
33106661
|
| 2021 |
Desmin, the major type III intermediate filament in muscle, is a binding partner for STIM1 (identified by yeast 2-hybrid and confirmed by Co-IP); desmin interacts with the CC1-SOAR domains of STIM1 to enhance STIM1 oligomerization yet limit SOCE; desmin connects STIM1 at the Z-line to regulate the efficiency of Ca2+ refilling of the SR. |
Yeast 2-hybrid screen, Co-immunoprecipitation, immunolocalization, SOCE measurements in desmin-KO mice |
JCI insight |
High |
34494555
|
| 2021 |
A neuronal splice variant of STIM1, STIM1B (spliced-in domain B), shows exclusive neuronal expression and slower kinetics of ER-PM cluster formation and ICRAC with reduced inactivation; STIM1B is targeted to presynaptic sites where it converts synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement at high-frequency stimulation. |
Splice variant characterization, patch-clamp (ICRAC), live-cell STIM1B cluster kinetics, primary neuron Ca2+ imaging, synaptic physiology |
Cell reports |
High |
33730587
|
| 2022 |
ER-resident STIM1/2 are binding partners of Pannexin-1 (Panx1), interacting at a hydrophobic region within the Panx1 N-terminus; STIM1/2 recruitment couples Ca2+ entry via NMDARs to Panx1 large-pore activation in neurons. |
Co-immunoprecipitation, domain deletion mutagenesis, function-blocking antibody, Ca2+ imaging, Panx1 KO neuron reconstitution |
Proceedings of the National Academy of Sciences of the United States of America |
High |
36037373
|
| 2023 |
The SOAR domain of STIM1 directly interacts with plasma membrane phosphoinositides via a conserved cluster of lysine residues to form ER-PM membrane contact sites; this interaction is co-regulated by STIM1 coiled-coil 1 and inactivation domains; SOAR oligomerization promotes direct PM phosphoinositide interaction to trap STIM1 at ER-PM MCSs. |
Electron microscopy, fluorescence microscopy, protein-lipid interaction assays (protein-lipid overlay, liposome sedimentation), mutagenesis |
Cell reports |
High |
36906853
|
| 2012 |
Surf4 associates with STIM1 in the endoplasmic reticulum; deletion of Surf4 in DT40 B cells resulted in markedly increased SOCE and facilitated STIM1 clustering upon store depletion, indicating Surf4 negatively modulates STIM1-mediated SOCE. |
Affinity purification/Co-IP of STIM1-binding proteins, Surf4 knockout DT40 cells, SOCE measurement, STIM1 clustering assay |
Biochemical and biophysical research communications |
Medium |
22609200
|
| 2014 |
STIM1 phosphorylation at ERK1/2 target sites (Ser575, Ser608, Ser621) is triggered by EGF/H-Ras signaling; Ser-to-Ala mutations impairing phosphorylation reduce cell migration and EMT marker changes (vimentin, E-cadherin) while phosphomimetic mutations restore them; EGF also triggers STIM1 dissociation from EB1 (microtubule plus-end regulator). |
Phospho-site mutagenesis (S→A and S→E), pharmacological ERK inhibition, wound healing assay, Co-IP (STIM1-EB1), Ca2+ imaging in Ishikawa cells |
Biochimica et biophysica acta |
Medium |
25447552
|
| 2015 |
Calsequestrin 1 (CSQ1) interacts with STIM1 in the ER; monomeric CSQ1 induced by store depletion or trifluoperazine enhances CSQ1-STIM1 interaction, which interferes with STIM1 oligomerization and reduces STIM1-Orai1 association and SOCE, providing a brake to SOCE under physiological conditions. |
Co-immunoprecipitation, pharmacological manipulation of CSQ folding, SOCE measurement, domain deletion mutagenesis in HEK293 cells |
Scientific reports |
Medium |
26087026
|
| 2016 |
STIM1 has a cholesterol-binding domain located within the SOAR region; STIM1/SOAR associates with cholesterol at the inner plasma membrane leaflet; cholesterol depletion induces SOAR detachment from the plasma membrane and enhances its association with Orai1, modulating SOCE. |
Cholesterol-binding assay, FRET, Ca2+ imaging, cholesterol depletion, domain mutagenesis |
Scientific reports |
Medium |
27459950
|
| 2011 |
STIM1 and STIM2 are located in acidic Ca2+ stores (lysosome-related organelles and dense granules) in human platelets; depletion of acidic stores enhances STIM1/STIM2 association with each other and with Orai1, TRPC1, and TRPC6; STIM2-SERCA3 association is also enhanced by acidic store depletion. |
Immunomagnetic organelle sorting, Co-immunoprecipitation in human platelets |
The Journal of biological chemistry |
Medium |
21321120
|
| 2014 |
Mitochondrial Ca2+ uptake (via MCU and UCP2) is required for efficient IP3-mediated STIM1 oligomerization; knockdown of MCU or UCP2 decelerated STIM1 oligomerization and impaired SOCE; MCU-dependent mitochondrial Ca2+ sequestration of Ca2+ entering through SOCE is essential to prevent slow deactivation of SOCE. |
shRNA knockdown of MCU/UCP2, STIM1 oligomerization FRET assay, SOCE measurement in HEK293 cells |
Journal of cell science |
Medium |
24806964
|
| 2019 |
STIM1 phosphorylation at Y316 regulates SOCE and ICRAC; the Y316F phospho-defective mutant reduces STIM1-Orai1 colocalization, decreases SOCE and ICRAC, alters the pattern of STIM1-SARAF interaction, and enhances slow Ca2+-dependent inactivation (SCDI); Y316 phosphorylation controls the STIM1-SARAF interaction that modulates SCDI. |
Site-directed mutagenesis, Ca2+ imaging, patch-clamp, Co-IP (STIM1-SARAF), siRNA SARAF knockdown in HEK293 and NG115-401L cells |
Journal of cell science |
Medium |
30975919
|
| 2023 |
TSPAN18 directly interacts with STIM1 and competitively inhibits E3 ligase TRIM32-mediated ubiquitination and degradation of STIM1, thereby increasing STIM1 protein stability and augmenting SOCE-mediated Ca2+ influx and prostate cancer bone metastasis. |
Mass spectrometry identification, Co-IP, ubiquitination assay, CRISPR-Cas9 STIM1 knockout, SOCE measurement, in vitro invasion assay, in vivo bone metastasis model |
Journal of experimental & clinical cancer research : CR |
Medium |
37542345
|
| 2009 |
Phosphatidylinositol 4-phosphate (PtdIns4P) rather than PtdIns(4,5)P2 is a likely determinant of Orai1 channel activity downstream of STIM1; PLC activation or PI4K inhibition substantially reduced SOCE and ICRAC without preventing STIM1 movements toward the PM, indicating that PtdIns4P is required for Orai1 activation but not STIM1 translocation. |
Chemically induced phosphoinositide 5-phosphatase recruitment, PI4K inhibition, patch-clamp, STIM1 imaging in HEK293 cells |
The Journal of biological chemistry |
Medium |
19483082
|
| 2015 |
Homer1 mediates the interaction between STIM1 and Cav1.2 voltage-operated Ca2+ channels; store depletion induces co-immunoprecipitation of Homer1 with STIM1 and Cav1.2 α1 subunit; disruption of Homer function reduces STIM1-Cav1.2 association and enhances nifedipine-sensitive Ca2+ entry, indicating Homer1 supports STIM1-mediated suppression of L-type channels. |
Co-immunoprecipitation, Homer1 siRNA, synthetic Homer-blocking peptide (PPKKFR), Ca2+ imaging in HEK293 cells |
Biochimica et biophysica acta |
Medium |
25712868
|
| 2017 |
STIM1 promotes phagosomal maturation in dendritic cells by facilitating delivery of endolysosomal enzymes to phagosomes; STIM1 ablation impairs phagosomal proteolysis, leucyl aminopeptidase activity, IRAP recruitment, and phagosome-endosome/lysosome fusion, thereby reducing antigen cross-presentation and DC migration. |
Conditional STIM1 knockout in myeloid cells, phagosomal pH/ROS assay, proteolysis assay, Ca2+ imaging, chemotaxis assay, cross-presentation assay in bone-marrow-derived DCs |
Nature communications |
High |
29176619
|
| 2010 |
STIM1 is regulated by the ubiquitin-proteasome system (UPS): STIM1 is ubiquitinated in cells; proteasome inhibition increases surface STIM1 levels and thapsigargin-induced SOCE; E3 ubiquitin ligase POSH overexpression decreases STIM1 surface levels. |
Surface biotinylation, proteasome inhibition, POSH overexpression, Ca2+ imaging in HEK293 cells and hippocampal neurons |
PloS one |
Medium |
20976103
|