Affinage

STIM1

Stromal interaction molecule 1 · UniProt Q13586

Length
685 aa
Mass
77.4 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STIM1 is an ER-resident single-pass transmembrane Ca2+ sensor that couples depletion of ER Ca2+ stores to activation of plasma-membrane Ca2+ channels, driving store-operated Ca2+ entry (SOCE) across diverse physiological settings (PMID:16906149, PMID:30382093). Sensing operates through the luminal domain, which carries the canonical EF-hand plus several additional energetically coupled Ca2+-binding sites; Ca2+ dissociation destabilizes the EF-hands and triggers disassembly of a hydrophobic cleft formed with the SAM domain, switching the protein into an activated conformation rather than unfolding it (PMID:30382093, PMID:31744929). Disease- and cancer-associated mutations in the EF-hand or hydrophobic cleft, and a gain-of-function mutation in coiled-coil 1 (R304W) that causes a platelet bleeding disorder, lock STIM1 into a constitutively clustered, channel-activating state (PMID:24591628, PMID:24619930, PMID:31744929). Activated STIM1 oligomerizes and is trapped at ER-PM junctions through SOAR-domain interactions with plasma-membrane phosphoinositides and cholesterol, bridging a ~12-nm ER-PM gap to form nanoscale clusters with its target channels (PMID:26351694, PMID:27459950, PMID:36906853). The SOAR/CAD region (residues 344-442) is necessary and sufficient to gate Orai channels, with helix α3 transmitting binding into channel opening at a defined STIM1-Orai1 gating interface, operating through a unimolecular coupling mechanism (PMID:19182790, PMID:26399906, PMID:30831274). Beyond Orai, the polybasic lysine-rich domain electrostatically gates TRPC1/4 channels (PMID:16906149, PMID:17517433, PMID:19574740). STIM1 activity is tuned by phosphorylation (Pyk2 at Y361 for Orai1 recruitment, Y316 regulating SARAF interaction and inactivation, ERK1/2 serines promoting migration), by S-glutathionylation at C56 conferring oxidant-activated Ca2+ entry, by Ca2+-calmodulin-mediated complex disassembly driving slow inactivation, and by TRIM32-mediated ubiquitination opposed by TSPAN18 (PMID:20679432, PMID:28218251, PMID:29051492, PMID:30975919, PMID:37542345, PMID:25447552). Through these mechanisms STIM1-dependent Ca2+ signaling controls T-cell and FcγR immune responses, dendritic-cell cross-presentation, directed cell migration and cancer invasion, vascular smooth-muscle coupling, and, via the neuronal splice variant STIM1B, presynaptic short-term synaptic enhancement (PMID:18250319, PMID:24463606, PMID:35147077, PMID:33730587, PMID:18941110, PMID:29176619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 Medium

    Before its Ca2+-sensing role was known, STIM1 was characterized biochemically as a phosphorylated, N-glycosylated, cell-surface-localized protein, establishing the basic protein chemistry and a surface pool later revisited functionally.

    Evidence Immunofluorescence, surface biotinylation, and PTM analysis in K562 cells

    PMID:11004585

    Open questions at the time
    • No link to Ca2+ signaling established at this stage
    • Relative size of surface vs ER pool not quantified
    • Function of glycosylation/phosphorylation not addressed
  2. 2006 High

    Established that the cytosolic STIM1 C-terminus is sufficient to activate SOC, ICRAC, and TRPC1 channels, and mapped distinct domains (ERM for TRPC binding, lysine-rich region for TRPC1 gating), defining STIM1 as a multi-channel activator.

    Evidence Domain deletion constructs, siRNA, electrophysiology, co-IP, dominant-negative analysis

    PMID:16906149

    Open questions at the time
    • Did not resolve the Orai-activating subregion within the C-terminus
    • Mechanism of luminal Ca2+ sensing not addressed
    • Direct vs indirect TRPC gating not distinguished
  3. 2007 Medium

    Demonstrated a store-independent function for the plasma-membrane STIM1 pool in gating ARC channels, distinguishing it from the ER store-operated mechanism.

    Evidence Extracellular antibody block, N-glycosylation mutants, CRAC vs ARC current recordings

    PMID:17391754

    Open questions at the time
    • Molecular interface with ARC channels not mapped
    • Physiological contexts for surface STIM1 not defined here
    • Single-lab observation
  4. 2008 High

    Resolved the physical coupling logic of activation: store depletion drives direct STIM1-Orai1 interaction with an Orai1 conformational change, STIM1 puncta form at predetermined ER-PM loci, and electrostatic charge-swap experiments defined the polybasic-domain mechanism gating TRPC1.

    Evidence Live-cell FRET, EYFP-STIM1 imaging, charge-swap mutagenesis, SOCE pharmacology

    PMID:17517433 PMID:18285445 PMID:18635545 PMID:18832420 PMID:19574740

    Open questions at the time
    • Atomic structure of the STIM1-Orai1 interface unresolved
    • Identity of factors defining puncta loci unknown
    • Stoichiometry of coupling not yet determined
  5. 2008 High

    Placed STIM1 in immune effector physiology, showing recruitment to the immunological synapse and an essential role in FcγR-mediated Ca2+ entry, phagocytosis, and multiple antibody-driven disease models.

    Evidence Live imaging of T-cell/DC conjugates, conditional KO macrophages, in vivo disease models

    PMID:18250319 PMID:18941110

    Open questions at the time
    • Downstream Ca2+-dependent effectors not fully dissected
    • Cell-type-specific channel partners not defined
    • Initial synapse accumulation mechanism (Orai-independent) unexplained
  6. 2009 High

    Defined the minimal Orai-activating module SOAR (344-442) as necessary and sufficient to gate all Orai isoforms and showed co-clustering alone is insufficient, separating recruitment from gating.

    Evidence Truncation/point mutagenesis, electrophysiology, co-clustering assays in HEK293

    PMID:19182790

    Open questions at the time
    • Residues transmitting binding into gating not yet pinpointed
    • Conformational basis of SOAR activation unresolved
    • Structural model of the coupled complex absent
  7. 2011 Medium

    Showed that STIM1 abundance is a tunable signaling variable, where elevated STIM1 engages a proapoptotic PKC-δ/RasGRP/Erk pathway in B-cell negative selection distinct from DAG-driven Erk.

    Evidence Genetic mouse models and biochemical epistasis

    PMID:21441934

    Open questions at the time
    • Direct link between SOCE magnitude and Erk activation not biochemically reconstituted
    • Generalizability beyond developing B cells unclear
    • Single-lab finding
  8. 2014 Medium

    Connected STIM1 to directed migration and metastasis: microtubule plus-end transport polarizes STIM1 to the migrating front, ERK1/2 phosphorylation at S575/S608/S621 controls EB1 dissociation and migration, and STIM1/Orai1 Ca2+ oscillations drive invadopodium-mediated invasion.

    Evidence Live imaging, phospho-site mutagenesis, invadopodium/MT1-MMP trafficking assays, xenograft models

    PMID:18802022 PMID:24463606 PMID:25404747 PMID:25447552

    Open questions at the time
    • Hierarchy between trafficking, phosphorylation, and Ca2+ entry not fully ordered
    • Direct kinase-substrate verification limited
    • In vivo relevance of EB1 dissociation not established
  9. 2014 High

    Identified STIM1 R304W in coiled-coil 1 as a human gain-of-function mutation causing constitutive CRAC activation and a platelet bleeding/preactivation phenotype, demonstrating CC1 maintains the resting state.

    Evidence Patient genetics, heterologous expression, platelet Ca2+ measurements, zebrafish model

    PMID:24591628 PMID:24619930

    Open questions at the time
    • Structural mechanism by which CC1 enforces autoinhibition not resolved
    • Full spectrum of clinical manifestations not delineated
    • Relationship to tubular aggregate myopathy mutations not addressed here
  10. 2015 High

    Provided structural and mechanistic refinement of activation: ultrastructural imaging showed STIM1 bridges a ~12-nm ER-PM gap forming nanoscale Orai1 clusters, and concatemer-dimer mutagenesis established a unimolecular STIM1-Orai1 coupling mechanism.

    Evidence EM and freeze-fracture imaging, SOAR F394H concatemer dimers, electrophysiology

    PMID:26351694 PMID:26399906

    Open questions at the time
    • Exact stoichiometry of STIM1 per Orai1 hexamer not fixed
    • Dynamics of cluster assembly not captured
    • Lipid contribution to junction formation not yet defined
  11. 2015 Medium

    Identified luminal/ER modulators CSQ1 and Surf4 as negative regulators that limit STIM1-Orai1 association and clustering, adding upstream brakes on SOCE.

    Evidence Co-IP, deletion mutants, KO cells, SOCE measurements

    PMID:22609200 PMID:26087026

    Open questions at the time
    • Physiological settings where these brakes dominate unclear
    • Direct vs indirect modulation not fully separated
    • Single-lab findings
  12. 2016 Medium

    Showed SOAR contains a cholesterol-binding domain and that membrane lipid composition governs SOAR-PM attachment and SOAR-Orai1 association, introducing lipid regulation of coupling.

    Evidence Protein-lipid assays, cholesterol depletion, SOAR constructs

    PMID:27459950

    Open questions at the time
    • In vivo relevance of cholesterol regulation untested
    • Interplay with phosphoinositide binding not resolved here
    • Single-lab finding
  13. 2017 High

    Defined regulatory inputs controlling activation and inactivation: Pyk2 phosphorylation at Y361 is required for Orai1 recruitment, and Ca2+-calmodulin binding adjacent to the coupling region disassembles STIM1-Orai1 complexes and oligomers for slow inactivation.

    Evidence Mutagenesis, phospho-detection, CaM-binding mapping, SOCE/inactivation assays, in vivo vascular permeability

    PMID:28218251 PMID:29051492

    Open questions at the time
    • Spatiotemporal coordination of Y361 phosphorylation with clustering unclear
    • CaM-binding site structure not solved
    • Crosstalk between these regulatory layers unmapped
  14. 2017 High

    Defined a specific intracellular trafficking function of STIM1 in dendritic cells, showing Ca2+ signaling promotes endolysosomal enzyme delivery and phagosome-endolysosome fusion required for cross-presentation, independent of phagosomal pH and ROS.

    Evidence Myeloid conditional KO, cross-presentation, chemotaxis, phagosome fusion and IRAP assays

    PMID:29176619

    Open questions at the time
    • Direct Ca2+ targets controlling fusion not identified
    • Channel partner in dendritic cells not specified here
    • Link between chemotaxis and trafficking defects not separated
  15. 2018 High

    Established the luminal sensing mechanism in molecular detail, demonstrating 5-6 Ca2+-binding sites energetically coupled to the canonical EF-hand and that Ca2+ loss drives a conformational switch rather than unfolding.

    Evidence Biophysical Ca2+-binding, structural analysis, mutagenesis, cell SOCE assays

    PMID:30382093

    Open questions at the time
    • Full atomic structure of the activated luminal state incomplete
    • How luminal switch propagates to cytosolic SOAR not resolved here
    • Quantitative Ca2+ thresholds in cells not fixed
  16. 2019 High

    Refined activation mechanics: MD plus live-cell work resolved sequential luminal conformational changes, helix α3 (400-403) was shown to transmit binding into Orai1 gating at a defined gating interface (SOGI), and Y316 phosphorylation was tied to SARAF interaction and inactivation.

    Evidence MD simulations, cysteine crosslinking, mutagenesis, electrophysiology, co-IP

    PMID:30831274 PMID:30975919 PMID:31744929

    Open questions at the time
    • High-resolution structure of the gated STIM1-Orai1 interface still absent
    • Kinase responsible for Y316 not identified here
    • Integration of α3 gating with luminal switch not mechanistically continuous
  17. 2021 High

    Expanded the partner and tissue repertoire: desmin retains STIM1 at the skeletal-muscle Z-line and modulates SOCE, and a neuronal splice variant STIM1B targets presynaptic sites to convert synaptic depression into Ca2+/Orai-dependent short-term enhancement.

    Evidence Y2H, co-IP, KO mouse, splice-variant cloning, ICRAC and synaptic plasticity recordings

    PMID:33730587 PMID:34494555

    Open questions at the time
    • Mechanism by which STIM1B insertion alters kinetics not structurally defined
    • Desmin-STIM1 interface not mapped at residue level
    • Generality of STIM1B function across synapse types unknown
  18. 2022 High

    Demonstrated a store-depletion-independent constitutive role for STIM1 in maintaining ER-PM peripheral coupling in contractile vascular smooth muscle and a novel ER-STIM/pannexin-1 coupling mechanism in neurons.

    Evidence SMC-specific inducible KO with junction imaging and contractility; Panx1 interface mapping with function-blocking antibody

    PMID:35147077 PMID:36037373

    Open questions at the time
    • Molecular determinants of constitutive coupling vs store-operated mode not separated
    • Panx1-STIM physiological output beyond Ca2+ entry unclear
    • Conservation across smooth-muscle beds untested
  19. 2023 Medium

    Identified protein-stability and lipid-trapping control of STIM1: SOAR oligomerization engages PM phosphoinositides to trap STIM1 at ER-PM contacts, and TSPAN18 competitively blocks TRIM32-mediated ubiquitination to stabilize STIM1 and boost SOCE.

    Evidence EM/fluorescence imaging, protein-lipid assays, LC-MS/MS, co-IP, ubiquitination and stability assays

    PMID:36906853 PMID:37542345

    Open questions at the time
    • Triggers controlling TRIM32 vs TSPAN18 balance in vivo unclear
    • Coordination of phosphoinositide and cholesterol binding unresolved
    • Single-lab mechanistic claims

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the discrete regulatory layers (luminal Ca2+ switch, phosphorylation, glutathionylation, CaM/SARAF inactivation, lipid trapping, and ubiquitin-mediated turnover) are integrated in time and space to produce graded, tissue-specific SOCE remains unresolved.
  • No high-resolution structure of the activated full-length STIM1-Orai1 complex
  • Quantitative model linking regulatory inputs to channel output absent
  • Mechanistic basis for switching between store-operated and constitutive coupling modes undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005635 nuclear envelope 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3
Partners
CALM1DESORAI1PANX1SARAFTRIM32TRPC1TSPAN18
Complex memberships
STIM1-Orai1 CRAC channel complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 The STIM1 fragment 344-442 (SOAR, STIM1 Orai Activating Region) is both necessary and sufficient to fully activate all Orai channels; STIM1 residues 450-485 regulate the strength of STIM1-Orai1 interaction; the polybasic STIM1 domain (672-685) mediates inward rectification of Orai1 by interacting with a Pro-rich region in the Orai1 N-terminus; STIM1-Orai1 co-clustering is not sufficient for Orai1 activation; an intact C-terminal alpha-helical region of Orai is required for activation by SOAR. Truncation/deletion mutants, point mutagenesis, electrophysiology, co-clustering assays in HEK293 cells Nature cell biology High 19182790
2006 The cytosolic C-terminus of STIM1 is sufficient to activate SOC, ICRAC, and TRPC1 channels even after endogenous STIM1 depletion; the ERM domain mediates selective binding of STIM1 to TRPC1, 2, and 4 (but not TRPC3, 6, or 7); the cationic lysine-rich region is essential for gating TRPC1; deletion of either region converts the constitutively active STIM1(D76A) into a dominant-negative that blocks native SOC, TRPC1, and ICRAC. Domain deletion constructs, siRNA knockdown, electrophysiology, co-immunoprecipitation, dominant-negative mutant analysis Nature cell biology High 16906149
2010 STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress, which activates constitutive Ca2+ entry independent of intracellular Ca2+ store depletion; 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, STIM1/Orai1 knockout/knockdown cells The Journal of cell biology High 20679432
2008 STIM1 and Orai1 are recruited to the immunological synapse between T cells and dendritic cells, where Ca2+ influx is localized at the contact zone; expression of dominant-negative Orai1 blocked T cell Ca2+ signaling but did not prevent initial accumulation of STIM1, Orai1, and CD3 at the contact zone. Live fluorescence microscopy, intracellular Ca2+ imaging with EGTA, dominant-negative Orai1 expression, primary human T cell/dendritic cell conjugates Proceedings of the National Academy of Sciences of the United States of America High 18250319
2008 Store depletion triggers a STIM1-dependent conformational change in Orai1 (decrease in Orai1-Orai1 FRET) concurrent with a large increase in STIM1-Orai1 FRET, indicating direct physical interaction; Orai1 exists as a multimer in resting cells; the Orai1 conformational change requires STIM1 co-expression and is abrogated by Orai1 mutations that impair STIM1 interaction. Live-cell FRET microscopy, CFP/YFP-tagged STIM1 and Orai1 constructs, point mutagenesis of Orai1 STIM1-interaction sites The Journal of physiology High 18832420
2008 Reversal of STIM1 puncta formation (and thus SOCE termination) absolutely requires SOCE-dependent store refilling; ML-9 causes rapid, store-independent reversal of STIM1 puncta and inhibits SOCE and ICRAC; STIM1 puncta form at specific predetermined cellular loci; ML-9 effect is not mediated through MLCK inhibition. Live-cell fluorescence imaging of EYFP-STIM1, SOCE pharmacology, MLCK inhibitor comparisons, EF-hand constitutively active mutant Journal of cell science Medium 18285445
2008 STIM1 co-immunoprecipitates with TRPC1; STIM1 gates TRPC1 by electrostatic interaction between lysines K684 and K685 of the STIM1 polybasic domain and conserved negative charges (aspartates/glutamates) in TRPC channels; charge-swap mutants of STIM1(K684E,K685E) with TRPC1(D639E,D640E) restore channel activation. Co-immunoprecipitation, charge-swap mutagenesis, electrophysiology, siRNA knockdown Cell calcium High 17517433 19574740
2008 STIM1 is present both in the ER and at the plasma membrane surface; the Ca2+-binding-defective STIM1(EF) mutant localizes exclusively in stable near-PM ER junctions and is not trafficked to the plasma membrane; surface STIM1(WT) plays a regulatory role in SOC activation as external anti-N-terminal STIM1 antibody blocked STIM1(EF)-mediated Ca2+ entry only in cells co-expressing endogenous STIM1(WT). Surface biotinylation, streptavidin pulldown, EF-hand mutagenesis (D76A/E87A), extracellular antibody application, Ca2+ imaging The Journal of biological chemistry Medium 18635545
2000 STIM1 protein is located at the cell surface of K562 cells (established by immunofluorescence and cell-surface biotinylation); STIM1 is phosphorylated predominantly on serine residues in vivo and undergoes N-linked glycosylation; STIM1 is not secreted and does not undergo proteolytic processing. Immunofluorescence, cell-surface biotinylation, phosphorylation analysis, western blot, specific antibodies Biochimica et biophysica acta Medium 11004585
2014 STIM1 gain-of-function mutation R304W (in coiled-coil 1 domain) causes constitutive activation of the CRAC channel; platelets from patients show elevated resting Ca2+ levels and preactivated state; the coiled-coil 1 domain plays a role in keeping STIM1 inactive. Patient genetics, heterologous expression of STIM1 p.R304W, Ca2+ measurements in platelets, zebrafish model recapitulating bleeding phenotype Proceedings of the National Academy of Sciences of the United States of America / Human mutation High 24591628 24619930
2015 STIM1 dimers activate Orai1 through unimolecular coupling: introducing the F394H mutation in only one monomer of a SOAR concatemer-dimer has no effect on Orai1 binding or activation, whereas mutation in both monomers abolishes function; this argues against dimeric interaction between STIM1 and two adjacent Orai1 subunits. SOAR concatemer-dimer constructs with F394H point mutations, Orai1 binding assays, electrophysiology Nature communications High 26399906
2018 The STIM1 luminal domain has 5–6 Ca2+-binding sites; Ca2+ binding at these sites is energetically coupled to the canonical EF-hand site; Ca2+ dissociation controls a switch to a second structured conformation rather than protein unfolding; mutations at the other luminal Ca2+-binding sites affect physiological STIM1 activation in cells. Biophysical Ca2+-binding measurements, NMR/structural analysis, mutagenesis of luminal domain, cell-based SOCE assays Nature communications High 30382093
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 a hydrophobic cleft formed with the SAM domain; a single Ca2+ ion is sufficient to stabilize the luminal complex in MD simulations; point mutations in the canonical EF-hand and hydrophobic cleft (associated with tubular aggregate myopathy or cancer) yield constitutively clustered STIM1 and constitutive Orai1 activation. Molecular dynamics simulations, live-cell Ca2+ recordings, site-directed mutagenesis of EF-hand and hydrophobic cleft residues Science signaling High 31744929
2015 STIM1 and Orai1 form nanoscale clusters at ER-PM junctions upon store depletion; STIM1 extended molecules bridge a ~12-nm ER-PM gap; Orai1 cluster into puncta on raised membrane subdomains; the stoichiometry of Orai1 channels is unchanged by store depletion or STIM1 co-expression; a portion of Orai1 channels are spaced ~15 nm apart, consistent with interaction with small STIM1 clusters. Transmission and freeze-fracture electron microscopy of STIM1/Orai1-expressing HEK293 cells, thapsigargin-induced store depletion, Monte Carlo analysis Proceedings of the National Academy of Sciences of the United States of America High 26351694
2017 ER Ca2+ store depletion induces STIM1 phosphorylation at tyrosine 361 (Y361) via Pyk2 kinase; the phospho-defective Y361F mutant forms puncta but fails to recruit Orai1, preventing SOCE; in mouse lungs, Y361F expression prevented PAR1-induced vascular permeability increase. Site-directed mutagenesis (Y361F), phospho-specific detection, co-localization imaging, Pyk2 kinase identification, SOCE measurements, in vivo vascular permeability assay Scientific reports Medium 28218251
2014 STIM1 is transported by microtubule plus ends to the front of migrating endothelial leader cells; local ER Ca2+ depletion at the front activates STIM1; polarized STIM1 activity supports pulsatile front retraction and adhesion during directed cell migration. Live-cell fluorescence imaging of STIM1 and microtubule dynamics, STIM1 localization in migrating leader cells, Ca2+ imaging Nature cell biology Medium 24463606
2011 STIM1 concentration controls the magnitude of store-operated Ca2+ entry, and elevated STIM1 concentration activates a Ca2+-driven, PKC-δ- and RasGRP-dependent proapoptotic Erk signaling pathway in developing B cells; overexpression of STIM1 conferred a competitive disadvantage to developing B cells; this pathway is biochemically distinct from DAG-induced Erk activation. Genetic mouse models (PKC-δ KO, STIM1 overexpression), biochemical pathway analysis, epistasis with PKC-δ and RasGRP Nature immunology Medium 21441934
2017 Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 at a site adjacent to the STIM1-Orai1 coupling region; this interaction disrupts the STIM1-Orai1 complex and disassembles STIM1 oligomers, facilitating slow Ca2+-dependent inactivation of SOCE. Co-immunoprecipitation, CaM-binding site mapping by mutagenesis, SOCE/ICRAC measurements with wild-type and constitutively active STIM1 mutant, STIM1 oligomer analysis Nature communications High 29051492
2019 STIM1 helix α3 (residues 400-403) within SOAR/CAD does not mediate initial STIM1-Orai1 interaction but is essential for transmitting STIM1 binding into Orai1 channel gating; cysteine crosslinking revealed proximity of STIM1 α3 to Orai1 TM3, defining a STIM1-Orai1 gating interface (SOGI). Mutagenesis of STIM1 α3, cysteine crosslinking, co-immunoprecipitation, electrophysiology Cell calcium High 30831274
2016 STIM1 contains a cholesterol-binding domain located within the SOAR region; STIM1/SOAR associates functionally with cholesterol at the inner plasma membrane leaflet; cholesterol depletion causes SOAR detachment from the plasma membrane and enhances SOAR-Orai1 association. Protein-lipid interaction assays, fluorescence microscopy, cholesterol depletion, SOAR domain constructs Scientific reports Medium 27459950
2023 STIM1 SOAR oligomerization promotes direct interaction with plasma membrane phosphoinositides to trap STIM1 at ER-PM contact sites; a cluster of conserved lysine residues within SOAR mediates this lipid interaction; the interaction is co-regulated by STIM1 coiled-coil 1 and inactivation domains. Electron and fluorescence microscopy, protein-lipid interaction assays, mutagenesis of SOAR lysine cluster Cell reports Medium 36906853
2015 Calsequestrin 1 (CSQ1) physically interacts with STIM1; increased monomeric CSQ1 enhances CSQ1-STIM1 interaction and reduces STIM1-Orai1 association and SOCE; C-terminal deletions in CSQ1 abolish its ability to modulate STIM1-Orai1 interaction. Co-immunoprecipitation, CSQ1 overexpression and deletion mutants, SOCE measurements in HEK293 cells Scientific reports Medium 26087026
2012 Surf4 associates with STIM1 in the ER (identified by affinity purification); deletion of Surf4 in DT40 B cells markedly increases SOCE and facilitates STIM1 clustering upon store depletion, indicating Surf4 is a negative modulator of STIM1-mediated SOCE. Affinity purification/mass spectrometry for binding partner identification, Surf4 knockout DT40 cells, SOCE measurements, STIM1 clustering assay Biochemical and biophysical research communications Medium 22609200
2021 Desmin (major skeletal muscle intermediate filament protein) interacts with the CC1-SOAR domains of STIM1; desmin-STIM1 interaction enhances STIM1 oligomerization yet limits SOCE; in desmin-KO mice, STIM1 retention at the Z-line is lost and SR Ca2+ refilling efficiency is altered. Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization, desmin-KO mouse analysis, Ca2+ signaling measurements JCI insight Medium 34494555
2022 STIM1 constitutively maintains ER-PM peripheral coupling in contractile vascular smooth muscle cells (VSMCs) independent of ER Ca2+ store depletion; STIM1 KO in VSMCs reduces the number/size of SR-PM junctions, disrupts nanoscale colocalization of Ca2+-release sites with Ca2+-activated channels, diminishes channel activity, and causes hypotension and blunted arterial contractility. SMC-specific inducible STIM1 knockout mice, SR-PM junction imaging, nanoscale colocalization analysis, Ca2+ signaling, vascular contractility measurements eLife High 35147077
2021 A neuronal splice variant STIM1B, containing an inserted domain B, shows exclusive neuronal expression, slower ER-PM cluster formation kinetics, slower ICRAC activation, and reduced inactivation compared to canonical STIM1; STIM1B targets to presynaptic sites via domain B and converts synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement at high-frequency stimulation. Cloning and characterization of STIM1B splice variant, ICRAC electrophysiology, live imaging of cluster formation, presynaptic targeting, synaptic plasticity recordings in primary neurons Cell reports High 33730587
2008 STIM1 deficiency in macrophages abolishes FcγR-induced Ca2+ entry and phagocytosis; STIM1-deficient mice are resistant to experimental immune thrombocytopenia, anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis, establishing STIM1 as an essential component of FcγR activation. STIM1 conditional knockout macrophages, Ca2+ imaging, phagocytosis assay, multiple in vivo disease models Blood High 18941110
2007 STIM1 in the plasma membrane (constitutively surface-localized pool) regulates ARC (arachidonic acid-regulated Ca2+-selective) channels in a manner independent of store depletion, EF-hand Ca2+ binding, and STIM1 translocation to the plasma membrane; extracellular antibody targeting the N-terminal domain of STIM1 selectively inhibits ARC channel activity; mutations preventing N-glycosylation-dependent plasma membrane expression of STIM1 specifically inhibit ARC channels without affecting CRAC. Extracellular antibody inhibition, N-glycosylation mutants preventing PM expression, CRAC vs. ARC channel current recordings Cell calcium Medium 17391754
2010 STIM1 regulates TRPC6 expression at the plasma membrane, causing translocation of TRPC6 to the ER; STIM1-mediated TRPC6 internalization reduces TRPC6-TRPC1 and TRPC6-TRPC3 heteromultimerization; TRPC6 expression in the ER increases passive Ca2+ efflux and basal cytosolic Ca2+. Co-immunoprecipitation, subcellular fractionation, TRPC6 localization imaging, Ca2+ measurements The Biochemical journal Medium 25088676
2014 STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by facilitating invadopodium precursor assembly via Src activation; Orai1 blockade inhibits MT1-MMP recycling to the plasma membrane and entraps MT1-MMP in endocytic compartments, inhibiting ECM degradation; STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft model. Ca2+ imaging, STIM1/Orai1 knockdown, invadopodium assembly assays, MT1-MMP trafficking assays, xenograft mouse model The Journal of cell biology Medium 25404747
2022 ER-resident STIM1/2 physically interacts with pannexin-1 (Panx1) at a hydrophobic region within the Panx1 N-terminus; STIM recruitment couples Ca2+ entry via NMDARs to large-pore Panx1 activation; a Panx1 N-terminus-recognizing antibody blocks large-pore activation by STIM1/2. Co-immunoprecipitation, interaction interface mapping with Panx1 deletion mutants, function-blocking antibody, Ca2+ entry assays in neurons Proceedings of the National Academy of Sciences of the United States of America Medium 36037373
2019 STIM1 phosphorylation at Y316 positively regulates STIM1-Orai1 colocalization and SOCE/ICRAC; the phospho-defective Y316F mutant reduces STIM1 tyrosine phosphorylation, SOCE, and ICRAC; Y316F alters STIM1-SARAF interaction under both resting and Ca2+-store-depleted conditions and enhances slow Ca2+-dependent inactivation. Y316F mutagenesis, STIM1-Orai1 colocalization imaging, SOCE and ICRAC measurements, STIM1-SARAF co-immunoprecipitation, SARAF knockdown epistasis Journal of cell science Medium 30975919
2014 STIM1 promotes cell migration in vascular smooth muscle cells (VSMCs); STIM1 interacts with TRPC1 in VSMCs; extracellular antibody against the N-terminal STIM1 domain inhibits store-depletion-evoked Ca2+ current and cell migration but not proliferation; plasma-membrane-localized STIM1 contributes to TRPC1-independent store-operated cationic current and migration. STIM1 siRNA, extracellular antibody application, Ca2+ entry and current measurements, migration assays, co-immunoprecipitation Circulation research Medium 18802022
2023 TSPAN18 directly interacts with STIM1 and competitively inhibits TRIM32-mediated ubiquitination and degradation of STIM1, thereby increasing STIM1 protein stability and SOCE-dependent Ca2+ influx. LC-MS/MS identification of TSPAN18, co-immunoprecipitation, TRIM32 ubiquitination assay, STIM1 stability measurements Journal of experimental & clinical cancer research Medium 37542345
2014 ERK1/2-mediated phosphorylation of STIM1 at Ser575, Ser608, and Ser621 is triggered by EGF/H-Ras signaling and promotes STIM1 dissociation from EB1 (microtubule plus-end regulator); phospho-defective Ser-to-Ala mutations impair EGF-triggered cell migration while phosphomimetic mutations restore it; STIM1 phosphorylation is upstream of Ca2+ entry activation. Site-directed mutagenesis (S575A/S608A/S621A and S575E/S608E/S621E), ERK1/2 inhibition, STIM1-EB1 co-immunoprecipitation, migration assays, EMT marker analysis Biochimica et biophysica acta Medium 25447552
2017 STIM1 ablation in dendritic cells impairs antigen cross-presentation and chemotaxis in vivo and in vitro; STIM1 deficiency disrupts phagosomal proteolysis, leucyl aminopeptidase activity, IRAP recruitment, and phagosome-endolysosome fusion without affecting phagosomal pH or ROS production; STIM1-dependent Ca2+ signaling promotes delivery of endolysosomal enzymes to phagosomes. Stim1 conditional KO in myeloid cells, cross-presentation assay, chemotaxis assay, phagosomal pH and ROS measurements, phagosome-endolysosome fusion assay, IRAP localization Nature communications High 29176619
2020 STIM1 stabilizes Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway during HCC tumor growth; downregulated STIM1 in metastatic HCC cells shifts metabolism from glycolysis toward AMPK-activated fatty acid oxidation (FAO), promoting anoikis-resistance and metastasis driven by Snail1; Snail1 suppresses STIM1/SOCE during metastasis creating a feedback loop. CRISPR-Cas9 STIM1 KO, lentiviral overexpression, Seahorse metabolic analysis, in vivo lung metastasis model, pathway (CaMKII/AKT/GSK-3β) analysis Theranostics Medium 32483465

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature cell biology 578 19182790
2006 STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nature cell biology 541 16906149
2015 Diseases caused by mutations in ORAI1 and STIM1. Annals of the New York Academy of Sciences 374 26469693
2008 Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circulation research 326 18845811
2008 Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proceedings of the National Academy of Sciences of the United States of America 223 18250319
2014 Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proceedings of the National Academy of Sciences of the United States of America 210 24591628
2010 S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. The Journal of cell biology 203 20679432
2014 A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration. Nature cell biology 201 24463606
2016 TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces. Cell calcium 187 28089266
2000 STIM1: a novel phosphoprotein located at the cell surface. Biochimica et biophysica acta 187 11004585
2008 STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. The Journal of physiology 184 18832420
2007 TRPC channels as STIM1-regulated store-operated channels. Cell calcium 182 17517433
2013 STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Archiv : European journal of physiology 164 23515871
2008 Ca2+-store-dependent and -independent reversal of Stim1 localization and function. Journal of cell science 152 18285445
2010 Immunodeficiency due to mutations in ORAI1 and STIM1. Clinical immunology (Orlando, Fla.) 146 20189884
2014 A dominant STIM1 mutation causes Stormorken syndrome. Human mutation 139 24619930
2014 STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion. The Journal of cell biology 139 25404747
2010 Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. Journal of molecular and cellular cardiology 130 20138887
2014 STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression. Oncogene 122 25381814
1997 GOK: a gene at 11p15 involved in rhabdomyosarcoma and rhabdoid tumor development. Cancer research 116 9377559
2009 An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS letters 112 19944100
2010 Polarized but differential localization and recruitment of STIM1, Orai1 and TRPC channels in secretory cells. Traffic (Copenhagen, Denmark) 109 21054717
2014 Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochimica et biophysica acta 103 24583265
2011 STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature immunology 101 21441934
2009 TRPC channels as STIM1-regulated SOCs. Channels (Austin, Tex.) 90 19574740
2011 Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems. Trends in cell biology 88 21288721
2018 STIM1 activation of Orai1. Cell calcium 87 30530091
2008 STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation. Blood 87 18941110
2015 The STIM1-ORAI1 microdomain. Cell calcium 86 26215475
2020 STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma. Theranostics 79 32483465
2008 Interactions, functions, and independence of plasma membrane STIM1 and TRPC1 in vascular smooth muscle cells. Circulation research 79 18802022
2014 STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia. Glia 76 25471906
2015 STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1. Cell reports 71 26166565
1996 Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5. Genomics 70 8921403
2009 STIM1-independent T cell development and effector function in vivo. Journal of immunology (Baltimore, Md. : 1950) 68 19265116
2018 ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Science signaling 66 30563862
2015 STIM1 dimers undergo unimolecular coupling to activate Orai1 channels. Nature communications 62 26399906
2018 Calcium sensing by the STIM1 ER-luminal domain. Nature communications 61 30382093
2017 STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production. Blood 60 28724541
2012 Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK. Cell calcium 60 22682960
2010 STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode. The Journal of biological chemistry 57 20926378
2017 STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells. Nature communications 56 29176619
2007 STIM1 and the noncapacitative ARC channels. Cell calcium 56 17391754
2019 Molecular basis of allosteric Orai1 channel activation by STIM1. The Journal of physiology 55 30950063
2013 Suppression of STIM1 inhibits human glioblastoma cell proliferation and induces G0/G1 phase arrest. Journal of experimental & clinical cancer research : CR 54 23578185
2013 Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets. Thrombosis and haemostasis 54 23846758
2024 Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis. Pharmacological research 52 38438089
2017 STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca2+ Entry. Scientific reports 51 28218251
2015 Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proceedings of the National Academy of Sciences of the United States of America 51 26351694
2011 The closing and opening of TRPC channels by Homer1 and STIM1. Acta physiologica (Oxford, England) 50 21518270
2016 A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions. Scientific reports 48 27459950
2015 Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin. Scientific reports 47 26087026
2017 Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers. Nature communications 46 29051492
2015 STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization. The Journal of biological chemistry 46 25805497
2019 A novel STIM1-Orai1 gating interface essential for CRAC channel activation. Cell calcium 45 30831274
1999 Exon structure and promoter identification of STIM1 (alias GOK), a human gene causing growth arrest of the human tumor cell lines G401 and RD. Cytogenetics and cell genetics 45 10575208
2020 Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions. Frontiers in immunology 44 32038646
2008 Location and function of STIM1 in the activation of Ca2+ entry signals. The Journal of biological chemistry 43 18635545
2010 Regulation of STIM1 and SOCE by the ubiquitin-proteasome system (UPS). PloS one 42 20976103
2021 A short isoform of STIM1 confers frequency-dependent synaptic enhancement. Cell reports 41 33730587
2019 Sequential activation of STIM1 links Ca2+ with luminal domain unfolding. Science signaling 40 31744929
2013 The STIM1/Orai signaling machinery. Channels (Austin, Tex.) 39 24107921
2014 The TRPCs-STIM1-Orai interaction. Handbook of experimental pharmacology 37 24961979
2012 Surf4 modulates STIM1-dependent calcium entry. Biochemical and biophysical research communications 33 22609200
2022 STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells. eLife 31 35147077
2019 STIM1 phosphorylation at Y316 modulates its interaction with SARAF and the activation of SOCE and ICRAC. Journal of cell science 30 30975919
2014 STIM1 phosphorylation triggered by epidermal growth factor mediates cell migration. Biochimica et biophysica acta 30 25447552
2013 Alternative forms of the store-operated calcium entry mediators, STIM1 and Orai1. Current topics in membranes 30 23890113
2023 TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination. Journal of experimental & clinical cancer research : CR 29 37542345
2018 SOCE and STIM1 signaling in the heart: Timing and location matter. Cell calcium 29 30508734
2010 Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid. Journal of molecular endocrinology 29 20194530
2023 The SOAR of STIM1 interacts with plasma membrane lipids to form ER-PM contact sites. Cell reports 28 36906853
2017 STIM-TRP Pathways and Microdomain Organization: Ca2+ Influx Channels: The Orai-STIM1-TRPC Complexes. Advances in experimental medicine and biology 28 28900913
2021 Desmin interacts with STIM1 and coordinates Ca2+ signaling in skeletal muscle. JCI insight 27 34494555
2010 Ca2+ signaling and STIM1. Progress in biophysics and molecular biology 27 20226808
2018 The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression. Oncotarget 26 30034631
2017 Regulation of membrane ruffling by polarized STIM1 and ORAI1 in cortactin-rich domains. Scientific reports 26 28341841
2017 STIM1 silencing inhibits the migration and invasion of A549 cells. Molecular medicine reports 26 28713917
2015 Cooperative and alternate functions for STIM1 and STIM2 in macrophage activation and in the context of inflammation. Immunity, inflammation and disease 26 26417434
2011 WT1/EGR1-mediated control of STIM1 expression and function in cancer cells. Frontiers in bioscience (Landmark edition) 26 21622185
2022 ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation. Proceedings of the National Academy of Sciences of the United States of America 25 36037373
2018 STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. Cell calcium 25 30390422
2016 The STIM1: Orai Interaction. Advances in experimental medicine and biology 24 27161223
2013 Involvement of STIM1 and Orai1 in EGF-mediated cell growth in retinal pigment epithelial cells. Journal of biomedical science 23 23800047
2013 The regulation of STIM1 by phosphorylation. Communicative & integrative biology 23 24505502
2013 The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation. STIM1 binds to novel proteins in human platelets. Cellular signalling 22 24308967
2011 STIM1 and Orai1: novel targets for vascular diseases? Science China. Life sciences 22 21786201
2018 STIM1 and Orai1 regulate Ca2+ microdomains for activation of transcription. Biochimica et biophysica acta. Molecular cell research 21 30408546
2021 STIM1 Mediates Calcium-Dependent Epigenetic Reprogramming in Pancreatic Cancer. Cancer research 20 33436389
2021 STIM1 Regulates Endothelial Calcium Overload and Cytokine Upregulation During Sepsis. The Journal of surgical research 20 33713955
2017 Stim1 Regulates Enamel Mineralization and Ameloblast Modulation. Journal of dental research 20 28732182
2016 Role of STIM1 in the surface expression of SARAF. Channels (Austin, Tex.) 20 27414851
2008 How strict is the correlation between STIM1 and Orai1 expression, puncta formation, and ICRAC activation? American journal of physiology. Cell physiology 20 18768920
2022 HSP70 protects H9C2 cells from hypoxia and reoxygenation injury through STIM1/IP3R. Cell stress & chaperones 17 35841499
2020 Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension. Journal of the American Heart Association 17 32075490
2020 TRIC-A shapes oscillatory Ca2+ signals by interaction with STIM1/Orai1 complexes. PLoS biology 17 32330125
2016 Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction. American journal of physiology. Cell physiology 17 26739495
2014 STIM1 regulates TRPC6 heteromultimerization and subcellular location. The Biochemical journal 17 25088676
2021 Pathophysiological Effects of Overactive STIM1 on Murine Muscle Function and Structure. Cells 16 34359900
2018 Role of STIM1 in neurodegeneration. World journal of biological chemistry 16 30568747

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