{"gene":"SRI","run_date":"2026-06-14T21:20:50+00:00","timeline":{"discoveries":[{"year":1997,"finding":"Sorcin directly inhibits cardiac ryanodine receptor (RyR) open probability (IC50 ~480 nM) and completely inhibits [3H]ryanodine binding (IC50 ~700 nM) when applied to the cytoplasmic side; inhibition is independent of calmodulin/calpain pathways. Phosphorylation of sorcin by the catalytic subunit of PKA significantly decreased its ability to inhibit RyR, placing PKA signaling as an upstream regulator of sorcin's RyR modulatory activity.","method":"Single-channel recordings of purified RyR, [3H]ryanodine binding assays with recombinant sorcin, in vitro PKA phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro single-channel and binding assays, mutagenesis/phosphorylation functional follow-up, replicated across multiple readouts","pmids":["9312152"],"is_preprint":false},{"year":1995,"finding":"Sorcin undergoes calcium-dependent translocation from the cytosol to cellular membranes. Calcium binding to purified recombinant sorcin at micromolar concentrations induces a conformational change that renders the protein soluble in the non-ionic detergent Triton X-114, suggesting lipids as membrane targets.","method":"Cell fractionation, detergent-phase partitioning (Triton X-114), calcium-binding assay with purified recombinant sorcin","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of conformational change plus cell fractionation, two orthogonal methods in one study","pmids":["7835417"],"is_preprint":false},{"year":2003,"finding":"Sorcin overexpression in transgenic mouse hearts reduces contraction and relaxation indices, depresses Ca2+ transient amplitudes, and accelerates L-type Ca2+ channel inactivation; sorcin associates with both cardiac RyR and L-type Ca2+ channels. In failing hearts, co-localization of sorcin with RyR at Z-lines is markedly disrupted.","method":"Transgenic mouse overexpression, in vivo hemodynamics, isolated myocyte Ca2+ imaging, whole-cell patch clamp, Xenopus oocyte expression, co-immunoprecipitation, confocal co-localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transgenic model, electrophysiology, Ca2+ imaging, Co-IP, oocyte expression), replicated across systems","pmids":["12754254"],"is_preprint":false},{"year":2015,"finding":"X-ray crystal structures of sorcin in apo and calcium-bound states show that calcium binding to EF1-3 hands drives a large conformational change (movement of the D-helix, opening of EF1) that exposes a hydrophobic pocket. This exposed pocket accommodates sorcin's own N-terminal domain bearing a consensus GYYPGG-like motif and mediates interaction with PDCD6 (a pro-apoptotic penta-EF hand protein carrying the same motif); PDCD6 co-localizes with sorcin in the perinuclear region and midbody.","method":"X-ray crystallography (apo and Ca2+-bound structures), phage display identification of binding motif, co-localization by fluorescence microscopy","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures in two states plus phage display and cell-based co-localization, multiple orthogonal methods in one study","pmids":["26577048"],"is_preprint":false},{"year":2016,"finding":"Sorcin maintains ER Ca2+ stores in pancreatic β-cells by inhibiting ryanodine receptor activity and terminating Ca2+-induced Ca2+ release. Sorcin-null mice are glucose intolerant with impaired glucose-stimulated insulin secretion; β-cell-specific sorcin overexpression under high-fat diet improves glucose tolerance and increases cytosolic and ER Ca2+. Palmitate-induced sorcin downregulation increases G6PC2 levels, contributing to lipotoxicity.","method":"Sorcin knockout mouse, β-cell-specific transgenic overexpression, glucose tolerance tests, insulin secretion assays, Ca2+ imaging in islets, high-fat diet model, human islet palmitate treatment","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO, transgenic OE), physiological readouts, replicated in mouse and human islets","pmids":["26822088"],"is_preprint":false},{"year":2017,"finding":"Sorcin directly binds doxorubicin, vincristine, paclitaxel, and cisplatin with high affinity. The X-ray structure of the sorcin–doxorubicin complex identifies a binding site at the interface of the EF5 loop, the G helix, and the EF4 loop. Sorcin cellular localization changes upon doxorubicin treatment. Sorcin silencing increases nuclear doxorubicin accumulation, decreases MDR1 expression, and reduces doxorubicin efflux via MDR1.","method":"Surface plasmon resonance, fluorescence titration, X-ray crystallography (sorcin–doxorubicin complex), confocal microscopy, siRNA knockdown with drug accumulation and efflux assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding demonstrated by three orthogonal biophysical methods plus structural determination and functional cell-based validation","pmids":["28726784"],"is_preprint":false},{"year":2017,"finding":"Sorcin ablation in mice generates an arrhythmogenic substrate: sorcin KO mice develop ventricular arrhythmia and sudden death upon isoproterenol+caffeine challenge. Isoproterenol stimulation causes spontaneous Ca2+ release events in KO cardiomyocytes. Adult KO hearts develop compensatory overexpression of L-type Ca2+ channel and Na+-Ca2+ exchanger, enhancing ICa and INCX and promoting delayed afterdepolarizations.","method":"Sorcin knockout mouse model, in vivo isoproterenol+caffeine challenge, transverse aortic constriction, Ca2+ imaging in isolated cardiomyocytes, patch clamp (ICa, INCX), Western blot","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO model with defined electrophysiological and Ca2+ phenotypes, multiple orthogonal readouts","pmids":["29174767"],"is_preprint":false},{"year":2011,"finding":"Sorcin overexpression confers multidrug resistance in gastric cancer cells and decreases intracellular vincristine concentration; sorcin overexpression upregulates P-glycoprotein (P-gp/MDR1) expression, and P-gp inhibition with verapamil partially reverses sorcin-mediated MDR.","method":"Gene transfection overexpression, antisense oligonucleotide knockdown, intracellular drug accumulation assay, Western blot, P-gp inhibitor rescue experiment","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with drug accumulation and pharmacological rescue, single lab","pmids":["21109982"],"is_preprint":false},{"year":2013,"finding":"Sorcin depletion in MDA-MB-231 breast cancer cells reduces the CD44+/CD24- and ALDH1high cancer stem cell pool, reduces mammosphere-forming capacity, induces an epithelial-like phenotype by modulating E-cadherin and VEGF expression, and suppresses metastasis in nude mice.","method":"RNAi knockdown (transient and stable), lentiviral overexpression, flow cytometry for CSC markers, mammosphere assay, Western blot for EMT markers, in vivo xenograft metastasis assay","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with in vitro and in vivo readouts, single lab, mechanistic detail limited to E-cadherin/VEGF","pmids":["24337682"],"is_preprint":false},{"year":2023,"finding":"Sorcin directly binds EGFR in a calcium-dependent manner, controls EGFR proteostasis and signaling, and increases EGFR phosphorylation, leading to increased EGF-dependent cell migration and invasion. Sorcin silencing cooperates with EGFR inhibitors to reduce migration.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, migration/invasion assays, EGFR inhibitor combination studies","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP plus functional phenotypic readouts and pharmacological cooperativity, single lab","pmids":["37442828"],"is_preprint":false},{"year":2023,"finding":"Sorcin interacts with the NLRP3 inflammasome (demonstrated by co-immunoprecipitation and immunofluorescence) and negatively regulates pyroptosis in hepatocellular carcinoma cells; sorcin knockdown activates Caspase-1-dependent pyroptosis and suppresses HCC tumor growth in vivo.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, NLRP3 inhibitor (MCC950) and Caspase-1 inhibitor (VX765) rescue, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus pharmacological rescue and in vivo validation, single lab","pmids":["37833249"],"is_preprint":false},{"year":2021,"finding":"Sorcin overexpression increases ATF6 transcriptional activity in HEK293 cells, while sorcin knockout reduces ATF6 transcriptional activity and increases ER stress markers, indicating sorcin promotes the protective ATF6-branch of the unfolded protein response.","method":"Sorcin overexpression, CRISPR/siRNA knockout in HEK293 cells, ATF6 transcriptional reporter assay, Western blot for ER stress markers","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementary gain- and loss-of-function with transcriptional reporter readout, single lab","pmids":["33960419"],"is_preprint":false},{"year":2025,"finding":"Sorcin interacts with PAX5 in the cytoplasm and inhibits PAX5 nuclear translocation; disrupting the sorcin-PAX5 interaction (by the natural product celastrol binding to Cys194 of sorcin) promotes PAX5 nuclear translocation, increases FBXL12 expression, enhances ALDH1A1 ubiquitination, and induces ferroptosis in pancreatic cancer cells.","method":"Co-immunoprecipitation, ChIP, luciferase reporter, proteomics, surface plasmon resonance, in vivo xenograft with genetic/pharmacological rescue","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP and reporter assays with pharmacological target identification, single lab with multiple orthogonal methods","pmids":["40055736"],"is_preprint":false},{"year":2024,"finding":"Sorcin interacts with STAT3 (demonstrated by co-immunoprecipitation and immunofluorescence) and activates the NF-κB signaling pathway, thereby inhibiting mitochondrial apoptosis in hepatocellular carcinoma; sorcin knockdown reduces NF-κB activity and increases apoptosis in vitro and in vivo.","method":"Co-immunoprecipitation, immunofluorescence, Western blot for NF-κB pathway components, mitochondrial membrane potential assay, siRNA knockdown, in vivo xenograft","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding plus functional NF-κB pathway analysis and in vivo validation, single lab","pmids":["39000312"],"is_preprint":false},{"year":2020,"finding":"Proteomic peptide phage display identified a peptide from protein phosphatase 1 regulatory subunit 3G (PPP1R3G) as a calcium-dependent Sorcin-binding partner, with confirmation by biophysical assays and cell-based approaches, revealing a potential link between glucose homeostasis and calcium concentration.","method":"Proteomic peptide phage display (ProP-PD), biophysical binding assays, cell-based interaction assays, molecular dynamics simulations","journal":"Biochimica et biophysica acta. General subjects","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phage display plus biophysical follow-up without detailed in-cell mechanistic dissection, single lab","pmids":["32305337"],"is_preprint":false},{"year":2024,"finding":"NMR backbone resonance assignment of full-length sorcin in the calcium-free state reveals that most of the N-terminal domain is disordered; secondary structure prediction from chemical shifts provides a structural foundation for studying Ca2+ sensing by full-length sorcin.","method":"Solution NMR (1H, 13C, 15N backbone resonance assignment), TALOS+/CSI 3.0 secondary structure prediction","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 1 / Weak — structural NMR assignment only, no functional validation reported in abstract, single lab","pmids":["39215797"],"is_preprint":false},{"year":2025,"finding":"Stopped-flow light scattering showed that calcium-induced sorcin aggregation is reversible, cooperative, and primarily concentration-dependent rather than directly determined by physiological calcium levels, suggesting sorcin's calcium sensitivity is tuned by its expression level.","method":"Stopped-flow light scattering, calcium-titration aggregation assay with purified recombinant sorcin","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro biophysical assay, single lab, no cellular functional validation reported in abstract","pmids":["41133884"],"is_preprint":false},{"year":2024,"finding":"Sorcin forms a positive feedback loop with STAT3 to increase transcription of serpin E1 and CCL5, and sorcin overexpression induces pancreatic β-cell dysfunction; sorcin-driven secretion of serpin E1 and CCL5 contributes to pancreatic cancer-associated new-onset diabetes.","method":"In vitro sorcin overexpression in β-cell lines, co-IP, STAT3 pathway inhibition, cytokine measurement, in vivo mouse model","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway partially defined but limited orthogonal validation; single lab","pmids":["39516378"],"is_preprint":false},{"year":2025,"finding":"Sorcin knockout (Sri-/-) mice display impaired lung alveolarization, reduced surfactant protein expression (Sp-b, Sp-c, Abca3), type II pneumocyte immaturity, and reduced EGFR, RAS, and RAB5C protein levels, implicating sorcin in EGFR-linked lung morphogenesis and surfactant protein recycling.","method":"Sorcin knockout mouse model, histology, real-time PCR, Western blot, confocal microscopy","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO model with multiple molecular and histological readouts, single lab, mechanistic link to EGFR/RAB5C pathway","pmids":["41148307"],"is_preprint":false}],"current_model":"Sorcin is a penta-EF hand calcium-sensing protein that undergoes calcium-dependent conformational changes exposing a hydrophobic interaction surface, enabling translocation to membranes and calcium-dependent binding to partners including cardiac ryanodine receptors (which it inhibits), L-type Ca2+ channels (accelerating inactivation), EGFR, PDCD6, STAT3, PAX5, and NLRP3 inflammasome; PKA phosphorylation attenuates its RyR-inhibitory activity, while its interactions with STAT3 and PAX5 regulate NF-κB-dependent apoptosis suppression and ferroptosis, respectively, and its maintenance of ER Ca2+ stores supports ATF6-mediated UPR activation and β-cell function."},"narrative":{"mechanistic_narrative":"Sorcin (SRI) is a penta-EF hand calcium-sensing protein that translates micromolar calcium signals into membrane targeting and partner binding to regulate cardiac calcium handling, ER calcium homeostasis, and a range of calcium-dependent signaling events [PMID:7835417, PMID:26577048]. Calcium binding to its EF1-3 hands drives a large conformational change that moves the D-helix, opens EF1, and exposes a hydrophobic pocket, while inducing translocation from cytosol to membranes; this exposed surface accommodates its own N-terminal motif and mediates interaction with the penta-EF hand protein PDCD6 [PMID:7835417, PMID:26577048]. In the heart, sorcin directly inhibits the cardiac ryanodine receptor and accelerates L-type Ca2+ channel inactivation, and PKA phosphorylation attenuates its RyR-inhibitory activity [PMID:9312152, PMID:12754254]. Loss of sorcin produces an arrhythmogenic substrate with spontaneous Ca2+ release and compensatory upregulation of the L-type channel and Na+-Ca2+ exchanger [PMID:29174767]. The same RyR-inhibitory, ER-Ca2+-preserving function operates in pancreatic β-cells, where sorcin supports glucose-stimulated insulin secretion and promotes the protective ATF6 branch of the unfolded protein response [PMID:26822088, PMID:33960419]. In cancer, sorcin acts as a calcium-dependent hub: it binds chemotherapeutics directly and drives MDR1/P-glycoprotein-mediated multidrug resistance [PMID:28726784, PMID:21109982], binds EGFR to control its proteostasis and pro-migratory signaling [PMID:37442828], and through interactions with STAT3, PAX5, and the NLRP3 inflammasome modulates NF-κB-dependent apoptosis suppression, ferroptosis, and pyroptosis respectively [PMID:37833249, PMID:40055736, PMID:39000312].","teleology":[{"year":1995,"claim":"Established that sorcin is a genuine calcium sensor whose calcium binding triggers a conformational change and membrane translocation, defining the mechanistic basis for all its calcium-dependent activities.","evidence":"Cell fractionation and Triton X-114 phase partitioning with purified recombinant sorcin and calcium-binding assay","pmids":["7835417"],"confidence":"High","gaps":["Did not identify the membrane lipids or protein partners engaged after translocation","Conformational change not yet resolved structurally"]},{"year":1997,"claim":"Identified the cardiac ryanodine receptor as a direct sorcin target inhibited from the cytoplasmic side, and placed PKA phosphorylation upstream as a regulator that relieves this inhibition.","evidence":"Single-channel recordings of purified RyR, [3H]ryanodine binding, and in vitro PKA phosphorylation with recombinant sorcin","pmids":["9312152"],"confidence":"High","gaps":["Phosphosite mediating PKA effect not mapped","In vivo relevance of RyR inhibition not yet tested"]},{"year":2003,"claim":"Demonstrated in vivo that sorcin regulates cardiac contractility by associating with and modulating both RyR and L-type Ca2+ channels, and that this co-localization is disrupted in heart failure.","evidence":"Transgenic mouse overexpression, hemodynamics, myocyte Ca2+ imaging, patch clamp, oocyte expression, Co-IP, confocal co-localization","pmids":["12754254"],"confidence":"High","gaps":["Whether L-type channel effect is direct or RyR-secondary not fully resolved","Mechanism of co-localization loss in failing hearts unknown"]},{"year":2016,"claim":"Extended the RyR-inhibitory function to pancreatic β-cells, showing sorcin preserves ER Ca2+ stores required for glucose-stimulated insulin secretion and protects against lipotoxicity.","evidence":"Sorcin KO and β-cell-specific transgenic mice, glucose tolerance and insulin secretion assays, islet Ca2+ imaging, high-fat diet, human islet palmitate treatment","pmids":["26822088"],"confidence":"High","gaps":["Link between sorcin loss and G6PC2 upregulation mechanistically incomplete","Relative contribution of RyR vs other targets in β-cells not isolated"]},{"year":2015,"claim":"Provided the structural mechanism of calcium sensing, showing how Ca2+ binding to EF1-3 exposes a hydrophobic pocket that engages partners bearing a GYYPGG-like motif, including PDCD6.","evidence":"X-ray crystallography of apo and Ca2+-bound sorcin, phage display motif mapping, fluorescence co-localization","pmids":["26577048"],"confidence":"High","gaps":["Functional consequence of PDCD6 binding not established","Disordered N-terminal domain not resolved in apo state"]},{"year":2017,"claim":"Identified sorcin as a direct drug-binding protein and effector of multidrug resistance, linking its localization changes to MDR1-mediated chemotherapeutic efflux.","evidence":"SPR, fluorescence titration, X-ray structure of sorcin–doxorubicin complex, siRNA with drug accumulation/efflux assays","pmids":["28726784","21109982"],"confidence":"High","gaps":["Mechanism linking drug binding to MDR1 transcriptional regulation unknown","Whether calcium sensing modulates drug binding not addressed"]},{"year":2017,"claim":"Showed that sorcin ablation creates an arrhythmogenic substrate, confirming its physiological role in suppressing spontaneous Ca2+ release in the heart.","evidence":"Sorcin KO mouse, isoproterenol+caffeine challenge, transverse aortic constriction, cardiomyocyte Ca2+ imaging, patch clamp, Western blot","pmids":["29174767"],"confidence":"High","gaps":["Trigger for compensatory L-type channel and NCX upregulation unknown","Human arrhythmia relevance not established"]},{"year":2021,"claim":"Connected sorcin's ER Ca2+ maintenance to proteostasis by showing it promotes the protective ATF6 branch of the unfolded protein response.","evidence":"Overexpression and CRISPR/siRNA knockout in HEK293, ATF6 reporter assay, ER stress marker Western blots","pmids":["33960419"],"confidence":"Medium","gaps":["Whether ATF6 effect is purely Ca2+-store-dependent or involves direct interaction unclear","Single cell-line context"]},{"year":2023,"claim":"Defined sorcin as a calcium-dependent EGFR-binding protein controlling EGFR proteostasis and pro-migratory signaling, broadening its role into receptor tyrosine kinase regulation.","evidence":"Co-IP, Western blot, siRNA, migration/invasion assays, EGFR inhibitor combination","pmids":["37442828"],"confidence":"Medium","gaps":["Direct binding interface on EGFR not mapped","Reciprocal Co-IP and structural validation absent"]},{"year":2024,"claim":"Established sorcin as a regulator of cell-death programs in cancer through STAT3-NF-κB-mediated apoptosis suppression, NLRP3-dependent pyroptosis inhibition, and PAX5-dependent ferroptosis control.","evidence":"Co-IP, immunofluorescence, ChIP, reporter assays, pharmacological rescue (MCC950, VX765, celastrol), in vivo xenografts","pmids":["39000312","37833249","40055736"],"confidence":"Medium","gaps":["Whether these partner interactions are direct and calcium-dependent not uniformly established","Each interaction shown by a single lab"]},{"year":2025,"claim":"Implicated sorcin in EGFR-linked lung morphogenesis and surfactant protein recycling through a knockout developmental phenotype.","evidence":"Sorcin KO mouse, histology, RT-PCR, Western blot, confocal microscopy","pmids":["41148307"],"confidence":"Medium","gaps":["Causal chain from sorcin loss to reduced EGFR/RAS/RAB5C not dissected","Single model system"]},{"year":null,"claim":"How the disordered N-terminal domain, expression-level-tuned calcium sensitivity, and partner selection are integrated into a unified switching mechanism across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length calcium-bound structure with disordered N-terminus unresolved","No quantitative model linking sorcin abundance to partner choice","PPP1R3G and PPP1R3G-linked glucose-homeostasis function not validated in cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,12,13]}],"complexes":[],"partners":["RYR2","CACNA1C","PDCD6","EGFR","STAT3","PAX5","NLRP3","PPP1R3G"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30626","full_name":"Sorcin","aliases":["22 kDa protein","CP-22","CP22","V19"],"length_aa":198,"mass_kda":21.7,"function":"Calcium-binding protein that modulates excitation-contraction coupling in the heart. Contributes to calcium homeostasis in the heart sarcoplasmic reticulum. Modulates the activity of RYR2 calcium channels","subcellular_location":"Cytoplasm; Sarcoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P30626/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRI","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000075142","cell_line_id":"CID001916","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"NOL10","stoichiometry":10.0},{"gene":"ANAPC2","stoichiometry":0.2},{"gene":"ANLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001916","total_profiled":1310},"omim":[{"mim_id":"621558","title":"RETINAL DYSTROPHY, ZEITZ-HAN TYPE; RDZH","url":"https://www.omim.org/entry/621558"},{"mim_id":"621543","title":"UBIQUITIN-ASSOCIATED PROTEIN 1-LIKE PROTEIN; UBAP1L","url":"https://www.omim.org/entry/621543"},{"mim_id":"621307","title":"ALSAHAN-HARRIS SYNDROME; ALHAS","url":"https://www.omim.org/entry/621307"},{"mim_id":"620265","title":"CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE; CMYO2B","url":"https://www.omim.org/entry/620265"},{"mim_id":"619967","title":"CONGENITAL MYOPATHY 11; CMYO11","url":"https://www.omim.org/entry/619967"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":529.7}],"url":"https://www.proteinatlas.org/search/SRI"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P30626","domains":[{"cath_id":"1.10.238.10","chopping":"33-196","consensus_level":"medium","plddt":92.3113,"start":33,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30626","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30626-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30626-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRI","jax_strain_url":"https://www.jax.org/strain/search?query=SRI"},"sequence":{"accession":"P30626","fasta_url":"https://rest.uniprot.org/uniprotkb/P30626.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30626/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30626"}},"corpus_meta":[{"pmid":"9312152","id":"PMC_9312152","title":"Modulation of cardiac ryanodine receptors by sorcin.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9312152","citation_count":126,"is_preprint":false},{"pmid":"7835417","id":"PMC_7835417","title":"Calcium-dependent translocation of sorcin to membranes: functional relevance in contractile tissue.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7835417","citation_count":63,"is_preprint":false},{"pmid":"3606647","id":"PMC_3606647","title":"Sorcin (V19), a soluble acidic calcium-binding protein overproduced in multidrug-resistant cells. Identification of the protein by anti-sorcin antibody.","date":"1987","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/3606647","citation_count":63,"is_preprint":false},{"pmid":"30216763","id":"PMC_30216763","title":"Sorcin a Potential Molecular Target for Cancer Therapy.","date":"2018","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30216763","citation_count":60,"is_preprint":false},{"pmid":"25197934","id":"PMC_25197934","title":"Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells.","date":"2014","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/25197934","citation_count":57,"is_preprint":false},{"pmid":"26822088","id":"PMC_26822088","title":"Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores.","date":"2016","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/26822088","citation_count":46,"is_preprint":false},{"pmid":"21109982","id":"PMC_21109982","title":"Overexpression of sorcin results in multidrug resistance in gastric cancer cells with up-regulation of P-gp.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21109982","citation_count":46,"is_preprint":false},{"pmid":"26577048","id":"PMC_26577048","title":"Structural basis of Sorcin-mediated calcium-dependent signal transduction.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26577048","citation_count":44,"is_preprint":false},{"pmid":"12754254","id":"PMC_12754254","title":"Sorcin regulates excitation-contraction coupling in the heart.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12754254","citation_count":44,"is_preprint":false},{"pmid":"28726784","id":"PMC_28726784","title":"Binding of doxorubicin to Sorcin impairs cell death and increases drug resistance in cancer cells.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28726784","citation_count":43,"is_preprint":false},{"pmid":"24337682","id":"PMC_24337682","title":"Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo.","date":"2013","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/24337682","citation_count":38,"is_preprint":false},{"pmid":"32268494","id":"PMC_32268494","title":"Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32268494","citation_count":36,"is_preprint":false},{"pmid":"29273681","id":"PMC_29273681","title":"Sorcin is involved during embryo implantation via activating VEGF/PI3K/Akt pathway in mice.","date":"2017","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29273681","citation_count":35,"is_preprint":false},{"pmid":"29262638","id":"PMC_29262638","title":"Sorcin induces gastric cancer cell migration and invasion contributing to STAT3 activation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29262638","citation_count":32,"is_preprint":false},{"pmid":"25567655","id":"PMC_25567655","title":"Sorcin Enhances Metastasis and Promotes Epithelial-to-Mesenchymal Transition of Colorectal Cancer.","date":"2015","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/25567655","citation_count":26,"is_preprint":false},{"pmid":"24376145","id":"PMC_24376145","title":"Reversing effect of sorcin in the drug resistance of human nasopharyngeal carcinoma.","date":"2013","source":"Anatomical record (Hoboken, N.J. : 2007)","url":"https://pubmed.ncbi.nlm.nih.gov/24376145","citation_count":23,"is_preprint":false},{"pmid":"37833249","id":"PMC_37833249","title":"Sorcin regulate pyroptosis by interacting with NLRP3 inflammasomes to facilitate the progression of hepatocellular carcinoma.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37833249","citation_count":21,"is_preprint":false},{"pmid":"26045737","id":"PMC_26045737","title":"shRNA-mediated silencing of sorcin increases drug chemosensitivity in myeloma KM3/DDP and U266/ADM cell lines.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26045737","citation_count":16,"is_preprint":false},{"pmid":"37442828","id":"PMC_37442828","title":"Sorcin promotes migration in cancer and regulates the EGF-dependent EGFR signaling pathways.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37442828","citation_count":15,"is_preprint":false},{"pmid":"29174767","id":"PMC_29174767","title":"Sorcin ablation plus β-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29174767","citation_count":15,"is_preprint":false},{"pmid":"40055736","id":"PMC_40055736","title":"Disruption of the sorcin‒PAX5 protein‒protein interaction induces ferroptosis by promoting the FBXL12-mediated ubiquitination of ALDH1A1 in pancreatic cancer.","date":"2025","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40055736","citation_count":14,"is_preprint":false},{"pmid":"8561500","id":"PMC_8561500","title":"Purification, cDNA cloning, and expression of human sorcin in vincristine-resistant HOB1 lymphoma cell lines.","date":"1996","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/8561500","citation_count":14,"is_preprint":false},{"pmid":"39516378","id":"PMC_39516378","title":"Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39516378","citation_count":12,"is_preprint":false},{"pmid":"32946798","id":"PMC_32946798","title":"The potential mechanism of action of Sorcin and its interacting proteins.","date":"2020","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32946798","citation_count":10,"is_preprint":false},{"pmid":"32305337","id":"PMC_32305337","title":"Profiling calcium-dependent interactions between Sorcin and intrinsically disordered regions of human proteome.","date":"2020","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/32305337","citation_count":9,"is_preprint":false},{"pmid":"31496794","id":"PMC_31496794","title":"Sorcin: a novel potential target in therapies of cancers.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31496794","citation_count":7,"is_preprint":false},{"pmid":"28855589","id":"PMC_28855589","title":"Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial-mesenchymal Transition in Hepatocellular Carcinoma.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28855589","citation_count":6,"is_preprint":false},{"pmid":"38536659","id":"PMC_38536659","title":"Sorcin promotes proliferation of hepatocellular carcinoma by regulating VEGFA/B via PI3K pathway.","date":"2024","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38536659","citation_count":5,"is_preprint":false},{"pmid":"33960419","id":"PMC_33960419","title":"The Ca2+ -binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6.","date":"2021","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/33960419","citation_count":5,"is_preprint":false},{"pmid":"33675811","id":"PMC_33675811","title":"Knockdown of sorcin increases HEI-OC1 cell damage induced by cisplatin in vitro.","date":"2021","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33675811","citation_count":4,"is_preprint":false},{"pmid":"39000312","id":"PMC_39000312","title":"Sorcin Inhibits Mitochondrial Apoptosis by Interacting with STAT3 via NF-κB Pathway.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39000312","citation_count":4,"is_preprint":false},{"pmid":"39199583","id":"PMC_39199583","title":"Sorcin in Cancer Development and Chemotherapeutic Drug Resistance.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39199583","citation_count":3,"is_preprint":false},{"pmid":"39673665","id":"PMC_39673665","title":"Sorcin: mechanisms of action in cancer hallmarks, drug resistance and opportunities in therapeutics.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39673665","citation_count":2,"is_preprint":false},{"pmid":"39215797","id":"PMC_39215797","title":"Solution NMR backbone resonance assignment of the full-length resistance-related calcium-binding protein Sorcin.","date":"2024","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/39215797","citation_count":2,"is_preprint":false},{"pmid":"37709787","id":"PMC_37709787","title":"Identification of a novel Sorcin isoform with a different C-terminal but intact dimerization property.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37709787","citation_count":2,"is_preprint":false},{"pmid":"37098805","id":"PMC_37098805","title":"Uncovering allostery and regulation in SORCIN through molecular dynamics simulations.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/37098805","citation_count":1,"is_preprint":false},{"pmid":"41148307","id":"PMC_41148307","title":"Sorcin regulates alveolarization and airway tissue remodeling during lung morphogenesis.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41148307","citation_count":0,"is_preprint":false},{"pmid":"41133884","id":"PMC_41133884","title":"Kinetic investigation of calcium-induced Sorcin aggregation by stopped-flow light scattering.","date":"2025","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41133884","citation_count":0,"is_preprint":false},{"pmid":"42041546","id":"PMC_42041546","title":"Protein Expression Analysis and Functional Characterization of Sorcin in Gallbladder Cancer.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/42041546","citation_count":0,"is_preprint":false},{"pmid":"40611756","id":"PMC_40611756","title":"Biochemical and Histological Characterization of Sorcin Overexpression in Patients Who Underwent Radical Prostatectomy.","date":"2025","source":"Urology research & practice","url":"https://pubmed.ncbi.nlm.nih.gov/40611756","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"sonnet_model":"claude-sonnet-4-6","sonnet_input_tokens":20043,"sonnet_output_tokens":4845,"sonnet_usd":0.1328,"sonnet_elapsed_seconds":84.6,"stage1_stop_reason":"end_turn"},"stage2":{"opus_model":"claude-opus-4-8","opus_input_tokens":13145,"opus_output_tokens":3855,"opus_usd":0.1621,"opus_elapsed_seconds":41.7,"stage2_stop_reason":"end_turn"},"total_usd":0.2949},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Sorcin directly inhibits cardiac ryanodine receptor (RyR) open probability (IC50 ~480 nM) and completely inhibits [3H]ryanodine binding (IC50 ~700 nM) when applied to the cytoplasmic side; inhibition is independent of calmodulin/calpain pathways. Phosphorylation of sorcin by the catalytic subunit of PKA significantly decreased its ability to inhibit RyR, placing PKA signaling as an upstream regulator of sorcin's RyR modulatory activity.\",\n      \"method\": \"Single-channel recordings of purified RyR, [3H]ryanodine binding assays with recombinant sorcin, in vitro PKA phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro single-channel and binding assays, mutagenesis/phosphorylation functional follow-up, replicated across multiple readouts\",\n      \"pmids\": [\"9312152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sorcin undergoes calcium-dependent translocation from the cytosol to cellular membranes. Calcium binding to purified recombinant sorcin at micromolar concentrations induces a conformational change that renders the protein soluble in the non-ionic detergent Triton X-114, suggesting lipids as membrane targets.\",\n      \"method\": \"Cell fractionation, detergent-phase partitioning (Triton X-114), calcium-binding assay with purified recombinant sorcin\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of conformational change plus cell fractionation, two orthogonal methods in one study\",\n      \"pmids\": [\"7835417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sorcin overexpression in transgenic mouse hearts reduces contraction and relaxation indices, depresses Ca2+ transient amplitudes, and accelerates L-type Ca2+ channel inactivation; sorcin associates with both cardiac RyR and L-type Ca2+ channels. In failing hearts, co-localization of sorcin with RyR at Z-lines is markedly disrupted.\",\n      \"method\": \"Transgenic mouse overexpression, in vivo hemodynamics, isolated myocyte Ca2+ imaging, whole-cell patch clamp, Xenopus oocyte expression, co-immunoprecipitation, confocal co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transgenic model, electrophysiology, Ca2+ imaging, Co-IP, oocyte expression), replicated across systems\",\n      \"pmids\": [\"12754254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"X-ray crystal structures of sorcin in apo and calcium-bound states show that calcium binding to EF1-3 hands drives a large conformational change (movement of the D-helix, opening of EF1) that exposes a hydrophobic pocket. This exposed pocket accommodates sorcin's own N-terminal domain bearing a consensus GYYPGG-like motif and mediates interaction with PDCD6 (a pro-apoptotic penta-EF hand protein carrying the same motif); PDCD6 co-localizes with sorcin in the perinuclear region and midbody.\",\n      \"method\": \"X-ray crystallography (apo and Ca2+-bound structures), phage display identification of binding motif, co-localization by fluorescence microscopy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures in two states plus phage display and cell-based co-localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26577048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sorcin maintains ER Ca2+ stores in pancreatic β-cells by inhibiting ryanodine receptor activity and terminating Ca2+-induced Ca2+ release. Sorcin-null mice are glucose intolerant with impaired glucose-stimulated insulin secretion; β-cell-specific sorcin overexpression under high-fat diet improves glucose tolerance and increases cytosolic and ER Ca2+. Palmitate-induced sorcin downregulation increases G6PC2 levels, contributing to lipotoxicity.\",\n      \"method\": \"Sorcin knockout mouse, β-cell-specific transgenic overexpression, glucose tolerance tests, insulin secretion assays, Ca2+ imaging in islets, high-fat diet model, human islet palmitate treatment\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO, transgenic OE), physiological readouts, replicated in mouse and human islets\",\n      \"pmids\": [\"26822088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sorcin directly binds doxorubicin, vincristine, paclitaxel, and cisplatin with high affinity. The X-ray structure of the sorcin–doxorubicin complex identifies a binding site at the interface of the EF5 loop, the G helix, and the EF4 loop. Sorcin cellular localization changes upon doxorubicin treatment. Sorcin silencing increases nuclear doxorubicin accumulation, decreases MDR1 expression, and reduces doxorubicin efflux via MDR1.\",\n      \"method\": \"Surface plasmon resonance, fluorescence titration, X-ray crystallography (sorcin–doxorubicin complex), confocal microscopy, siRNA knockdown with drug accumulation and efflux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding demonstrated by three orthogonal biophysical methods plus structural determination and functional cell-based validation\",\n      \"pmids\": [\"28726784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sorcin ablation in mice generates an arrhythmogenic substrate: sorcin KO mice develop ventricular arrhythmia and sudden death upon isoproterenol+caffeine challenge. Isoproterenol stimulation causes spontaneous Ca2+ release events in KO cardiomyocytes. Adult KO hearts develop compensatory overexpression of L-type Ca2+ channel and Na+-Ca2+ exchanger, enhancing ICa and INCX and promoting delayed afterdepolarizations.\",\n      \"method\": \"Sorcin knockout mouse model, in vivo isoproterenol+caffeine challenge, transverse aortic constriction, Ca2+ imaging in isolated cardiomyocytes, patch clamp (ICa, INCX), Western blot\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with defined electrophysiological and Ca2+ phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"29174767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sorcin overexpression confers multidrug resistance in gastric cancer cells and decreases intracellular vincristine concentration; sorcin overexpression upregulates P-glycoprotein (P-gp/MDR1) expression, and P-gp inhibition with verapamil partially reverses sorcin-mediated MDR.\",\n      \"method\": \"Gene transfection overexpression, antisense oligonucleotide knockdown, intracellular drug accumulation assay, Western blot, P-gp inhibitor rescue experiment\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with drug accumulation and pharmacological rescue, single lab\",\n      \"pmids\": [\"21109982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sorcin depletion in MDA-MB-231 breast cancer cells reduces the CD44+/CD24- and ALDH1high cancer stem cell pool, reduces mammosphere-forming capacity, induces an epithelial-like phenotype by modulating E-cadherin and VEGF expression, and suppresses metastasis in nude mice.\",\n      \"method\": \"RNAi knockdown (transient and stable), lentiviral overexpression, flow cytometry for CSC markers, mammosphere assay, Western blot for EMT markers, in vivo xenograft metastasis assay\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with in vitro and in vivo readouts, single lab, mechanistic detail limited to E-cadherin/VEGF\",\n      \"pmids\": [\"24337682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sorcin directly binds EGFR in a calcium-dependent manner, controls EGFR proteostasis and signaling, and increases EGFR phosphorylation, leading to increased EGF-dependent cell migration and invasion. Sorcin silencing cooperates with EGFR inhibitors to reduce migration.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, migration/invasion assays, EGFR inhibitor combination studies\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP plus functional phenotypic readouts and pharmacological cooperativity, single lab\",\n      \"pmids\": [\"37442828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sorcin interacts with the NLRP3 inflammasome (demonstrated by co-immunoprecipitation and immunofluorescence) and negatively regulates pyroptosis in hepatocellular carcinoma cells; sorcin knockdown activates Caspase-1-dependent pyroptosis and suppresses HCC tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, NLRP3 inhibitor (MCC950) and Caspase-1 inhibitor (VX765) rescue, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus pharmacological rescue and in vivo validation, single lab\",\n      \"pmids\": [\"37833249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sorcin overexpression increases ATF6 transcriptional activity in HEK293 cells, while sorcin knockout reduces ATF6 transcriptional activity and increases ER stress markers, indicating sorcin promotes the protective ATF6-branch of the unfolded protein response.\",\n      \"method\": \"Sorcin overexpression, CRISPR/siRNA knockout in HEK293 cells, ATF6 transcriptional reporter assay, Western blot for ER stress markers\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementary gain- and loss-of-function with transcriptional reporter readout, single lab\",\n      \"pmids\": [\"33960419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sorcin interacts with PAX5 in the cytoplasm and inhibits PAX5 nuclear translocation; disrupting the sorcin-PAX5 interaction (by the natural product celastrol binding to Cys194 of sorcin) promotes PAX5 nuclear translocation, increases FBXL12 expression, enhances ALDH1A1 ubiquitination, and induces ferroptosis in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter, proteomics, surface plasmon resonance, in vivo xenograft with genetic/pharmacological rescue\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP and reporter assays with pharmacological target identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40055736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sorcin interacts with STAT3 (demonstrated by co-immunoprecipitation and immunofluorescence) and activates the NF-κB signaling pathway, thereby inhibiting mitochondrial apoptosis in hepatocellular carcinoma; sorcin knockdown reduces NF-κB activity and increases apoptosis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blot for NF-κB pathway components, mitochondrial membrane potential assay, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding plus functional NF-κB pathway analysis and in vivo validation, single lab\",\n      \"pmids\": [\"39000312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Proteomic peptide phage display identified a peptide from protein phosphatase 1 regulatory subunit 3G (PPP1R3G) as a calcium-dependent Sorcin-binding partner, with confirmation by biophysical assays and cell-based approaches, revealing a potential link between glucose homeostasis and calcium concentration.\",\n      \"method\": \"Proteomic peptide phage display (ProP-PD), biophysical binding assays, cell-based interaction assays, molecular dynamics simulations\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phage display plus biophysical follow-up without detailed in-cell mechanistic dissection, single lab\",\n      \"pmids\": [\"32305337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NMR backbone resonance assignment of full-length sorcin in the calcium-free state reveals that most of the N-terminal domain is disordered; secondary structure prediction from chemical shifts provides a structural foundation for studying Ca2+ sensing by full-length sorcin.\",\n      \"method\": \"Solution NMR (1H, 13C, 15N backbone resonance assignment), TALOS+/CSI 3.0 secondary structure prediction\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural NMR assignment only, no functional validation reported in abstract, single lab\",\n      \"pmids\": [\"39215797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Stopped-flow light scattering showed that calcium-induced sorcin aggregation is reversible, cooperative, and primarily concentration-dependent rather than directly determined by physiological calcium levels, suggesting sorcin's calcium sensitivity is tuned by its expression level.\",\n      \"method\": \"Stopped-flow light scattering, calcium-titration aggregation assay with purified recombinant sorcin\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biophysical assay, single lab, no cellular functional validation reported in abstract\",\n      \"pmids\": [\"41133884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sorcin forms a positive feedback loop with STAT3 to increase transcription of serpin E1 and CCL5, and sorcin overexpression induces pancreatic β-cell dysfunction; sorcin-driven secretion of serpin E1 and CCL5 contributes to pancreatic cancer-associated new-onset diabetes.\",\n      \"method\": \"In vitro sorcin overexpression in β-cell lines, co-IP, STAT3 pathway inhibition, cytokine measurement, in vivo mouse model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway partially defined but limited orthogonal validation; single lab\",\n      \"pmids\": [\"39516378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sorcin knockout (Sri-/-) mice display impaired lung alveolarization, reduced surfactant protein expression (Sp-b, Sp-c, Abca3), type II pneumocyte immaturity, and reduced EGFR, RAS, and RAB5C protein levels, implicating sorcin in EGFR-linked lung morphogenesis and surfactant protein recycling.\",\n      \"method\": \"Sorcin knockout mouse model, histology, real-time PCR, Western blot, confocal microscopy\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with multiple molecular and histological readouts, single lab, mechanistic link to EGFR/RAB5C pathway\",\n      \"pmids\": [\"41148307\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Sorcin is a penta-EF hand calcium-sensing protein that undergoes calcium-dependent conformational changes exposing a hydrophobic interaction surface, enabling translocation to membranes and calcium-dependent binding to partners including cardiac ryanodine receptors (which it inhibits), L-type Ca2+ channels (accelerating inactivation), EGFR, PDCD6, STAT3, PAX5, and NLRP3 inflammasome; PKA phosphorylation attenuates its RyR-inhibitory activity, while its interactions with STAT3 and PAX5 regulate NF-κB-dependent apoptosis suppression and ferroptosis, respectively, and its maintenance of ER Ca2+ stores supports ATF6-mediated UPR activation and β-cell function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Sorcin (SRI) is a penta-EF hand calcium-sensing protein that translates micromolar calcium signals into membrane targeting and partner binding to regulate cardiac calcium handling, ER calcium homeostasis, and a range of calcium-dependent signaling events [#1, #3]. Calcium binding to its EF1-3 hands drives a large conformational change that moves the D-helix, opens EF1, and exposes a hydrophobic pocket, while inducing translocation from cytosol to membranes; this exposed surface accommodates its own N-terminal motif and mediates interaction with the penta-EF hand protein PDCD6 [#1, #3]. In the heart, sorcin directly inhibits the cardiac ryanodine receptor and accelerates L-type Ca2+ channel inactivation, and PKA phosphorylation attenuates its RyR-inhibitory activity [#0, #2]. Loss of sorcin produces an arrhythmogenic substrate with spontaneous Ca2+ release and compensatory upregulation of the L-type channel and Na+-Ca2+ exchanger [#6]. The same RyR-inhibitory, ER-Ca2+-preserving function operates in pancreatic β-cells, where sorcin supports glucose-stimulated insulin secretion and promotes the protective ATF6 branch of the unfolded protein response [#4, #11]. In cancer, sorcin acts as a calcium-dependent hub: it binds chemotherapeutics directly and drives MDR1/P-glycoprotein-mediated multidrug resistance [#5, #7], binds EGFR to control its proteostasis and pro-migratory signaling [#9], and through interactions with STAT3, PAX5, and the NLRP3 inflammasome modulates NF-κB-dependent apoptosis suppression, ferroptosis, and pyroptosis respectively [#10, #12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that sorcin is a genuine calcium sensor whose calcium binding triggers a conformational change and membrane translocation, defining the mechanistic basis for all its calcium-dependent activities.\",\n      \"evidence\": \"Cell fractionation and Triton X-114 phase partitioning with purified recombinant sorcin and calcium-binding assay\",\n      \"pmids\": [\"7835417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the membrane lipids or protein partners engaged after translocation\", \"Conformational change not yet resolved structurally\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the cardiac ryanodine receptor as a direct sorcin target inhibited from the cytoplasmic side, and placed PKA phosphorylation upstream as a regulator that relieves this inhibition.\",\n      \"evidence\": \"Single-channel recordings of purified RyR, [3H]ryanodine binding, and in vitro PKA phosphorylation with recombinant sorcin\",\n      \"pmids\": [\"9312152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite mediating PKA effect not mapped\", \"In vivo relevance of RyR inhibition not yet tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated in vivo that sorcin regulates cardiac contractility by associating with and modulating both RyR and L-type Ca2+ channels, and that this co-localization is disrupted in heart failure.\",\n      \"evidence\": \"Transgenic mouse overexpression, hemodynamics, myocyte Ca2+ imaging, patch clamp, oocyte expression, Co-IP, confocal co-localization\",\n      \"pmids\": [\"12754254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether L-type channel effect is direct or RyR-secondary not fully resolved\", \"Mechanism of co-localization loss in failing hearts unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the RyR-inhibitory function to pancreatic β-cells, showing sorcin preserves ER Ca2+ stores required for glucose-stimulated insulin secretion and protects against lipotoxicity.\",\n      \"evidence\": \"Sorcin KO and β-cell-specific transgenic mice, glucose tolerance and insulin secretion assays, islet Ca2+ imaging, high-fat diet, human islet palmitate treatment\",\n      \"pmids\": [\"26822088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between sorcin loss and G6PC2 upregulation mechanistically incomplete\", \"Relative contribution of RyR vs other targets in β-cells not isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural mechanism of calcium sensing, showing how Ca2+ binding to EF1-3 exposes a hydrophobic pocket that engages partners bearing a GYYPGG-like motif, including PDCD6.\",\n      \"evidence\": \"X-ray crystallography of apo and Ca2+-bound sorcin, phage display motif mapping, fluorescence co-localization\",\n      \"pmids\": [\"26577048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PDCD6 binding not established\", \"Disordered N-terminal domain not resolved in apo state\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified sorcin as a direct drug-binding protein and effector of multidrug resistance, linking its localization changes to MDR1-mediated chemotherapeutic efflux.\",\n      \"evidence\": \"SPR, fluorescence titration, X-ray structure of sorcin–doxorubicin complex, siRNA with drug accumulation/efflux assays\",\n      \"pmids\": [\"28726784\", \"21109982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking drug binding to MDR1 transcriptional regulation unknown\", \"Whether calcium sensing modulates drug binding not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that sorcin ablation creates an arrhythmogenic substrate, confirming its physiological role in suppressing spontaneous Ca2+ release in the heart.\",\n      \"evidence\": \"Sorcin KO mouse, isoproterenol+caffeine challenge, transverse aortic constriction, cardiomyocyte Ca2+ imaging, patch clamp, Western blot\",\n      \"pmids\": [\"29174767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for compensatory L-type channel and NCX upregulation unknown\", \"Human arrhythmia relevance not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected sorcin's ER Ca2+ maintenance to proteostasis by showing it promotes the protective ATF6 branch of the unfolded protein response.\",\n      \"evidence\": \"Overexpression and CRISPR/siRNA knockout in HEK293, ATF6 reporter assay, ER stress marker Western blots\",\n      \"pmids\": [\"33960419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATF6 effect is purely Ca2+-store-dependent or involves direct interaction unclear\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined sorcin as a calcium-dependent EGFR-binding protein controlling EGFR proteostasis and pro-migratory signaling, broadening its role into receptor tyrosine kinase regulation.\",\n      \"evidence\": \"Co-IP, Western blot, siRNA, migration/invasion assays, EGFR inhibitor combination\",\n      \"pmids\": [\"37442828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface on EGFR not mapped\", \"Reciprocal Co-IP and structural validation absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established sorcin as a regulator of cell-death programs in cancer through STAT3-NF-κB-mediated apoptosis suppression, NLRP3-dependent pyroptosis inhibition, and PAX5-dependent ferroptosis control.\",\n      \"evidence\": \"Co-IP, immunofluorescence, ChIP, reporter assays, pharmacological rescue (MCC950, VX765, celastrol), in vivo xenografts\",\n      \"pmids\": [\"39000312\", \"37833249\", \"40055736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these partner interactions are direct and calcium-dependent not uniformly established\", \"Each interaction shown by a single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated sorcin in EGFR-linked lung morphogenesis and surfactant protein recycling through a knockout developmental phenotype.\",\n      \"evidence\": \"Sorcin KO mouse, histology, RT-PCR, Western blot, confocal microscopy\",\n      \"pmids\": [\"41148307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from sorcin loss to reduced EGFR/RAS/RAB5C not dissected\", \"Single model system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the disordered N-terminal domain, expression-level-tuned calcium sensitivity, and partner selection are integrated into a unified switching mechanism across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full-length calcium-bound structure with disordered N-terminus unresolved\", \"No quantitative model linking sorcin abundance to partner choice\", \"PPP1R3G and PPP1R3G-linked glucose-homeostasis function not validated in cells\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RYR2\", \"CACNA1C\", \"PDCD6\", \"EGFR\", \"STAT3\", \"PAX5\", \"NLRP3\", \"PPP1R3G\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}