{"gene":"GCA","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2019,"finding":"Grancalcin (GCA) activates TRAF6 ubiquitin ligase activity, inducing Lys63-linked ubiquitination of ULK1, which stabilizes and activates ULK1 to promote autophagy, thereby driving imatinib resistance in chronic myeloid leukemia.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assays, autophagy flux assays in CML cell lines and patient samples","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, reciprocal Co-IP and functional knockdown with defined pathway placement (GCA→TRAF6→ULK1 ubiquitination→autophagy), but no structural validation or independent replication","pmids":["30929559"],"is_preprint":false},{"year":2016,"finding":"Grancalcin (GCA) directly binds TLR9 (demonstrated by yeast two-hybrid and co-immunoprecipitation in an overexpression system) and positively regulates TLR9-mediated type I IFN production, cytokine/chemokine secretion, IRF7 nuclear localization, NF-κB activation, and MAPK activation in plasmacytoid dendritic cells; siRNA-mediated knockdown of GCA reduced these downstream signaling outputs.","method":"Yeast two-hybrid, co-immunoprecipitation (overexpression system), siRNA knockdown, reporter assays for NF-κB/IRF7, cytokine ELISA in plasmacytoid dendritic cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP establish interaction; siRNA knockdown with multiple downstream readouts in one lab; no independent replication or structural confirmation","pmids":["26648480"],"is_preprint":false},{"year":2023,"finding":"Bone marrow-derived GCA+ immune cells secrete grancalcin, which competitively binds to LRP1 in microglia, inhibiting microglial phagocytosis and clearance of amyloid-β, thereby potentiating Alzheimer's disease neuropathology; CCR10 mediates preferential homing of GCA+ cells to the hippocampus and cortex. Genetic ablation of GCA in the hematopoietic compartment improved cognitive function, and GCA-neutralizing antibody treatment reduced AD progression in mouse models.","method":"Bone marrow transplantation, stereotaxic injection of recombinant GCA protein, hematopoietic-specific genetic knockout, competitive binding assay for LRP1, phagocytosis assays in microglia, cognitive behavioral tests in AD mouse models, GCA-neutralizing antibody treatment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function, recombinant protein gain-of-function, and competitive binding assay provide orthogonal evidence in a single lab; mechanistic link (GCA→LRP1 competition→impaired Aβ phagocytosis) supported by multiple methods but awaits independent replication","pmids":["37949676"],"is_preprint":false}],"current_model":"Grancalcin (GCA) is a penta-EF-hand calcium-binding protein that functions as a signaling scaffold: it activates TRAF6 ubiquitin ligase to drive Lys63-ubiquitination and stabilization of ULK1 (promoting autophagy and imatinib resistance in CML), directly heterodimerizes with TLR9 to potentiate innate immune signaling (type I IFN, NF-κB, MAPK) in plasmacytoid dendritic cells, and is secreted by bone marrow-derived immune cells to competitively inhibit LRP1-mediated amyloid-β clearance in microglia, thereby exacerbating Alzheimer's disease pathology."},"narrative":{"mechanistic_narrative":"Grancalcin (GCA) acts as a calcium-binding signaling scaffold and secreted modulator that potentiates innate immune and stress-response pathways across distinct cellular contexts [PMID:30929559, PMID:26648480, PMID:37949676]. In chronic myeloid leukemia cells, GCA activates the ubiquitin ligase TRAF6 to drive Lys63-linked ubiquitination of ULK1, stabilizing and activating ULK1 to promote autophagy and thereby conferring imatinib resistance [PMID:30929559]. In plasmacytoid dendritic cells, GCA directly binds TLR9 and positively regulates TLR9-driven type I IFN production, IRF7 nuclear localization, NF-κB activation, and MAPK activation [PMID:26648480]. GCA is also secreted by bone marrow-derived immune cells, which home to the hippocampus and cortex via CCR10, where secreted GCA competitively binds microglial LRP1 to inhibit phagocytic clearance of amyloid-β and exacerbate Alzheimer's disease pathology; hematopoietic GCA ablation or GCA-neutralizing antibody treatment improved outcomes in mouse models [PMID:37949676]. Beyond these three contexts, the structural basis of GCA's interactions and its calcium-dependence have not been characterized in the available corpus.","teleology":[{"year":2016,"claim":"Established GCA as a direct binding partner of TLR9 and a positive regulator of innate immune signaling, linking this calcium-binding protein to nucleic-acid sensing for the first time.","evidence":"Yeast two-hybrid and overexpression co-IP for interaction, plus siRNA knockdown with NF-κB/IRF7 reporters and cytokine ELISA in plasmacytoid dendritic cells","pmids":["26648480"],"confidence":"Medium","gaps":["Interaction shown only in overexpression system without endogenous reciprocal validation","No structural basis for the GCA–TLR9 interaction","Calcium-dependence of the interaction not tested"]},{"year":2019,"claim":"Placed GCA upstream of an autophagy-driving ubiquitination cascade, explaining how it promotes drug resistance in leukemia.","evidence":"siRNA knockdown, reciprocal co-IP, ubiquitination assays, and autophagy flux assays in CML cell lines and patient samples","pmids":["30929559"],"confidence":"Medium","gaps":["No structural validation of the GCA–TRAF6 interaction","Mechanism by which GCA activates TRAF6 ligase activity not defined","Not independently replicated"]},{"year":2023,"claim":"Identified GCA as a secreted factor that impairs microglial amyloid-β clearance via LRP1 competition, defining a peripheral-immune contribution to Alzheimer's pathology.","evidence":"Bone marrow transplantation, hematopoietic-specific knockout, recombinant GCA injection, LRP1 competitive binding assay, microglial phagocytosis assays, and neutralizing antibody treatment in AD mouse models","pmids":["37949676"],"confidence":"Medium","gaps":["LRP1 binding site and competition stoichiometry not resolved","Mechanism of GCA secretion not defined","Single lab; awaits independent replication"]},{"year":null,"claim":"Whether the three reported functions reflect a single unifying biochemical activity of GCA, and how its penta-EF-hand calcium binding governs each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of GCA in complex with any partner","Calcium-dependence of binding events not experimentally linked across contexts","No integration of intracellular scaffold versus secreted functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":[],"partners":["TRAF6","ULK1","TLR9","LRP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P28676","full_name":"Grancalcin","aliases":[],"length_aa":217,"mass_kda":24.0,"function":"Calcium-binding protein that may play a role in the adhesion of neutrophils to fibronectin. May play a role in the formation of focal adhesions","subcellular_location":"Cytoplasm; Cytoplasmic granule membrane","url":"https://www.uniprot.org/uniprotkb/P28676/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GCA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GCA","total_profiled":1310},"omim":[{"mim_id":"618412","title":"GLOBAL DEVELOPMENTAL DELAY, PROGRESSIVE ATAXIA, AND ELEVATED GLUTAMINE; GDPAG","url":"https://www.omim.org/entry/618412"},{"mim_id":"617096","title":"TRANSMEMBRANE PROTEIN 59-LIKE; TMEM59L","url":"https://www.omim.org/entry/617096"},{"mim_id":"613890","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 2; HSD3B2","url":"https://www.omim.org/entry/613890"},{"mim_id":"610155","title":"TYPE 1 DIABETES MELLITUS 19; T1D19","url":"https://www.omim.org/entry/610155"},{"mim_id":"610033","title":"PENTA-EF-HAND DOMAIN-CONTAINING PROTEIN 1; PEF1","url":"https://www.omim.org/entry/610033"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":307.8}],"url":"https://www.proteinatlas.org/search/GCA"},"hgnc":{"alias_symbol":["GCL"],"prev_symbol":[]},"alphafold":{"accession":"P28676","domains":[{"cath_id":"1.10.238.10","chopping":"54-217","consensus_level":"high","plddt":93.8004,"start":54,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28676","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28676-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28676-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GCA","jax_strain_url":"https://www.jax.org/strain/search?query=GCA"},"sequence":{"accession":"P28676","fasta_url":"https://rest.uniprot.org/uniprotkb/P28676.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28676/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28676"}},"corpus_meta":[{"pmid":"11579707","id":"PMC_11579707","title":"A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA).","date":"2001","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/11579707","citation_count":255,"is_preprint":false},{"pmid":"10871408","id":"PMC_10871408","title":"The complete nucleotide sequence of the mitochondrial genome of sugar beet (Beta vulgaris L.) reveals a novel gene for tRNA(Cys)(GCA).","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10871408","citation_count":239,"is_preprint":false},{"pmid":"37308659","id":"PMC_37308659","title":"Disease stratification in GCA and PMR: state of the art and future perspectives.","date":"2023","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/37308659","citation_count":94,"is_preprint":false},{"pmid":"28040244","id":"PMC_28040244","title":"Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): A nested case-control analysis.","date":"2016","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/28040244","citation_count":80,"is_preprint":false},{"pmid":"8103637","id":"PMC_8103637","title":"Peptide-regulated guanylate cyclase pathways in rat colon: in situ localization of GCA, GCC, and guanylin mRNA.","date":"1993","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8103637","citation_count":78,"is_preprint":false},{"pmid":"2324677","id":"PMC_2324677","title":"Epidemiology of biopsy-proven giant cell arteritis (GCA).","date":"1990","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2324677","citation_count":73,"is_preprint":false},{"pmid":"11907014","id":"PMC_11907014","title":"Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice.","date":"2002","source":"Heart (British Cardiac Society)","url":"https://pubmed.ncbi.nlm.nih.gov/11907014","citation_count":73,"is_preprint":false},{"pmid":"30929559","id":"PMC_30929559","title":"GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30929559","citation_count":52,"is_preprint":false},{"pmid":"7583654","id":"PMC_7583654","title":"Structure of a single-cytidine hairpin loop formed by the DNA triplet GCA.","date":"1995","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/7583654","citation_count":52,"is_preprint":false},{"pmid":"34513311","id":"PMC_34513311","title":"5'-tiRNA-Cys-GCA regulates VSMC proliferation and phenotypic transition by targeting STAT4 in aortic dissection.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/34513311","citation_count":49,"is_preprint":false},{"pmid":"18285833","id":"PMC_18285833","title":"IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk.","date":"2008","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/18285833","citation_count":48,"is_preprint":false},{"pmid":"17206530","id":"PMC_17206530","title":"Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China.","date":"2007","source":"Cancer causes & control : CCC","url":"https://pubmed.ncbi.nlm.nih.gov/17206530","citation_count":47,"is_preprint":false},{"pmid":"1998601","id":"PMC_1998601","title":"Antithrombin Vicenza, Ala 384 to Pro (GCA to CCA) mutation, transforming the inhibitor into a substrate.","date":"1991","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/1998601","citation_count":47,"is_preprint":false},{"pmid":"31008443","id":"PMC_31008443","title":"The utility of ESR, CRP and platelets in the diagnosis of GCA.","date":"2019","source":"BMC rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/31008443","citation_count":45,"is_preprint":false},{"pmid":"18021519","id":"PMC_18021519","title":"Management guidelines and outcome measures in giant cell arteritis (GCA).","date":"2007","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/18021519","citation_count":42,"is_preprint":false},{"pmid":"32994361","id":"PMC_32994361","title":"Probability-based algorithm using ultrasound and additional tests for suspected GCA in a fast-track clinic.","date":"2020","source":"RMD open","url":"https://pubmed.ncbi.nlm.nih.gov/32994361","citation_count":42,"is_preprint":false},{"pmid":"22693300","id":"PMC_22693300","title":"Successful use of tocilizumab in polymyalgic onset biopsy positive GCA with large vessel involvement.","date":"2011","source":"BMJ case reports","url":"https://pubmed.ncbi.nlm.nih.gov/22693300","citation_count":41,"is_preprint":false},{"pmid":"20066148","id":"PMC_20066148","title":"Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart.","date":"2009","source":"Current cardiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/20066148","citation_count":39,"is_preprint":false},{"pmid":"19277817","id":"PMC_19277817","title":"Tongue necrosis as first symptom of giant cell arteritis (GCA).","date":"2009","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/19277817","citation_count":36,"is_preprint":false},{"pmid":"22258388","id":"PMC_22258388","title":"Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA--a simultaneous study of 130 potentially functional SNPs in 14 candidate genes.","date":"2012","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22258388","citation_count":35,"is_preprint":false},{"pmid":"31379838","id":"PMC_31379838","title":"Decreased Expression of Negative Immune Checkpoint VISTA by CD4+ T Cells Facilitates T Helper 1, T Helper 17, and T Follicular Helper Lineage Differentiation in GCA.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31379838","citation_count":31,"is_preprint":false},{"pmid":"30827250","id":"PMC_30827250","title":"Giant Cell Arteritis (GCA): Pathogenesis, Clinical Aspects and Treatment Approaches.","date":"2019","source":"Current rheumatology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/30827250","citation_count":30,"is_preprint":false},{"pmid":"10948748","id":"PMC_10948748","title":"Clinical features of GCA/PMR.","date":"2000","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/10948748","citation_count":29,"is_preprint":false},{"pmid":"10948756","id":"PMC_10948756","title":"Laboratory investigations useful in the evaluation of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA).","date":"2000","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/10948756","citation_count":29,"is_preprint":false},{"pmid":"19837875","id":"PMC_19837875","title":"Expression of guanylyl cyclase (GC)-A and GC-B during brain development: evidence for a role of GC-B in perinatal neurogenesis.","date":"2009","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19837875","citation_count":28,"is_preprint":false},{"pmid":"23274351","id":"PMC_23274351","title":"Glycyrrhizic acid (GCA) as 11β-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis.","date":"2012","source":"Journal of bone and mineral metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23274351","citation_count":28,"is_preprint":false},{"pmid":"22133375","id":"PMC_22133375","title":"Guanylyl cyclase (GC)-A and GC-B activities in ventricles and cardiomyocytes from failed and non-failed human hearts: GC-A is inactive in the failed cardiomyocyte.","date":"2011","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/22133375","citation_count":27,"is_preprint":false},{"pmid":"9753721","id":"PMC_9753721","title":"The hypotrichous ciliate Euplotes octocarinatus has only one type of tRNACys with GCA anticodon encoded on a single macronuclear DNA molecule.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9753721","citation_count":26,"is_preprint":false},{"pmid":"18046624","id":"PMC_18046624","title":"An investigation on the polymorphisms of two DNA repair genes and susceptibility to ESCC and GCA of high-incidence region in northern China.","date":"2007","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/18046624","citation_count":24,"is_preprint":false},{"pmid":"22820967","id":"PMC_22820967","title":"Systematic review of the literature and a case report informing biopsy-proven giant cell arteritis (GCA) with normal C-reactive protein.","date":"2012","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/22820967","citation_count":23,"is_preprint":false},{"pmid":"8548534","id":"PMC_8548534","title":"Prevalence of gca, a gene involved in synthesis of A-band common antigen polysaccharide in Pseudomonas aeruginosa.","date":"1995","source":"Clinical and diagnostic laboratory immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8548534","citation_count":22,"is_preprint":false},{"pmid":"26156043","id":"PMC_26156043","title":"MMP-3 can distinguish isolated PMR from PMR with GCA: A retrospective study regarding PMR and GCA in Japan.","date":"2015","source":"Modern rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/26156043","citation_count":20,"is_preprint":false},{"pmid":"17573798","id":"PMC_17573798","title":"Plastid tRNA genes trnC-GCA and trnN-GUU are essential for plant cell development.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17573798","citation_count":19,"is_preprint":false},{"pmid":"31576487","id":"PMC_31576487","title":"Validating a diagnostic GCA ultrasonography service against temporal artery biopsy and long-term clinical outcomes.","date":"2019","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/31576487","citation_count":19,"is_preprint":false},{"pmid":"10948747","id":"PMC_10948747","title":"Classification/diagnostic criteria for GCA/PMR.","date":"2000","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/10948747","citation_count":19,"is_preprint":false},{"pmid":"7913429","id":"PMC_7913429","title":"Sodium status affects GC-B natriuretic peptide receptor mRNA levels, but not GC-A or C receptor mRNA levels, in the sheep kidney.","date":"1994","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/7913429","citation_count":18,"is_preprint":false},{"pmid":"37949676","id":"PMC_37949676","title":"Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37949676","citation_count":17,"is_preprint":false},{"pmid":"25409453","id":"PMC_25409453","title":"A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25409453","citation_count":17,"is_preprint":false},{"pmid":"34644662","id":"PMC_34644662","title":"Incidence, survival, and diagnostic trends in GCA across seven decades in a North American population-based cohort.","date":"2021","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/34644662","citation_count":17,"is_preprint":false},{"pmid":"27043686","id":"PMC_27043686","title":"A Retrospective Study of Chinese Patients With Giant Cell Arteritis (GCA): Clinical Features and Factors Associated With Severe Ischemic Manifestations.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27043686","citation_count":17,"is_preprint":false},{"pmid":"36426134","id":"PMC_36426134","title":"The tRNA-Cys-GCA Derived tsRNAs Suppress Tumor Progression of Gliomas via Regulating VAV2.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/36426134","citation_count":15,"is_preprint":false},{"pmid":"27084233","id":"PMC_27084233","title":"Blinded search for varicella zoster virus in giant cell arteritis (GCA)-positive and GCA-negative temporal arteries.","date":"2016","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27084233","citation_count":14,"is_preprint":false},{"pmid":"17134961","id":"PMC_17134961","title":"Nongenomic activation of the GC-A enzyme by resveratrol and estradiol downstream from membrane estrogen receptors in human coronary arterial cells.","date":"2006","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/17134961","citation_count":14,"is_preprint":false},{"pmid":"25059598","id":"PMC_25059598","title":"Evaluation of a 32-channel versus a 12-channel head coil for high-resolution post-contrast MRI in giant cell arteritis (GCA) at 3T.","date":"2014","source":"European journal of radiology","url":"https://pubmed.ncbi.nlm.nih.gov/25059598","citation_count":14,"is_preprint":false},{"pmid":"39919971","id":"PMC_39919971","title":"The giant cell arteritis (GCA) ultrasound score (OGUS) at diagnosis and after initial treatment predicts future relapses in GCA patients: results of a multicentre prospective study.","date":"2025","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39919971","citation_count":13,"is_preprint":false},{"pmid":"1701109","id":"PMC_1701109","title":"Structure and expression of tomato mitochondrial genes coding for tRNA(Cys) (GCA), tRNA(Asn) (GUU) and tRNA(Tyr) (GUA): a native tRNA(Cys) gene is present in dicot plants but absent in monocot plants.","date":"1990","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1701109","citation_count":13,"is_preprint":false},{"pmid":"18360023","id":"PMC_18360023","title":"Association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese.","date":"2008","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/18360023","citation_count":13,"is_preprint":false},{"pmid":"21724608","id":"PMC_21724608","title":"Role of the closing base pair for d(GCA) hairpin stability: free energy analysis and folding simulations.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21724608","citation_count":13,"is_preprint":false},{"pmid":"17220981","id":"PMC_17220981","title":"Chiral discrimination of alpha-amino acids by the DNA triplet GCA.","date":"2006","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17220981","citation_count":13,"is_preprint":false},{"pmid":"35407411","id":"PMC_35407411","title":"Treatment of Giant Cell Arteritis (GCA).","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35407411","citation_count":12,"is_preprint":false},{"pmid":"26648480","id":"PMC_26648480","title":"Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9.","date":"2016","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26648480","citation_count":11,"is_preprint":false},{"pmid":"20444705","id":"PMC_20444705","title":"GREBP, a cGMP-response element-binding protein repressing the transcription of natriuretic peptide receptor 1 (NPR1/GCA).","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20444705","citation_count":11,"is_preprint":false},{"pmid":"39039568","id":"PMC_39039568","title":"Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation.","date":"2024","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/39039568","citation_count":10,"is_preprint":false},{"pmid":"18778744","id":"PMC_18778744","title":"Regulation of steroidogenesis by atrial natriuretic peptide (ANP) in the rat testis: differential involvement of GC-A and C receptors.","date":"2008","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/18778744","citation_count":10,"is_preprint":false},{"pmid":"32399772","id":"PMC_32399772","title":"Serious infections in people with polymyalgia rheumatica (PMR) or giant cell arteritis (GCA): a time-trend national US study.","date":"2020","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/32399772","citation_count":9,"is_preprint":false},{"pmid":"33815414","id":"PMC_33815414","title":"CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33815414","citation_count":8,"is_preprint":false},{"pmid":"30530109","id":"PMC_30530109","title":"Liposomal prodigiosin and plasmid encoding serial GCA nucleotides reduce inflammation in microglial and astrocyte cells by ATM/ATR signaling.","date":"2018","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/30530109","citation_count":8,"is_preprint":false},{"pmid":"39740930","id":"PMC_39740930","title":"Does tocilizumab eliminate inflammation in GCA? A cohort study on repeated temporal artery biopsies.","date":"2024","source":"RMD open","url":"https://pubmed.ncbi.nlm.nih.gov/39740930","citation_count":8,"is_preprint":false},{"pmid":"1347156","id":"PMC_1347156","title":"Comparison of a cloned ANF-sensitive guanylate cyclase (GC-A) with particulate guanylate cyclase from adrenal cortex.","date":"1992","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1347156","citation_count":8,"is_preprint":false},{"pmid":"33065420","id":"PMC_33065420","title":"Risk profiling for a refractory course of giant cell arteritis: The importance of age and body weight: \"Risk profiling for GC resistance in GCA\".","date":"2020","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/33065420","citation_count":7,"is_preprint":false},{"pmid":"2456957","id":"PMC_2456957","title":"Refinement of the solution structure of the RNA-DNA hybrid 5'-[r(GCA)d(TGC)]2. Combined use of nuclear magnetic resonance and restrained molecular dynamics.","date":"1988","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2456957","citation_count":7,"is_preprint":false},{"pmid":"14713365","id":"PMC_14713365","title":"Non-genomic effects of tamoxifen on the activation of membrane-bound guanylate cyclase GC-A.","date":"2003","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/14713365","citation_count":7,"is_preprint":false},{"pmid":"2544467","id":"PMC_2544467","title":"Anchorage-independent growth of RSV-transformed rat (GCA, W 12 and XC) cells.","date":"1989","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/2544467","citation_count":7,"is_preprint":false},{"pmid":"17365010","id":"PMC_17365010","title":"Further identification of Hb G-Coushatta [beta22(B4)Glu-->Ala (GAA-->GCA)] in Thailand by the polymerase chain reaction-single-strand conformation polymorphism technique and by amplification refractory mutation system-polymerase chain reaction.","date":"2007","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/17365010","citation_count":6,"is_preprint":false},{"pmid":"17605145","id":"PMC_17605145","title":"Chiral discrimination of alpha-amino acids by the DNA triplet GCA using amino acids as a co-selector.","date":"2007","source":"Journal of mass spectrometry : JMS","url":"https://pubmed.ncbi.nlm.nih.gov/17605145","citation_count":6,"is_preprint":false},{"pmid":"38713083","id":"PMC_38713083","title":"Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors.","date":"2024","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/38713083","citation_count":5,"is_preprint":false},{"pmid":"35623066","id":"PMC_35623066","title":"The haplotypes GCA and ACA in ESR1 gene are associated with the susceptibility of recurrent spontaneous abortion (RSA) in Chinese Han: A case-control study and meta-analysis.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35623066","citation_count":5,"is_preprint":false},{"pmid":"24845230","id":"PMC_24845230","title":"Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides.","date":"2014","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/24845230","citation_count":5,"is_preprint":false},{"pmid":"11071862","id":"PMC_11071862","title":"Molecular cloning of a regulatory protein for membrane-bound guanylate cyclase GC-A.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11071862","citation_count":5,"is_preprint":false},{"pmid":"35070986","id":"PMC_35070986","title":"Case Report: A Novel Non-Reciprocal ALK Fusion: ALK-GCA and EML4-ALK Were Identified in Lung Adenocarcinoma, Which May Respond to Alectinib Adjuvant-Targeted Therapy.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35070986","citation_count":5,"is_preprint":false},{"pmid":"37153092","id":"PMC_37153092","title":"Incidence of biopsy-proven giant cell arteritis (GCA) in South Australia 2014-2020.","date":"2023","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37153092","citation_count":4,"is_preprint":false},{"pmid":"2005375","id":"PMC_2005375","title":"Histochemical reactivity of the Geodia cydonium agglutinin (GCA) in human tissues.","date":"1991","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/2005375","citation_count":4,"is_preprint":false},{"pmid":"38539453","id":"PMC_38539453","title":"An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38539453","citation_count":4,"is_preprint":false},{"pmid":"21602351","id":"PMC_21602351","title":"Functional significance of an evolutionarily conserved alanine (GCA) resume codon in tmRNA in Escherichia coli.","date":"2011","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/21602351","citation_count":4,"is_preprint":false},{"pmid":"33417014","id":"PMC_33417014","title":"The U.S. Veterans Health Administration national giant cell arteritis (GCA) database cohort: incident ophthalmic complications in biopsy-negative GCA patients.","date":"2021","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/33417014","citation_count":3,"is_preprint":false},{"pmid":"30383819","id":"PMC_30383819","title":"Regularization and grouping -omics data by GCA method: A transcriptomic case.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30383819","citation_count":3,"is_preprint":false},{"pmid":"38142617","id":"PMC_38142617","title":"Effectiveness and safety of a 26-week taper regimen of glucocorticoid in GCA patients: Results from a prospective cohort study.","date":"2023","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/38142617","citation_count":3,"is_preprint":false},{"pmid":"38059132","id":"PMC_38059132","title":"Tocilizumab Vs Methotrexate in a Cohort of Patients Affected by Active GCA: A Comparative Clinical and Ultrasonographic Study.","date":"2023","source":"Biologics : targets & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38059132","citation_count":3,"is_preprint":false},{"pmid":"38683207","id":"PMC_38683207","title":"The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.","date":"2024","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/38683207","citation_count":3,"is_preprint":false},{"pmid":"36873102","id":"PMC_36873102","title":"Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36873102","citation_count":3,"is_preprint":false},{"pmid":"40369682","id":"PMC_40369682","title":"An atypical manifestation of Giant cell arteritis (GCA): constitutional symptoms & lingual ulcer in a 78-Year-Old male with negative temporal artery biopsies.","date":"2025","source":"BMC rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/40369682","citation_count":3,"is_preprint":false},{"pmid":"29959857","id":"PMC_29959857","title":"Sp1 mediates phorbol ester (PMA)-induced expression of membrane-bound guanylyl cyclase GC-A in human monocytic THP-1 cells.","date":"2018","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/29959857","citation_count":3,"is_preprint":false},{"pmid":"22669872","id":"PMC_22669872","title":"Large-vessel GCA or a late presentation of Takayasu's arteritis?","date":"2012","source":"BMJ case reports","url":"https://pubmed.ncbi.nlm.nih.gov/22669872","citation_count":3,"is_preprint":false},{"pmid":"39427049","id":"PMC_39427049","title":"Characteristics associated with anterior ischemic optic neuropathy (AION) in giant cell arteritis (GCA).","date":"2024","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/39427049","citation_count":2,"is_preprint":false},{"pmid":"38114060","id":"PMC_38114060","title":"Utility of online GCA risk models in predicting the result of temporal artery biopsy within a clinical setting: study of diagnostic and screening tests.","date":"2023","source":"Canadian journal of ophthalmology. Journal canadien d'ophtalmologie","url":"https://pubmed.ncbi.nlm.nih.gov/38114060","citation_count":2,"is_preprint":false},{"pmid":"31011074","id":"PMC_31011074","title":"A Stab in the Dark: A Case Report of an Atypical Presentation of Giant Cell Arteritis (GCA).","date":"2018","source":"Geriatrics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31011074","citation_count":2,"is_preprint":false},{"pmid":"38065923","id":"PMC_38065923","title":"Case report: GCA like picture-preceding inaugural MOGAD presentation: A patient with a sudden-onset uniocular blindness.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38065923","citation_count":2,"is_preprint":false},{"pmid":"39347680","id":"PMC_39347680","title":"The Importance of Early Recognition of Rare Ischaemic Complications of GCA to Prevent Permanent Vision Loss.","date":"2024","source":"British journal of hospital medicine (London, England : 2005)","url":"https://pubmed.ncbi.nlm.nih.gov/39347680","citation_count":2,"is_preprint":false},{"pmid":"8388811","id":"PMC_8388811","title":"Alterations in morphology of REF cells induced by growth factors produced by ASV-transformed (GCA) cells.","date":"1993","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/8388811","citation_count":2,"is_preprint":false},{"pmid":"40514330","id":"PMC_40514330","title":"Exploring the limit of image resolution for human expert classification of vascular ultrasound images in giant cell arteritis and healthy subjects: the GCA-US-AI project.","date":"2025","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40514330","citation_count":1,"is_preprint":false},{"pmid":"39365665","id":"PMC_39365665","title":"Giant cell arteritis (GCA) as a risk factor for seizures: a cohort study.","date":"2024","source":"Postgraduate medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39365665","citation_count":1,"is_preprint":false},{"pmid":"39161396","id":"PMC_39161396","title":"Bing-Neel Syndrome: An Unknown GCA Mimicker.","date":"2024","source":"Case reports in rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/39161396","citation_count":1,"is_preprint":false},{"pmid":"39210189","id":"PMC_39210189","title":"Predictive biomarkers of response to tocilizumab in giant cell arteritis (GCA): correlations with imaging activity.","date":"2024","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/39210189","citation_count":1,"is_preprint":false},{"pmid":"38152789","id":"PMC_38152789","title":"Orbital MRI Findings in a Patient With Giant Cell Arteritis (GCA): A Case Report.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38152789","citation_count":1,"is_preprint":false},{"pmid":"41365838","id":"PMC_41365838","title":"The influence of baseline aortitis on aortic dilation risk in GCA: a multicentre imaging study.","date":"2026","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41365838","citation_count":1,"is_preprint":false},{"pmid":"8524644","id":"PMC_8524644","title":"Taq52 I, a novel and thermostable type II restriction endonuclease from the genus Thermus, recognising the pentanucleotide sequence GC(A or T)GC and cleaving DNA between the first and second bases of the recognition sequence: G decreased or reduced C(A or T)GC.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8524644","citation_count":1,"is_preprint":false},{"pmid":"41757512","id":"PMC_41757512","title":"m5C-Modified tRF3b-CysGCA-23 Suppresses Bladder Cancer Malignancy by Repressing H3K18 Lactylation via Stabilizing RBM4.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41757512","citation_count":0,"is_preprint":false},{"pmid":"39699045","id":"PMC_39699045","title":"Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/39699045","citation_count":0,"is_preprint":false},{"pmid":"40105678","id":"PMC_40105678","title":"Case Report: Concurrent Babesiosis and GCA/PMR.","date":"2025","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/40105678","citation_count":0,"is_preprint":false},{"pmid":"39463873","id":"PMC_39463873","title":"Ultrasound in GCA: Halo Sign Quantification and Visual Symptoms, Systemic Inflammation and Relapse Risk.","date":"2024","source":"Mediterranean journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/39463873","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50702,"output_tokens":1406,"usd":0.086598,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7675,"output_tokens":1700,"usd":0.040438,"stage2_stop_reason":"end_turn"},"total_usd":0.127036,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify the canonical gene \"GCA\" - which based on the most specific papers (PMID:30929559, PMID:26648480, PMID:37949676) is clearly **grancalcin (GCA)**, a penta-EF-hand calcium-binding protein. Many papers in this corpus use \"GCA\" as an abbreviation for \"giant cell arteritis\" - those are NOT about the gene and must be excluded. I also need to exclude papers about GC-A (guanylyl cyclase A / NPR1), tRNA-Cys-GCA, DNA triplet GCA, Pseudomonas gca gene, plant tRNA genes, and other symbol collisions.\n\nPapers about the canonical GCA protein (grancalcin):\n- PMID:30929559 — GCA/grancalcin in CML/autophagy\n- PMID:26648480 — GCA/grancalcin interacts with TLR9\n- PMID:37949676 — GCA/grancalcin in Alzheimer's disease\n- PMID:35070986 — ALK-GCA fusion (identifies GCA as grancalcin, but mechanistic content is limited)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Grancalcin (GCA) activates TRAF6 ubiquitin ligase activity, inducing Lys63-linked ubiquitination of ULK1, which stabilizes and activates ULK1 to promote autophagy, thereby driving imatinib resistance in chronic myeloid leukemia.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assays, autophagy flux assays in CML cell lines and patient samples\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, reciprocal Co-IP and functional knockdown with defined pathway placement (GCA→TRAF6→ULK1 ubiquitination→autophagy), but no structural validation or independent replication\",\n      \"pmids\": [\"30929559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Grancalcin (GCA) directly binds TLR9 (demonstrated by yeast two-hybrid and co-immunoprecipitation in an overexpression system) and positively regulates TLR9-mediated type I IFN production, cytokine/chemokine secretion, IRF7 nuclear localization, NF-κB activation, and MAPK activation in plasmacytoid dendritic cells; siRNA-mediated knockdown of GCA reduced these downstream signaling outputs.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (overexpression system), siRNA knockdown, reporter assays for NF-κB/IRF7, cytokine ELISA in plasmacytoid dendritic cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP establish interaction; siRNA knockdown with multiple downstream readouts in one lab; no independent replication or structural confirmation\",\n      \"pmids\": [\"26648480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bone marrow-derived GCA+ immune cells secrete grancalcin, which competitively binds to LRP1 in microglia, inhibiting microglial phagocytosis and clearance of amyloid-β, thereby potentiating Alzheimer's disease neuropathology; CCR10 mediates preferential homing of GCA+ cells to the hippocampus and cortex. Genetic ablation of GCA in the hematopoietic compartment improved cognitive function, and GCA-neutralizing antibody treatment reduced AD progression in mouse models.\",\n      \"method\": \"Bone marrow transplantation, stereotaxic injection of recombinant GCA protein, hematopoietic-specific genetic knockout, competitive binding assay for LRP1, phagocytosis assays in microglia, cognitive behavioral tests in AD mouse models, GCA-neutralizing antibody treatment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function, recombinant protein gain-of-function, and competitive binding assay provide orthogonal evidence in a single lab; mechanistic link (GCA→LRP1 competition→impaired Aβ phagocytosis) supported by multiple methods but awaits independent replication\",\n      \"pmids\": [\"37949676\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Grancalcin (GCA) is a penta-EF-hand calcium-binding protein that functions as a signaling scaffold: it activates TRAF6 ubiquitin ligase to drive Lys63-ubiquitination and stabilization of ULK1 (promoting autophagy and imatinib resistance in CML), directly heterodimerizes with TLR9 to potentiate innate immune signaling (type I IFN, NF-κB, MAPK) in plasmacytoid dendritic cells, and is secreted by bone marrow-derived immune cells to competitively inhibit LRP1-mediated amyloid-β clearance in microglia, thereby exacerbating Alzheimer's disease pathology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Grancalcin (GCA) acts as a calcium-binding signaling scaffold and secreted modulator that potentiates innate immune and stress-response pathways across distinct cellular contexts [#0, #1, #2]. In chronic myeloid leukemia cells, GCA activates the ubiquitin ligase TRAF6 to drive Lys63-linked ubiquitination of ULK1, stabilizing and activating ULK1 to promote autophagy and thereby conferring imatinib resistance [#0]. In plasmacytoid dendritic cells, GCA directly binds TLR9 and positively regulates TLR9-driven type I IFN production, IRF7 nuclear localization, NF-\\u03baB activation, and MAPK activation [#1]. GCA is also secreted by bone marrow-derived immune cells, which home to the hippocampus and cortex via CCR10, where secreted GCA competitively binds microglial LRP1 to inhibit phagocytic clearance of amyloid-\\u03b2 and exacerbate Alzheimer's disease pathology; hematopoietic GCA ablation or GCA-neutralizing antibody treatment improved outcomes in mouse models [#2]. Beyond these three contexts, the structural basis of GCA's interactions and its calcium-dependence have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established GCA as a direct binding partner of TLR9 and a positive regulator of innate immune signaling, linking this calcium-binding protein to nucleic-acid sensing for the first time.\",\n      \"evidence\": \"Yeast two-hybrid and overexpression co-IP for interaction, plus siRNA knockdown with NF-\\u03baB/IRF7 reporters and cytokine ELISA in plasmacytoid dendritic cells\",\n      \"pmids\": [\"26648480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown only in overexpression system without endogenous reciprocal validation\", \"No structural basis for the GCA\\u2013TLR9 interaction\", \"Calcium-dependence of the interaction not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GCA upstream of an autophagy-driving ubiquitination cascade, explaining how it promotes drug resistance in leukemia.\",\n      \"evidence\": \"siRNA knockdown, reciprocal co-IP, ubiquitination assays, and autophagy flux assays in CML cell lines and patient samples\",\n      \"pmids\": [\"30929559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural validation of the GCA\\u2013TRAF6 interaction\", \"Mechanism by which GCA activates TRAF6 ligase activity not defined\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified GCA as a secreted factor that impairs microglial amyloid-\\u03b2 clearance via LRP1 competition, defining a peripheral-immune contribution to Alzheimer's pathology.\",\n      \"evidence\": \"Bone marrow transplantation, hematopoietic-specific knockout, recombinant GCA injection, LRP1 competitive binding assay, microglial phagocytosis assays, and neutralizing antibody treatment in AD mouse models\",\n      \"pmids\": [\"37949676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LRP1 binding site and competition stoichiometry not resolved\", \"Mechanism of GCA secretion not defined\", \"Single lab; awaits independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the three reported functions reflect a single unifying biochemical activity of GCA, and how its penta-EF-hand calcium binding governs each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of GCA in complex with any partner\", \"Calcium-dependence of binding events not experimentally linked across contexts\", \"No integration of intracellular scaffold versus secreted functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF6\", \"ULK1\", \"TLR9\", \"LRP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}