{"gene":"CRTAC1","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2001,"finding":"CRTAC1 (identified as CEP-68) contains an N-terminal leader peptide and an EGF-like calcium-binding domain, defining a new protein family; it is expressed specifically in chondrocytes and distinguishes them from osteoblasts and mesenchymal stem cells in culture.","method":"Gene cloning, sequence analysis, cell culture marker assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — original gene characterization with domain identification and cell-type specificity, single lab","pmids":["11139377"],"is_preprint":false},{"year":2006,"finding":"CRTAC1-A isoform is secreted by chondrocytes and localizes to the extracellular matrix of articular cartilage; its secretion is stimulated by BMP4. The most C-terminal O-glycosylation motif in the CRTAC1-A last exon is modified, as demonstrated by serial C-terminal deletion mutants exposed to the O-glycosylation inhibitor Benzyl-alpha-GalNAc. Both isoforms contain four FG-GAP repeat domains and an RGD integrin-binding motif suggesting cell-cell or cell-matrix interaction potential.","method":"Deletion mutagenesis, O-glycosylation inhibitor assay, immunolocalization, BMP4 stimulation, protein secretion assay","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus biochemical inhibitor assay with functional localization, single lab but multiple orthogonal methods","pmids":["17074475"],"is_preprint":false},{"year":2010,"finding":"Structural prediction identified the N-terminal region of CRTAC1 as a seven-bladed beta-propeller structure related to integrin alpha chains and GPI-specific phospholipase D1; phylogenetic analysis confirmed this domain relationship across deeply divergent organisms.","method":"Structural prediction, phylogenetic analysis, sequence database searches","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 4 — computational/phylogenetic prediction only, no experimental structural validation","pmids":["20171266"],"is_preprint":false},{"year":2021,"finding":"CRTAC1 overexpression in bladder cancer cells inhibits cell proliferation, migration, invasion, and EMT. Mechanistically, CRTAC1 co-localizes with and co-immunoprecipitates with YY1, negatively regulates YY1 mRNA and protein expression, and inactivates the TGF-β pathway via YY1 downregulation. ChIP and luciferase reporter assays confirmed the CRTAC1–YY1 transcriptional regulatory interaction.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ChIP assay, luciferase reporter assay, Western blot, knockdown/overexpression functional assays","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple orthogonal methods (Co-IP, ChIP, luciferase) from single lab","pmids":["34818994"],"is_preprint":false},{"year":2022,"finding":"CRTAC1 transcription is suppressed by TPRG1-AS1 lncRNA (itself driven by TFAP2A) through recruitment of DNMT3A to the CRTAC1 promoter, increasing promoter DNA methylation; this epigenetic silencing of CRTAC1 promotes glycolysis and angiogenesis in bladder urothelial carcinoma.","method":"ChIP-qPCR, luciferase reporter assay, DNA methylation analysis, rescue experiments, knockdown/overexpression","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase with rescue validation, single lab","pmids":["36410635"],"is_preprint":false},{"year":2023,"finding":"CRTAC1 overexpression enhances cisplatin sensitivity in NSCLC by eliciting ryanodine receptor (RyR)-mediated intracellular Ca2+ release, which activates NFAT transcription, inducing STUB1 expression, accelerating Akt1 protein degradation, and enhancing cisplatin-induced apoptosis. Knockdown of CRTAC1 reduces chemosensitivity.","method":"In vitro overexpression/knockdown, calcium imaging, NFAT reporter assay, Western blot for STUB1/Akt1, in vivo mouse tumor experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo experiments with pathway dissection, single lab","pmids":["37633993"],"is_preprint":false},{"year":2024,"finding":"X-ray crystallography at 1.6 Å resolution reveals CRTAC1 has a three-domain fold comprising a novel compact β-propeller–TTR combination, where an extended TTR loop plugs the β-propeller core. Ten bound ions are observed: six calcium, three potassium, and one sodium. Potassium ions bind between β-propeller blades and are essential for structural stability; low potassium leads to tryptophan environment changes and exposure of two buried free cysteines. Mutating the two free cysteines to serines prevents covalent intermolecular interactions.","method":"X-ray crystallography, ion-dependent stability assays, tryptophan fluorescence, site-directed mutagenesis (Cys→Ser)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with mutagenesis and biochemical validation, single lab but multiple orthogonal methods","pmids":["39029889"],"is_preprint":false},{"year":2024,"finding":"In spinal ligament degeneration, SPP1+ macrophage-derived SPP1 activates ATF3 in CRTAC1+ chondrocyte-like cells; ATF3 drives the CRTAC1/MGP/CLU axis to promote ligament calcification. CellChat analysis combined with experimental validation identified the SPP1–CRTAC1+ cell interaction as a key intercellular signaling axis.","method":"Single-cell RNA sequencing, SCENIC transcription factor analysis, CellChat intercellular communication analysis, experimental validation of ATF3 as transcription factor","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — single-cell transcriptomics with experimental validation, single lab","pmids":["39158018"],"is_preprint":false},{"year":2025,"finding":"Senescent fibroblast-like synoviocyte (FLS)-derived CRTAC1 binds NRF2 in chondrocytes, suppressing SIRT3 transcription. Reduced SIRT3 promotes FOXO3a acetylation, leading to mitochondrial dysfunction and suppression of mitophagy, thereby contributing to chondrocyte degradation and OA progression. Intra-articular AAV-SIRT3 injection alleviated OA in mice.","method":"Co-immunoprecipitation (CRTAC1–NRF2 binding), in vitro SIRT3 transcription assay, acetylation assay (FOXO3a), mitophagy/mitochondrial function assays, in vivo AAV injection, single-cell sequencing","journal":"Acta pharmaceutica sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo rescue with multiple mechanistic endpoints, single lab","pmids":["41311393"],"is_preprint":false},{"year":2026,"finding":"CRTAC1 inhibits proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells in vitro and in vivo by suppressing integrin/FAK signaling.","method":"In vitro proliferation/migration/invasion assays, in vivo tumor models, Western blot for integrin/FAK pathway markers, knockdown/overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with defined signaling pathway, single lab","pmids":["41708954"],"is_preprint":false},{"year":2024,"finding":"CRTAC1 knockdown in gastric cancer cells inhibits proliferation and migration and promotes apoptosis; Western blot showed increased E-cadherin and reduced vimentin, p-PI3K, AKT2, p-AKT, and p-mTOR, placing CRTAC1 upstream of the PI3K/AKT/mTOR pathway and EMT in gastric cancer.","method":"siRNA knockdown, Western blot, CCK8/EdU/wound healing/Transwell assays, flow cytometry","journal":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","confidence":"Low","confidence_rationale":"Tier 3 — single-lab knockdown with Western blot pathway markers but no binding or reconstitution data","pmids":["39725632"],"is_preprint":false},{"year":2020,"finding":"In human lens epithelial cells (HLECs), CRTAC1 promotes UVB-induced pyroptosis through ROS production; CRTAC1 knockdown reduces pyroptosis markers (NLRP3, active Caspase-1, GSDMD-N, IL-1β, IL-18), while overexpression promotes pyroptosis, and this effect is blocked by the ROS inhibitor N-acetyl-l-cysteine.","method":"siRNA knockdown, overexpression, ROS inhibitor treatment, Western blot for pyroptosis markers, UVB irradiation model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single-lab functional assay with pharmacological inhibitor but no direct binding or upstream mechanism defined","pmids":["32838966"],"is_preprint":false}],"current_model":"CRTAC1 is a secreted, multi-domain glycoprotein (β-propeller–TTR fold stabilized by potassium and calcium ions) that localizes to the extracellular matrix of cartilage; it acts as a context-dependent signaling regulator—suppressing tumor cell proliferation, migration, and EMT by inhibiting integrin/FAK and TGF-β/YY1 pathways, enhancing cisplatin sensitivity via RyR-Ca²⁺-NFAT-STUB1-Akt1 degradation, and in osteoarthritis, senescent FLS-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing mitochondrial dysfunction and cartilage degradation."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing CRTAC1 as a novel chondrocyte-specific gene resolved the question of whether a molecular marker could distinguish chondrocytes from osteoblasts and mesenchymal stem cells, and identified its EGF-like calcium-binding domain.","evidence":"Gene cloning, sequence analysis, and cell-type-specific expression profiling in human chondrocyte/osteoblast/MSC cultures","pmids":["11139377"],"confidence":"Medium","gaps":["No functional assay performed","Expression restricted to cultured cells without in vivo tissue validation"]},{"year":2006,"claim":"Demonstrating that CRTAC1-A is secreted into cartilage ECM under BMP4 stimulation, and mapping its O-glycosylation and FG-GAP/RGD domain architecture, established CRTAC1 as a bona fide ECM glycoprotein with potential integrin-binding function.","evidence":"Deletion mutagenesis, O-glycosylation inhibitor assays, immunolocalization in articular cartilage, BMP4 stimulation in chondrocyte cultures","pmids":["17074475"],"confidence":"High","gaps":["No direct integrin binding demonstrated","Functional consequence of O-glycosylation unknown"]},{"year":2010,"claim":"Computational prediction of CRTAC1's N-terminal seven-bladed β-propeller fold related to integrin α-chains provided the first structural framework, later confirmed crystallographically.","evidence":"Structural prediction and phylogenetic analysis across deeply divergent organisms","pmids":["20171266"],"confidence":"Low","gaps":["Purely computational — awaited experimental structural validation","No functional implications tested"]},{"year":2021,"claim":"Revealing that CRTAC1 co-immunoprecipitates with YY1 and transcriptionally downregulates it to inactivate TGF-β signaling established the first intracellular signaling mechanism by which CRTAC1 suppresses tumor cell proliferation and EMT.","evidence":"Co-IP, immunofluorescence co-localization, ChIP, luciferase reporter, and functional overexpression/knockdown assays in bladder cancer cells","pmids":["34818994"],"confidence":"Medium","gaps":["CRTAC1–YY1 interaction domain not mapped","Unclear how a secreted protein physically interacts with a nuclear transcription factor","Single cancer type tested"]},{"year":2022,"claim":"Identifying DNMT3A-mediated promoter methylation as the mechanism of CRTAC1 silencing in bladder cancer explained how CRTAC1 tumor-suppressive function is epigenetically lost, linking lncRNA TPRG1-AS1/TFAP2A to CRTAC1 suppression.","evidence":"ChIP-qPCR, luciferase reporters, DNA methylation analysis, rescue experiments in bladder urothelial carcinoma cells","pmids":["36410635"],"confidence":"Medium","gaps":["Methylation-mediated silencing not validated in patient cohorts with matched expression data","Whether this epigenetic mechanism operates in other cancer types is unknown"]},{"year":2023,"claim":"Demonstrating that CRTAC1 enhances cisplatin sensitivity through RyR-mediated Ca²⁺ release → NFAT activation → STUB1 induction → Akt1 degradation provided a detailed signaling cascade linking CRTAC1 to chemotherapy response in NSCLC.","evidence":"Overexpression/knockdown, calcium imaging, NFAT reporter assays, Western blot, and in vivo mouse tumor xenograft experiments","pmids":["37633993"],"confidence":"Medium","gaps":["Direct molecular target of CRTAC1 that triggers RyR-mediated Ca²⁺ release not identified","Mechanism not reconstituted with purified components"]},{"year":2024,"claim":"The 1.6 Å crystal structure resolved CRTAC1's three-domain architecture (β-propeller–TTR) and revealed that potassium ions are critical structural cofactors, answering long-standing questions about its fold and ion dependence.","evidence":"X-ray crystallography, ion-dependent stability assays, tryptophan fluorescence, Cys→Ser mutagenesis","pmids":["39029889"],"confidence":"High","gaps":["No ligand or receptor co-crystal structure","Functional significance of the TTR domain remains undefined","Whether potassium-dependent conformational changes regulate signaling is untested"]},{"year":2024,"claim":"Single-cell analysis of spinal ligament degeneration identified CRTAC1+ chondrocyte-like cells as targets of SPP1+ macrophage signaling via ATF3, positioning CRTAC1 within an intercellular calcification axis.","evidence":"Single-cell RNA-seq, SCENIC TF analysis, CellChat, and experimental ATF3 validation","pmids":["39158018"],"confidence":"Medium","gaps":["CRTAC1's causal role in calcification not tested by loss-of-function","ATF3 direct binding to CRTAC1 promoter not confirmed by ChIP"]},{"year":2025,"claim":"Demonstrating that senescent FLS-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing FOXO3a acetylation and mitochondrial dysfunction, provided a paracrine mechanism for CRTAC1 in osteoarthritis cartilage degradation.","evidence":"Co-IP for CRTAC1–NRF2 binding, SIRT3 transcription and FOXO3a acetylation assays, mitophagy assays, in vivo AAV-SIRT3 rescue in mouse OA model, single-cell sequencing","pmids":["41311393"],"confidence":"Medium","gaps":["CRTAC1–NRF2 binding domain and stoichiometry unmapped","Whether intracellular CRTAC1–NRF2 interaction requires receptor-mediated uptake or an intracellular isoform is unclear"]},{"year":2026,"claim":"Showing that CRTAC1 suppresses lung adenocarcinoma via integrin/FAK pathway inhibition provided the first direct evidence that its RGD-containing domain functionally engages integrin signaling to exert tumor-suppressive effects.","evidence":"In vitro and in vivo tumor models with knockdown/overexpression, Western blot for integrin/FAK markers","pmids":["41708954"],"confidence":"Medium","gaps":["Specific integrin heterodimer bound by CRTAC1 not identified","No direct binding assay between CRTAC1 and integrin/FAK"]},{"year":null,"claim":"A central unresolved question is how a secreted ECM glycoprotein mechanistically engages intracellular signaling partners (YY1, NRF2) — whether through receptor-mediated internalization, an intracellular isoform, or another mechanism — and what the physiological ligand or receptor for CRTAC1's β-propeller domain is.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cell-surface receptor for CRTAC1 identified","No structural basis for CRTAC1–integrin or CRTAC1–NRF2 interaction","Knockout mouse phenotype not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,8,9]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,9]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,9,10]}],"complexes":[],"partners":["YY1","NRF2","STUB1","DNMT3A"],"other_free_text":[]},"mechanistic_narrative":"CRTAC1 is a secreted, multi-domain glycoprotein that functions as an extracellular matrix component in cartilage and as a context-dependent signaling regulator in multiple tissues. Its crystal structure reveals a compact β-propeller–TTR fold stabilized by calcium, potassium, and sodium ions, where potassium binding between β-propeller blades is essential for structural integrity and concealment of reactive free cysteines [PMID:39029889]. CRTAC1 is secreted by chondrocytes into cartilage ECM in a BMP4-stimulated manner and contains FG-GAP repeats and an RGD integrin-binding motif [PMID:17074475]; in tumor cells, it suppresses proliferation, migration, and EMT by inhibiting integrin/FAK signaling, downregulating YY1 to inactivate TGF-β, and enhancing cisplatin sensitivity through RyR-mediated Ca²⁺ release that activates NFAT–STUB1-dependent Akt1 degradation [PMID:41708954, PMID:34818994, PMID:37633993]. In osteoarthritis, senescent synoviocyte-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing mitochondrial dysfunction and cartilage degradation [PMID:41311393]."},"prefetch_data":{"uniprot":{"accession":"Q9NQ79","full_name":"Cartilage acidic protein 1","aliases":["68 kDa chondrocyte-expressed protein","CEP-68","ASPIC"],"length_aa":661,"mass_kda":71.4,"function":"","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9NQ79/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRTAC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRTAC1","total_profiled":1310},"omim":[{"mim_id":"614189","title":"GOLGIN A7 FAMILY, MEMBER B; GOLGA7B","url":"https://www.omim.org/entry/614189"},{"mim_id":"606276","title":"CARTILAGE ACIDIC PROTEIN 1; CRTAC1","url":"https://www.omim.org/entry/606276"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":61.8},{"tissue":"lung","ntpm":47.1},{"tissue":"urinary bladder","ntpm":50.4}],"url":"https://www.proteinatlas.org/search/CRTAC1"},"hgnc":{"alias_symbol":["FLJ10320","CEP-68","ASPIC1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQ79","domains":[{"cath_id":"2.130.10.130","chopping":"46-451","consensus_level":"medium","plddt":94.9409,"start":46,"end":451},{"cath_id":"-","chopping":"562-594","consensus_level":"medium","plddt":90.3539,"start":562,"end":594}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ79","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ79-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ79-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRTAC1","jax_strain_url":"https://www.jax.org/strain/search?query=CRTAC1"},"sequence":{"accession":"Q9NQ79","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ79.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ79/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ79"}},"corpus_meta":[{"pmid":"17074475","id":"PMC_17074475","title":"Chondrocyte secreted CRTAC1: a glycosylated extracellular matrix molecule of human articular cartilage.","date":"2006","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17074475","citation_count":68,"is_preprint":false},{"pmid":"33982893","id":"PMC_33982893","title":"The CRTAC1 Protein in Plasma Is Associated With Osteoarthritis and Predicts Progression to Joint Replacement: A Large-Scale Proteomics Scan in Iceland.","date":"2021","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/33982893","citation_count":51,"is_preprint":false},{"pmid":"35924962","id":"PMC_35924962","title":"Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression.","date":"2023","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35924962","citation_count":42,"is_preprint":false},{"pmid":"11139377","id":"PMC_11139377","title":"Chondrocyte expressed protein-68 (CEP-68), a novel human marker gene for cultured chondrocytes.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11139377","citation_count":38,"is_preprint":false},{"pmid":"34818994","id":"PMC_34818994","title":"CRTAC1 (Cartilage acidic protein 1) inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process in bladder cancer by downregulating Yin Yang 1 (YY1) to inactivate the TGF-β pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34818994","citation_count":26,"is_preprint":false},{"pmid":"32838966","id":"PMC_32838966","title":"Down-regulation of CRTAC1 attenuates UVB-induced pyroptosis in HLECs through inhibiting ROS production.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32838966","citation_count":25,"is_preprint":false},{"pmid":"36410635","id":"PMC_36410635","title":"The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis.","date":"2022","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/36410635","citation_count":17,"is_preprint":false},{"pmid":"20171266","id":"PMC_20171266","title":"CRTAC1 homolog proteins are conserved from cyanobacteria to man and secreted by the teleost fish pituitary gland.","date":"2010","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/20171266","citation_count":12,"is_preprint":false},{"pmid":"37633993","id":"PMC_37633993","title":"CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37633993","citation_count":11,"is_preprint":false},{"pmid":"39158018","id":"PMC_39158018","title":"Single-cell RNA sequencing reveals the CRTAC1+ population actively contributes to the pathogenesis of spinal ligament degeneration by SPP1+ macrophage.","date":"2024","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/39158018","citation_count":7,"is_preprint":false},{"pmid":"39682792","id":"PMC_39682792","title":"Polymorphisms Within the IQGAP2 and CRTAC1 Genes of Gannan Yaks and Their Association with Milk Quality Characteristics.","date":"2024","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39682792","citation_count":3,"is_preprint":false},{"pmid":"39029889","id":"PMC_39029889","title":"CRTAC1 has a Compact β-propeller-TTR Core Stabilized by Potassium Ions.","date":"2024","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39029889","citation_count":2,"is_preprint":false},{"pmid":"41311393","id":"PMC_41311393","title":"CRTAC1 derived from senescent FLSs induces chondrocyte mitochondrial dysfunction via modulating NRF2/SIRT3 axis in osteoarthritis progression.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41311393","citation_count":0,"is_preprint":false},{"pmid":"41580236","id":"PMC_41580236","title":"CRTAC1 as a biomarker for osteoarthritis: Link to inflammation and microRNA regulation.","date":"2026","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/41580236","citation_count":0,"is_preprint":false},{"pmid":"40408237","id":"PMC_40408237","title":"CRTAC1: a novel indicator of lung involvement in SSc.","date":"2025","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40408237","citation_count":0,"is_preprint":false},{"pmid":"39725632","id":"PMC_39725632","title":"[High expression of CRTAC1 promotes proliferation, migration and immune cell infiltration of gastric cancer by regulating the PI3K/AKT signaling pathway].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39725632","citation_count":0,"is_preprint":false},{"pmid":"41708954","id":"PMC_41708954","title":"CRTAC1 inhibits progression of lung adenocarcinoma by suppressing integrin/FAK signaling.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41708954","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.17.638761","title":"Proteomic characterisation of the early rheumatoid arthritis-cardiovascular disease multimorbid axis","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.638761","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.04.24313052","title":"Pharmacogenetic Study of Antipsychotic-Induced Lipid and BMI Changes in Chinese Schizophrenia Patients: A Genome-Wide Association Study","date":"2024-09-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.04.24313052","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11855,"output_tokens":3049,"usd":0.04065},"stage2":{"model":"claude-opus-4-6","input_tokens":6452,"output_tokens":2712,"usd":0.15009},"total_usd":0.19074,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CRTAC1 (identified as CEP-68) contains an N-terminal leader peptide and an EGF-like calcium-binding domain, defining a new protein family; it is expressed specifically in chondrocytes and distinguishes them from osteoblasts and mesenchymal stem cells in culture.\",\n      \"method\": \"Gene cloning, sequence analysis, cell culture marker assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original gene characterization with domain identification and cell-type specificity, single lab\",\n      \"pmids\": [\"11139377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRTAC1-A isoform is secreted by chondrocytes and localizes to the extracellular matrix of articular cartilage; its secretion is stimulated by BMP4. The most C-terminal O-glycosylation motif in the CRTAC1-A last exon is modified, as demonstrated by serial C-terminal deletion mutants exposed to the O-glycosylation inhibitor Benzyl-alpha-GalNAc. Both isoforms contain four FG-GAP repeat domains and an RGD integrin-binding motif suggesting cell-cell or cell-matrix interaction potential.\",\n      \"method\": \"Deletion mutagenesis, O-glycosylation inhibitor assay, immunolocalization, BMP4 stimulation, protein secretion assay\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus biochemical inhibitor assay with functional localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17074475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Structural prediction identified the N-terminal region of CRTAC1 as a seven-bladed beta-propeller structure related to integrin alpha chains and GPI-specific phospholipase D1; phylogenetic analysis confirmed this domain relationship across deeply divergent organisms.\",\n      \"method\": \"Structural prediction, phylogenetic analysis, sequence database searches\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/phylogenetic prediction only, no experimental structural validation\",\n      \"pmids\": [\"20171266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTAC1 overexpression in bladder cancer cells inhibits cell proliferation, migration, invasion, and EMT. Mechanistically, CRTAC1 co-localizes with and co-immunoprecipitates with YY1, negatively regulates YY1 mRNA and protein expression, and inactivates the TGF-β pathway via YY1 downregulation. ChIP and luciferase reporter assays confirmed the CRTAC1–YY1 transcriptional regulatory interaction.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ChIP assay, luciferase reporter assay, Western blot, knockdown/overexpression functional assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple orthogonal methods (Co-IP, ChIP, luciferase) from single lab\",\n      \"pmids\": [\"34818994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRTAC1 transcription is suppressed by TPRG1-AS1 lncRNA (itself driven by TFAP2A) through recruitment of DNMT3A to the CRTAC1 promoter, increasing promoter DNA methylation; this epigenetic silencing of CRTAC1 promotes glycolysis and angiogenesis in bladder urothelial carcinoma.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, DNA methylation analysis, rescue experiments, knockdown/overexpression\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase with rescue validation, single lab\",\n      \"pmids\": [\"36410635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRTAC1 overexpression enhances cisplatin sensitivity in NSCLC by eliciting ryanodine receptor (RyR)-mediated intracellular Ca2+ release, which activates NFAT transcription, inducing STUB1 expression, accelerating Akt1 protein degradation, and enhancing cisplatin-induced apoptosis. Knockdown of CRTAC1 reduces chemosensitivity.\",\n      \"method\": \"In vitro overexpression/knockdown, calcium imaging, NFAT reporter assay, Western blot for STUB1/Akt1, in vivo mouse tumor experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with pathway dissection, single lab\",\n      \"pmids\": [\"37633993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"X-ray crystallography at 1.6 Å resolution reveals CRTAC1 has a three-domain fold comprising a novel compact β-propeller–TTR combination, where an extended TTR loop plugs the β-propeller core. Ten bound ions are observed: six calcium, three potassium, and one sodium. Potassium ions bind between β-propeller blades and are essential for structural stability; low potassium leads to tryptophan environment changes and exposure of two buried free cysteines. Mutating the two free cysteines to serines prevents covalent intermolecular interactions.\",\n      \"method\": \"X-ray crystallography, ion-dependent stability assays, tryptophan fluorescence, site-directed mutagenesis (Cys→Ser)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with mutagenesis and biochemical validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39029889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In spinal ligament degeneration, SPP1+ macrophage-derived SPP1 activates ATF3 in CRTAC1+ chondrocyte-like cells; ATF3 drives the CRTAC1/MGP/CLU axis to promote ligament calcification. CellChat analysis combined with experimental validation identified the SPP1–CRTAC1+ cell interaction as a key intercellular signaling axis.\",\n      \"method\": \"Single-cell RNA sequencing, SCENIC transcription factor analysis, CellChat intercellular communication analysis, experimental validation of ATF3 as transcription factor\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — single-cell transcriptomics with experimental validation, single lab\",\n      \"pmids\": [\"39158018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Senescent fibroblast-like synoviocyte (FLS)-derived CRTAC1 binds NRF2 in chondrocytes, suppressing SIRT3 transcription. Reduced SIRT3 promotes FOXO3a acetylation, leading to mitochondrial dysfunction and suppression of mitophagy, thereby contributing to chondrocyte degradation and OA progression. Intra-articular AAV-SIRT3 injection alleviated OA in mice.\",\n      \"method\": \"Co-immunoprecipitation (CRTAC1–NRF2 binding), in vitro SIRT3 transcription assay, acetylation assay (FOXO3a), mitophagy/mitochondrial function assays, in vivo AAV injection, single-cell sequencing\",\n      \"journal\": \"Acta pharmaceutica sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo rescue with multiple mechanistic endpoints, single lab\",\n      \"pmids\": [\"41311393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRTAC1 inhibits proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells in vitro and in vivo by suppressing integrin/FAK signaling.\",\n      \"method\": \"In vitro proliferation/migration/invasion assays, in vivo tumor models, Western blot for integrin/FAK pathway markers, knockdown/overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with defined signaling pathway, single lab\",\n      \"pmids\": [\"41708954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRTAC1 knockdown in gastric cancer cells inhibits proliferation and migration and promotes apoptosis; Western blot showed increased E-cadherin and reduced vimentin, p-PI3K, AKT2, p-AKT, and p-mTOR, placing CRTAC1 upstream of the PI3K/AKT/mTOR pathway and EMT in gastric cancer.\",\n      \"method\": \"siRNA knockdown, Western blot, CCK8/EdU/wound healing/Transwell assays, flow cytometry\",\n      \"journal\": \"Nan fang yi ke da xue xue bao = Journal of Southern Medical University\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single-lab knockdown with Western blot pathway markers but no binding or reconstitution data\",\n      \"pmids\": [\"39725632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In human lens epithelial cells (HLECs), CRTAC1 promotes UVB-induced pyroptosis through ROS production; CRTAC1 knockdown reduces pyroptosis markers (NLRP3, active Caspase-1, GSDMD-N, IL-1β, IL-18), while overexpression promotes pyroptosis, and this effect is blocked by the ROS inhibitor N-acetyl-l-cysteine.\",\n      \"method\": \"siRNA knockdown, overexpression, ROS inhibitor treatment, Western blot for pyroptosis markers, UVB irradiation model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single-lab functional assay with pharmacological inhibitor but no direct binding or upstream mechanism defined\",\n      \"pmids\": [\"32838966\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRTAC1 is a secreted, multi-domain glycoprotein (β-propeller–TTR fold stabilized by potassium and calcium ions) that localizes to the extracellular matrix of cartilage; it acts as a context-dependent signaling regulator—suppressing tumor cell proliferation, migration, and EMT by inhibiting integrin/FAK and TGF-β/YY1 pathways, enhancing cisplatin sensitivity via RyR-Ca²⁺-NFAT-STUB1-Akt1 degradation, and in osteoarthritis, senescent FLS-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing mitochondrial dysfunction and cartilage degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CRTAC1 is a secreted, multi-domain glycoprotein that functions as an extracellular matrix component in cartilage and as a context-dependent signaling regulator in multiple tissues. Its crystal structure reveals a compact β-propeller–TTR fold stabilized by calcium, potassium, and sodium ions, where potassium binding between β-propeller blades is essential for structural integrity and concealment of reactive free cysteines [PMID:39029889]. CRTAC1 is secreted by chondrocytes into cartilage ECM in a BMP4-stimulated manner and contains FG-GAP repeats and an RGD integrin-binding motif [PMID:17074475]; in tumor cells, it suppresses proliferation, migration, and EMT by inhibiting integrin/FAK signaling, downregulating YY1 to inactivate TGF-β, and enhancing cisplatin sensitivity through RyR-mediated Ca²⁺ release that activates NFAT–STUB1-dependent Akt1 degradation [PMID:41708954, PMID:34818994, PMID:37633993]. In osteoarthritis, senescent synoviocyte-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing mitochondrial dysfunction and cartilage degradation [PMID:41311393].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing CRTAC1 as a novel chondrocyte-specific gene resolved the question of whether a molecular marker could distinguish chondrocytes from osteoblasts and mesenchymal stem cells, and identified its EGF-like calcium-binding domain.\",\n      \"evidence\": \"Gene cloning, sequence analysis, and cell-type-specific expression profiling in human chondrocyte/osteoblast/MSC cultures\",\n      \"pmids\": [\"11139377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay performed\", \"Expression restricted to cultured cells without in vivo tissue validation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that CRTAC1-A is secreted into cartilage ECM under BMP4 stimulation, and mapping its O-glycosylation and FG-GAP/RGD domain architecture, established CRTAC1 as a bona fide ECM glycoprotein with potential integrin-binding function.\",\n      \"evidence\": \"Deletion mutagenesis, O-glycosylation inhibitor assays, immunolocalization in articular cartilage, BMP4 stimulation in chondrocyte cultures\",\n      \"pmids\": [\"17074475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct integrin binding demonstrated\", \"Functional consequence of O-glycosylation unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Computational prediction of CRTAC1's N-terminal seven-bladed β-propeller fold related to integrin α-chains provided the first structural framework, later confirmed crystallographically.\",\n      \"evidence\": \"Structural prediction and phylogenetic analysis across deeply divergent organisms\",\n      \"pmids\": [\"20171266\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational — awaited experimental structural validation\", \"No functional implications tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing that CRTAC1 co-immunoprecipitates with YY1 and transcriptionally downregulates it to inactivate TGF-β signaling established the first intracellular signaling mechanism by which CRTAC1 suppresses tumor cell proliferation and EMT.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, ChIP, luciferase reporter, and functional overexpression/knockdown assays in bladder cancer cells\",\n      \"pmids\": [\"34818994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CRTAC1–YY1 interaction domain not mapped\", \"Unclear how a secreted protein physically interacts with a nuclear transcription factor\", \"Single cancer type tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying DNMT3A-mediated promoter methylation as the mechanism of CRTAC1 silencing in bladder cancer explained how CRTAC1 tumor-suppressive function is epigenetically lost, linking lncRNA TPRG1-AS1/TFAP2A to CRTAC1 suppression.\",\n      \"evidence\": \"ChIP-qPCR, luciferase reporters, DNA methylation analysis, rescue experiments in bladder urothelial carcinoma cells\",\n      \"pmids\": [\"36410635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methylation-mediated silencing not validated in patient cohorts with matched expression data\", \"Whether this epigenetic mechanism operates in other cancer types is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that CRTAC1 enhances cisplatin sensitivity through RyR-mediated Ca²⁺ release → NFAT activation → STUB1 induction → Akt1 degradation provided a detailed signaling cascade linking CRTAC1 to chemotherapy response in NSCLC.\",\n      \"evidence\": \"Overexpression/knockdown, calcium imaging, NFAT reporter assays, Western blot, and in vivo mouse tumor xenograft experiments\",\n      \"pmids\": [\"37633993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of CRTAC1 that triggers RyR-mediated Ca²⁺ release not identified\", \"Mechanism not reconstituted with purified components\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The 1.6 Å crystal structure resolved CRTAC1's three-domain architecture (β-propeller–TTR) and revealed that potassium ions are critical structural cofactors, answering long-standing questions about its fold and ion dependence.\",\n      \"evidence\": \"X-ray crystallography, ion-dependent stability assays, tryptophan fluorescence, Cys→Ser mutagenesis\",\n      \"pmids\": [\"39029889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand or receptor co-crystal structure\", \"Functional significance of the TTR domain remains undefined\", \"Whether potassium-dependent conformational changes regulate signaling is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Single-cell analysis of spinal ligament degeneration identified CRTAC1+ chondrocyte-like cells as targets of SPP1+ macrophage signaling via ATF3, positioning CRTAC1 within an intercellular calcification axis.\",\n      \"evidence\": \"Single-cell RNA-seq, SCENIC TF analysis, CellChat, and experimental ATF3 validation\",\n      \"pmids\": [\"39158018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CRTAC1's causal role in calcification not tested by loss-of-function\", \"ATF3 direct binding to CRTAC1 promoter not confirmed by ChIP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that senescent FLS-derived CRTAC1 binds NRF2 in chondrocytes to suppress SIRT3 transcription, causing FOXO3a acetylation and mitochondrial dysfunction, provided a paracrine mechanism for CRTAC1 in osteoarthritis cartilage degradation.\",\n      \"evidence\": \"Co-IP for CRTAC1–NRF2 binding, SIRT3 transcription and FOXO3a acetylation assays, mitophagy assays, in vivo AAV-SIRT3 rescue in mouse OA model, single-cell sequencing\",\n      \"pmids\": [\"41311393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CRTAC1–NRF2 binding domain and stoichiometry unmapped\", \"Whether intracellular CRTAC1–NRF2 interaction requires receptor-mediated uptake or an intracellular isoform is unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that CRTAC1 suppresses lung adenocarcinoma via integrin/FAK pathway inhibition provided the first direct evidence that its RGD-containing domain functionally engages integrin signaling to exert tumor-suppressive effects.\",\n      \"evidence\": \"In vitro and in vivo tumor models with knockdown/overexpression, Western blot for integrin/FAK markers\",\n      \"pmids\": [\"41708954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific integrin heterodimer bound by CRTAC1 not identified\", \"No direct binding assay between CRTAC1 and integrin/FAK\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is how a secreted ECM glycoprotein mechanistically engages intracellular signaling partners (YY1, NRF2) — whether through receptor-mediated internalization, an intracellular isoform, or another mechanism — and what the physiological ligand or receptor for CRTAC1's β-propeller domain is.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cell-surface receptor for CRTAC1 identified\", \"No structural basis for CRTAC1–integrin or CRTAC1–NRF2 interaction\", \"Knockout mouse phenotype not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YY1\",\n      \"NRF2\",\n      \"STUB1\",\n      \"DNMT3A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}