{"gene":"C1QL4","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2011,"finding":"C1QL4 (and other C1ql1-4 proteins) bind with high affinity to the extracellular thrombospondin-repeat domain of BAI3, a cell-adhesion GPCR; this binding is mediated by the globular C1q domain of C1QL proteins. Addition of submicromolar C1ql proteins to cultured neurons caused a significant decrease in synapse density, an effect blocked by the thrombospondin-repeat fragment of BAI3.","method":"Biochemical binding assays (pulldown/binding), neuronal culture experiments with recombinant proteins and competitor fragments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with domain-mapping, functional rescue experiment, replicated across all four C1ql family members","pmids":["21262840"],"is_preprint":false},{"year":2010,"finding":"C1QL4 is a secreted protein that forms both homomeric and heteromeric complexes with other C1ql family members. It also assembles hexameric and higher-order oligomers via N-terminal cysteine residues.","method":"Biochemical characterization in heterologous expression cells (secretion assays, oligomerization analysis)","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization in heterologous cells, single lab with multiple orthogonal assays","pmids":["20525073"],"is_preprint":false},{"year":2013,"finding":"CTRP11/C1QL4 is a secreted multimeric protein that forms disulfide-linked oligomers; the conserved N-terminal Cys-28 and Cys-32 residues are not required for higher-order oligomer assembly but unexpectedly modulate protein secretion. CTRP11 forms heteromeric complexes with CTRP10, CTRP13, and CRF (CTRP14) via C-terminal globular domains. CTRP11 inhibits 3T3-L1 adipocyte differentiation by suppressing PPARγ and C/EBPα expression, decreasing p42/44-MAPK signaling, and inhibiting mitotic clonal expansion.","method":"Site-directed mutagenesis of Cys residues, co-expression/co-immunoprecipitation for heteromeric complex formation, ectopic expression and recombinant protein treatment of 3T3-L1 cells, Western blot for signaling intermediates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of secretion-modulating residues, co-IP for complex formation, functional assay with multiple molecular readouts, single lab","pmids":["23449976"],"is_preprint":false},{"year":2018,"finding":"C1qL4 (and other C1q-like proteins) represses BAI3-mediated myoblast fusion by specifically interacting with BAI3. BAI3-knockout mice display small muscle fibers and inefficient muscle regeneration after cardiotoxin injury. In contrast, Stabilin-2 activates BAI3's GPCR activity, leading to heterotrimeric G-protein activation that recruits Elmo proteins to the membrane, which are then stabilized via direct interaction with BAI3.","method":"BAI3 knockout mouse model (cardiotoxin injury), proteomic approach to identify Stabilin-2 as BAI3 interactor, GPCR activity assays, co-immunoprecipitation for Elmo recruitment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype combined with proteomic interactor identification, GPCR activity assay, and Co-IP for pathway placement","pmids":["30367035"],"is_preprint":false},{"year":2016,"finding":"Recombinant C1QL4/CTRP11 globular domain directly stimulates migration and capillary tube formation of HUVECs in a dose-dependent manner, activating phosphorylation of c-Raf, MEK1/2, ERK1/2, and p90RSK. MEK1/2 inhibitor U0126 blocked these effects. BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 may mediate C1QL4-induced angiogenesis.","method":"Recombinant protein treatment of HUVECs, tube formation and migration assays, Western blot for kinase phosphorylation, pharmacological inhibition with U0126, chick yolk sac membrane angiogenesis assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with recombinant protein plus pharmacological pathway inhibition, single lab, BAI3 receptor assignment based only on immunoreactivity detection","pmids":["27734226"],"is_preprint":false},{"year":2019,"finding":"C1QL4 increases testosterone production in TM3 Leydig cells and seminiferous tubules, accompanied by upregulation of StAR protein and steroidogenic enzymes, via activation of c-Raf/MEK1/2/ERK1/2/MSK1 and cAMP/PKA/CREB signaling. BAI3, expressed in Leydig cells, mediates part of C1QL4-induced steroidogenesis; Bai3 knockdown reduced StAR expression. However, C1QL4-induced StAR expression was not completely suppressed in Bai3-deficient cells and ERK1/2/cAMP signaling was unchanged after C1QL4 stimulation in Bai3-KD cells, indicating an additional unidentified receptor mediates C1QL4-activated testosterone secretion.","method":"Recombinant C1QL4 treatment of TM3 Leydig cells, testosterone ELISA, Western blot for signaling molecules, Bai3 siRNA knockdown in Leydig cells","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with recombinant protein, gene knockdown with molecular readouts, single lab, partial mechanistic resolution","pmids":["30608882"],"is_preprint":false},{"year":2022,"finding":"CTRP11/C1QL4 knockout mice have normal skeletal muscle mass/function and testosterone levels, indicating CTRP11 is dispensable for skeletal muscle development and testosterone production in vivo. CTRP11 deficiency modestly exacerbates obesity-induced glucose intolerance and impairs fasting-refeeding metabolic responses in a sexually dimorphic manner.","method":"Ctrp11 knockout mouse model; metabolic phenotyping (glucose tolerance tests, indirect calorimetry, food intake measurements)","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined metabolic phenotypes; negative findings for muscle/testosterone are informative; single lab","pmids":["35579659"],"is_preprint":false},{"year":2023,"finding":"C1QL4 knockdown in breast cancer cells suppressed cancer stem cell properties, epithelial-mesenchymal transition, cell migration and invasion, promoted cell cycle progression, and enhanced apoptosis. Mechanistically, C1QL4 promotes NF-κB nuclear translocation and upregulates TNF-α and IL-1β; PI3K/AKT signaling inhibition suppressed C1QL4-induced stemness and EMT, placing C1QL4 upstream of PI3K/AKT/NF-κB.","method":"C1QL4 knockdown and overexpression in BC cell lines; flow cytometry (cell cycle, apoptosis, BCSC fraction); wound healing and Transwell assays; Western blot for pathway components; nude mouse tumor xenograft model","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cancer cell line experiments with no receptor/complex identification, pathway placement based on pharmacological inhibition only","pmids":["37324011"],"is_preprint":false}],"current_model":"C1QL4 (CTRP11/C1QTNF11) is a secreted, multimeric C1q-family protein that forms homo- and heteromeric disulfide-linked oligomers; it acts as a ligand for the cell-adhesion GPCR BAI3, binding via its globular C1q domain to BAI3's thrombospondin-repeat domain, thereby repressing synapse density in neurons and myoblast fusion in muscle progenitors, while also stimulating ERK1/2-dependent angiogenesis and testosterone secretion in Leydig cells, and inhibiting adipogenesis via suppression of PPARγ/C/EBPα and p42/44-MAPK signaling."},"narrative":{"mechanistic_narrative":"C1QL4 (CTRP11/C1QTNF11) is a secreted C1q-family protein that assembles into disulfide-linked homo- and heteromeric oligomers and acts as a signaling ligand across multiple tissues [PMID:20525073, PMID:23449976]. It binds with high affinity to the extracellular thrombospondin-repeat domain of the adhesion GPCR BAI3 through its globular C1q domain, and this interaction underlies its repressive activities on synapse density in neurons [PMID:21262840] and on BAI3-mediated myoblast fusion [PMID:30367035]. Beyond BAI3 antagonism, the recombinant globular domain drives c-Raf/MEK1/2/ERK1/2 (p90RSK/MSK1) signaling to stimulate endothelial migration and capillary tube formation [PMID:27734226] and to upregulate StAR and steroidogenic enzymes for testosterone production in Leydig cells, where BAI3 mediates only part of the response, indicating an additional unidentified receptor [PMID:30608882]. In adipocyte differentiation C1QL4 is inhibitory, suppressing PPARγ and C/EBPα, dampening p42/44-MAPK signaling, and blocking mitotic clonal expansion [PMID:23449976]. Despite these activities defined with recombinant protein, knockout mice have normal muscle and testosterone but show sexually dimorphic exacerbation of obesity-induced glucose intolerance, defining a physiological role in metabolic homeostasis [PMID:35579659]. Heteromeric partners include CTRP10, CTRP13, and CRF/CTRP14, formed via the C-terminal globular domains, while N-terminal Cys-28/Cys-32 modulate secretion [PMID:23449976].","teleology":[{"year":2010,"claim":"Establishing that C1QL4 is a secreted oligomeric protein answered the basic question of its biochemical form, framing it as a multimeric extracellular factor rather than a cell-intrinsic protein.","evidence":"Secretion and oligomerization assays in heterologous expression cells","pmids":["20525073"],"confidence":"Medium","gaps":["Did not assign a receptor or downstream function","Single lab characterization"]},{"year":2011,"claim":"Identifying BAI3 as a high-affinity receptor bound via the C1q globular domain converted C1QL4 from an orphan secreted protein into a defined ligand with a synaptic function.","evidence":"Domain-mapped binding/pulldown assays and neuronal culture with competitor thrombospondin-repeat fragment","pmids":["21262840"],"confidence":"High","gaps":["Downstream BAI3 signaling not resolved in this study","Specificity among C1QL family members for distinct neuronal contexts unclear"]},{"year":2013,"claim":"Mapping the determinants of oligomerization/secretion and demonstrating anti-adipogenic activity extended C1QL4 function beyond the nervous system into metabolic regulation.","evidence":"Cys mutagenesis, co-IP for heteromeric complexes, and 3T3-L1 differentiation assays with signaling readouts","pmids":["23449976"],"confidence":"High","gaps":["Receptor mediating anti-adipogenic effect not identified","Effects shown in cell line, not in vivo"]},{"year":2016,"claim":"Showing the globular domain activates Raf/MEK/ERK to drive angiogenesis established a pro-angiogenic, kinase-coupled signaling output for C1QL4.","evidence":"Recombinant protein HUVEC tube/migration assays, kinase phospho-Western blots, U0126 inhibition, chick yolk sac assay","pmids":["27734226"],"confidence":"Medium","gaps":["BAI3 involvement inferred only from immunoreactivity, not functional testing","Single lab"]},{"year":2019,"claim":"Demonstrating C1QL4-stimulated steroidogenesis through Raf/MEK/ERK and cAMP/PKA/CREB, only partly BAI3-dependent, revealed an endocrine role and implied a second unidentified receptor.","evidence":"Recombinant C1QL4 on TM3 Leydig cells, testosterone ELISA, signaling Westerns, Bai3 siRNA knockdown","pmids":["30608882"],"confidence":"Medium","gaps":["Identity of the BAI3-independent receptor unknown","In vitro Leydig cell system only"]},{"year":2018,"claim":"Genetic dissection of the BAI3 axis placed C1QL4 as a repressor of BAI3-driven myoblast fusion, opposite to the Stabilin-2 agonist arm that activates G-protein/Elmo signaling.","evidence":"BAI3 knockout mice with cardiotoxin injury, proteomic interactor ID, GPCR activity assays, co-IP","pmids":["30367035"],"confidence":"High","gaps":["C1QL4-specific (versus pan-C1QL) contribution to muscle phenotype not isolated","Mechanism of repression on BAI3 signaling not fully defined"]},{"year":2022,"claim":"Loss-of-function in mice tested whether the in vitro muscle/steroidogenic roles are required in vivo, showing dispensability there but a genuine metabolic role.","evidence":"Ctrp11 knockout mice with metabolic phenotyping (GTT, calorimetry, fasting-refeeding)","pmids":["35579659"],"confidence":"Medium","gaps":["Molecular basis of the metabolic and sexually dimorphic phenotype unresolved","Receptor mediating metabolic effect not identified"]},{"year":2023,"claim":"Cancer cell experiments proposed a pro-tumorigenic role via PI3K/AKT/NF-κB, broadening the signaling repertoire to inflammatory/stemness programs.","evidence":"C1QL4 knockdown/overexpression in breast cancer lines, flow cytometry, migration/invasion assays, xenografts, pathway inhibition","pmids":["37324011"],"confidence":"Low","gaps":["No receptor or complex identified; pathway placement rests on pharmacological inhibition only","Single lab, not independently confirmed"]},{"year":null,"claim":"The identity of the BAI3-independent receptor(s) and how a single secreted ligand selects among synaptic, metabolic, steroidogenic, and angiogenic outputs in different tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the C1QL4-receptor complex","Tissue-specific receptor repertoire unknown","Mechanism linking oligomer state to signaling output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["BAI3","CTRP10","CTRP13","CTRP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86Z23","full_name":"Complement C1q-like protein 4","aliases":["C1q and tumor necrosis factor-related protein 11","C1q/TNF-related protein 11"],"length_aa":238,"mass_kda":24.9,"function":"May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity). May inhibit adipocyte differentiation at an early stage of the process (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q86Z23/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QL4","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":[],"url":"https://opencell.sf.czbiohub.org/search/C1QL4","total_profiled":1310},"omim":[{"mim_id":"615229","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 4; C1QL4","url":"https://www.omim.org/entry/615229"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":3.9}],"url":"https://www.proteinatlas.org/search/C1QL4"},"hgnc":{"alias_symbol":["C1QTNF11","CTRP11"],"prev_symbol":[]},"alphafold":{"accession":"Q86Z23","domains":[{"cath_id":"2.60.120.40","chopping":"110-236","consensus_level":"high","plddt":95.7305,"start":110,"end":236}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86Z23","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86Z23-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86Z23-F1-predicted_aligned_error_v6.png","plddt_mean":80.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QL4","jax_strain_url":"https://www.jax.org/strain/search?query=C1QL4"},"sequence":{"accession":"Q86Z23","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86Z23.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86Z23/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86Z23"}},"corpus_meta":[{"pmid":"21262840","id":"PMC_21262840","title":"The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21262840","citation_count":151,"is_preprint":false},{"pmid":"20525073","id":"PMC_20525073","title":"Distinct expression of C1q-like family mRNAs in mouse brain and biochemical characterization of their encoded proteins.","date":"2010","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20525073","citation_count":77,"is_preprint":false},{"pmid":"24582973","id":"PMC_24582973","title":"Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24582973","citation_count":75,"is_preprint":false},{"pmid":"23449976","id":"PMC_23449976","title":"C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23449976","citation_count":60,"is_preprint":false},{"pmid":"30367035","id":"PMC_30367035","title":"Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30367035","citation_count":50,"is_preprint":false},{"pmid":"27734226","id":"PMC_27734226","title":"C1ql1/Ctrp14 and C1ql4/Ctrp11 promote angiogenesis of endothelial cells through activation of ERK1/2 signal pathway.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27734226","citation_count":25,"is_preprint":false},{"pmid":"38750748","id":"PMC_38750748","title":"Physiological and transcriptomic analysis provides new insights into osmoregulation mechanism of Ruditapes philippinarum under low and high salinity stress.","date":"2024","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/38750748","citation_count":19,"is_preprint":false},{"pmid":"30608882","id":"PMC_30608882","title":"Expression patterns of C1ql4 and its cell-adhesion GPCR Bai3 in the murine testis and functional roles in steroidogenesis.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30608882","citation_count":16,"is_preprint":false},{"pmid":"35579659","id":"PMC_35579659","title":"CTRP11 contributes modestly to systemic metabolism and energy balance.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35579659","citation_count":12,"is_preprint":false},{"pmid":"37324011","id":"PMC_37324011","title":"C1ql4 regulates breast cancer cell stemness and epithelial-mesenchymal transition through PI3K/AKT/NF-κB signaling pathway.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37324011","citation_count":3,"is_preprint":false},{"pmid":"37371880","id":"PMC_37371880","title":"Transcriptome Analysis Reveals the Genes Involved in Oxidative Stress Responses of Scallop to PST-Producing Algae and a Candidate Biomarker for PST Monitoring.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37371880","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8611,"output_tokens":2504,"usd":0.031697,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9652,"output_tokens":2856,"usd":0.05983,"stage2_stop_reason":"end_turn"},"total_usd":0.091527,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"C1QL4 (and other C1ql1-4 proteins) bind with high affinity to the extracellular thrombospondin-repeat domain of BAI3, a cell-adhesion GPCR; this binding is mediated by the globular C1q domain of C1QL proteins. Addition of submicromolar C1ql proteins to cultured neurons caused a significant decrease in synapse density, an effect blocked by the thrombospondin-repeat fragment of BAI3.\",\n      \"method\": \"Biochemical binding assays (pulldown/binding), neuronal culture experiments with recombinant proteins and competitor fragments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with domain-mapping, functional rescue experiment, replicated across all four C1ql family members\",\n      \"pmids\": [\"21262840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C1QL4 is a secreted protein that forms both homomeric and heteromeric complexes with other C1ql family members. It also assembles hexameric and higher-order oligomers via N-terminal cysteine residues.\",\n      \"method\": \"Biochemical characterization in heterologous expression cells (secretion assays, oligomerization analysis)\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization in heterologous cells, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"20525073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CTRP11/C1QL4 is a secreted multimeric protein that forms disulfide-linked oligomers; the conserved N-terminal Cys-28 and Cys-32 residues are not required for higher-order oligomer assembly but unexpectedly modulate protein secretion. CTRP11 forms heteromeric complexes with CTRP10, CTRP13, and CRF (CTRP14) via C-terminal globular domains. CTRP11 inhibits 3T3-L1 adipocyte differentiation by suppressing PPARγ and C/EBPα expression, decreasing p42/44-MAPK signaling, and inhibiting mitotic clonal expansion.\",\n      \"method\": \"Site-directed mutagenesis of Cys residues, co-expression/co-immunoprecipitation for heteromeric complex formation, ectopic expression and recombinant protein treatment of 3T3-L1 cells, Western blot for signaling intermediates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of secretion-modulating residues, co-IP for complex formation, functional assay with multiple molecular readouts, single lab\",\n      \"pmids\": [\"23449976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C1qL4 (and other C1q-like proteins) represses BAI3-mediated myoblast fusion by specifically interacting with BAI3. BAI3-knockout mice display small muscle fibers and inefficient muscle regeneration after cardiotoxin injury. In contrast, Stabilin-2 activates BAI3's GPCR activity, leading to heterotrimeric G-protein activation that recruits Elmo proteins to the membrane, which are then stabilized via direct interaction with BAI3.\",\n      \"method\": \"BAI3 knockout mouse model (cardiotoxin injury), proteomic approach to identify Stabilin-2 as BAI3 interactor, GPCR activity assays, co-immunoprecipitation for Elmo recruitment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype combined with proteomic interactor identification, GPCR activity assay, and Co-IP for pathway placement\",\n      \"pmids\": [\"30367035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recombinant C1QL4/CTRP11 globular domain directly stimulates migration and capillary tube formation of HUVECs in a dose-dependent manner, activating phosphorylation of c-Raf, MEK1/2, ERK1/2, and p90RSK. MEK1/2 inhibitor U0126 blocked these effects. BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 may mediate C1QL4-induced angiogenesis.\",\n      \"method\": \"Recombinant protein treatment of HUVECs, tube formation and migration assays, Western blot for kinase phosphorylation, pharmacological inhibition with U0126, chick yolk sac membrane angiogenesis assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with recombinant protein plus pharmacological pathway inhibition, single lab, BAI3 receptor assignment based only on immunoreactivity detection\",\n      \"pmids\": [\"27734226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C1QL4 increases testosterone production in TM3 Leydig cells and seminiferous tubules, accompanied by upregulation of StAR protein and steroidogenic enzymes, via activation of c-Raf/MEK1/2/ERK1/2/MSK1 and cAMP/PKA/CREB signaling. BAI3, expressed in Leydig cells, mediates part of C1QL4-induced steroidogenesis; Bai3 knockdown reduced StAR expression. However, C1QL4-induced StAR expression was not completely suppressed in Bai3-deficient cells and ERK1/2/cAMP signaling was unchanged after C1QL4 stimulation in Bai3-KD cells, indicating an additional unidentified receptor mediates C1QL4-activated testosterone secretion.\",\n      \"method\": \"Recombinant C1QL4 treatment of TM3 Leydig cells, testosterone ELISA, Western blot for signaling molecules, Bai3 siRNA knockdown in Leydig cells\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with recombinant protein, gene knockdown with molecular readouts, single lab, partial mechanistic resolution\",\n      \"pmids\": [\"30608882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP11/C1QL4 knockout mice have normal skeletal muscle mass/function and testosterone levels, indicating CTRP11 is dispensable for skeletal muscle development and testosterone production in vivo. CTRP11 deficiency modestly exacerbates obesity-induced glucose intolerance and impairs fasting-refeeding metabolic responses in a sexually dimorphic manner.\",\n      \"method\": \"Ctrp11 knockout mouse model; metabolic phenotyping (glucose tolerance tests, indirect calorimetry, food intake measurements)\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined metabolic phenotypes; negative findings for muscle/testosterone are informative; single lab\",\n      \"pmids\": [\"35579659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1QL4 knockdown in breast cancer cells suppressed cancer stem cell properties, epithelial-mesenchymal transition, cell migration and invasion, promoted cell cycle progression, and enhanced apoptosis. Mechanistically, C1QL4 promotes NF-κB nuclear translocation and upregulates TNF-α and IL-1β; PI3K/AKT signaling inhibition suppressed C1QL4-induced stemness and EMT, placing C1QL4 upstream of PI3K/AKT/NF-κB.\",\n      \"method\": \"C1QL4 knockdown and overexpression in BC cell lines; flow cytometry (cell cycle, apoptosis, BCSC fraction); wound healing and Transwell assays; Western blot for pathway components; nude mouse tumor xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cancer cell line experiments with no receptor/complex identification, pathway placement based on pharmacological inhibition only\",\n      \"pmids\": [\"37324011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL4 (CTRP11/C1QTNF11) is a secreted, multimeric C1q-family protein that forms homo- and heteromeric disulfide-linked oligomers; it acts as a ligand for the cell-adhesion GPCR BAI3, binding via its globular C1q domain to BAI3's thrombospondin-repeat domain, thereby repressing synapse density in neurons and myoblast fusion in muscle progenitors, while also stimulating ERK1/2-dependent angiogenesis and testosterone secretion in Leydig cells, and inhibiting adipogenesis via suppression of PPARγ/C/EBPα and p42/44-MAPK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QL4 (CTRP11/C1QTNF11) is a secreted C1q-family protein that assembles into disulfide-linked homo- and heteromeric oligomers and acts as a signaling ligand across multiple tissues [#1, #2]. It binds with high affinity to the extracellular thrombospondin-repeat domain of the adhesion GPCR BAI3 through its globular C1q domain, and this interaction underlies its repressive activities on synapse density in neurons [#0] and on BAI3-mediated myoblast fusion [#3]. Beyond BAI3 antagonism, the recombinant globular domain drives c-Raf/MEK1/2/ERK1/2 (p90RSK/MSK1) signaling to stimulate endothelial migration and capillary tube formation [#4] and to upregulate StAR and steroidogenic enzymes for testosterone production in Leydig cells, where BAI3 mediates only part of the response, indicating an additional unidentified receptor [#5]. In adipocyte differentiation C1QL4 is inhibitory, suppressing PPARγ and C/EBPα, dampening p42/44-MAPK signaling, and blocking mitotic clonal expansion [#2]. Despite these activities defined with recombinant protein, knockout mice have normal muscle and testosterone but show sexually dimorphic exacerbation of obesity-induced glucose intolerance, defining a physiological role in metabolic homeostasis [#6]. Heteromeric partners include CTRP10, CTRP13, and CRF/CTRP14, formed via the C-terminal globular domains, while N-terminal Cys-28/Cys-32 modulate secretion [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that C1QL4 is a secreted oligomeric protein answered the basic question of its biochemical form, framing it as a multimeric extracellular factor rather than a cell-intrinsic protein.\",\n      \"evidence\": \"Secretion and oligomerization assays in heterologous expression cells\",\n      \"pmids\": [\"20525073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not assign a receptor or downstream function\", \"Single lab characterization\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying BAI3 as a high-affinity receptor bound via the C1q globular domain converted C1QL4 from an orphan secreted protein into a defined ligand with a synaptic function.\",\n      \"evidence\": \"Domain-mapped binding/pulldown assays and neuronal culture with competitor thrombospondin-repeat fragment\",\n      \"pmids\": [\"21262840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream BAI3 signaling not resolved in this study\", \"Specificity among C1QL family members for distinct neuronal contexts unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the determinants of oligomerization/secretion and demonstrating anti-adipogenic activity extended C1QL4 function beyond the nervous system into metabolic regulation.\",\n      \"evidence\": \"Cys mutagenesis, co-IP for heteromeric complexes, and 3T3-L1 differentiation assays with signaling readouts\",\n      \"pmids\": [\"23449976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating anti-adipogenic effect not identified\", \"Effects shown in cell line, not in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing the globular domain activates Raf/MEK/ERK to drive angiogenesis established a pro-angiogenic, kinase-coupled signaling output for C1QL4.\",\n      \"evidence\": \"Recombinant protein HUVEC tube/migration assays, kinase phospho-Western blots, U0126 inhibition, chick yolk sac assay\",\n      \"pmids\": [\"27734226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BAI3 involvement inferred only from immunoreactivity, not functional testing\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating C1QL4-stimulated steroidogenesis through Raf/MEK/ERK and cAMP/PKA/CREB, only partly BAI3-dependent, revealed an endocrine role and implied a second unidentified receptor.\",\n      \"evidence\": \"Recombinant C1QL4 on TM3 Leydig cells, testosterone ELISA, signaling Westerns, Bai3 siRNA knockdown\",\n      \"pmids\": [\"30608882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the BAI3-independent receptor unknown\", \"In vitro Leydig cell system only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic dissection of the BAI3 axis placed C1QL4 as a repressor of BAI3-driven myoblast fusion, opposite to the Stabilin-2 agonist arm that activates G-protein/Elmo signaling.\",\n      \"evidence\": \"BAI3 knockout mice with cardiotoxin injury, proteomic interactor ID, GPCR activity assays, co-IP\",\n      \"pmids\": [\"30367035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C1QL4-specific (versus pan-C1QL) contribution to muscle phenotype not isolated\", \"Mechanism of repression on BAI3 signaling not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Loss-of-function in mice tested whether the in vitro muscle/steroidogenic roles are required in vivo, showing dispensability there but a genuine metabolic role.\",\n      \"evidence\": \"Ctrp11 knockout mice with metabolic phenotyping (GTT, calorimetry, fasting-refeeding)\",\n      \"pmids\": [\"35579659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the metabolic and sexually dimorphic phenotype unresolved\", \"Receptor mediating metabolic effect not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cancer cell experiments proposed a pro-tumorigenic role via PI3K/AKT/NF-κB, broadening the signaling repertoire to inflammatory/stemness programs.\",\n      \"evidence\": \"C1QL4 knockdown/overexpression in breast cancer lines, flow cytometry, migration/invasion assays, xenografts, pathway inhibition\",\n      \"pmids\": [\"37324011\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No receptor or complex identified; pathway placement rests on pharmacological inhibition only\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the BAI3-independent receptor(s) and how a single secreted ligand selects among synaptic, metabolic, steroidogenic, and angiogenic outputs in different tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the C1QL4-receptor complex\", \"Tissue-specific receptor repertoire unknown\", \"Mechanism linking oligomer state to signaling output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BAI3\", \"CTRP10\", \"CTRP13\", \"CTRP14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}