{"gene":"CCM2L","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2015,"finding":"CCM2L binds MEKK3 in a complex with CCM1, and both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target.","method":"In vitro binding assay (CCM2L-MEKK3-CCM1 complex), phosphorylation assay (MEK5 as substrate), zebrafish morpholino knockdown with genetic epistasis (mekk3 silencing rescues ccm2l/ccm2 morphant phenotype)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding and kinase assay combined with in vivo genetic epistasis in zebrafish; findings corroborated by CCM2 deletion activating ERK5/MEKK3 transcriptional program in endothelial cells","pmids":["26540726"],"is_preprint":false},{"year":2012,"finding":"CCM2L competitively blocks CCM2-mediated stabilizing signals; it is expressed selectively in endothelial cells during active cardiovascular growth and its loss reduces endocardial growth factor expression, impairing tumor growth and wound healing.","method":"Biochemical competition assay (CCM2L blocking CCM2 interactions), cultured endothelial cell experiments, in vivo loss-of-function in developing mice","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical competition assay plus in vivo mouse loss-of-function with defined phenotypic readouts, single lab","pmids":["22898778"],"is_preprint":false},{"year":2013,"finding":"Ccm2l binds Ccm1; deletion and mutational analyses defined the regions of Ccm1 that mediate its binding to Ccm2l (as well as to Ccm2 and Heg). Morpholino disruption of ccm2l causes dilated atrium and inflow tract defects, and ccm2 overexpression can partially rescue ccm2l morphant defects, placing ccm2l as a component of the Heg-CCM pathway.","method":"Co-immunoprecipitation/binding assay with deletion/mutational analysis; zebrafish morpholino knockdown; genetic rescue by ccm2 overexpression","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding with deletion mapping combined with in vivo genetic rescue in zebrafish, independently consistent with findings in PMID:26540726","pmids":["23328253"],"is_preprint":false},{"year":2021,"finding":"CCM2L deletion aggravates cerebral cavernous malformation through the Map3k3-KLF signaling pathway, extending the mechanistic link between CCM2L and MEKK3 (Map3k3) to include KLF transcription factors as downstream effectors.","method":"CCM2L deletion model with signaling pathway analysis (Map3k3-KLF pathway readout)","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined pathway placement (Map3k3-KLF), but abstract provides limited methodological detail; single lab","pmids":["33657857"],"is_preprint":false},{"year":2021,"finding":"Endothelial-specific overexpression of Ccm2l does not promote cardiomyocyte proliferation or heart repair after LAD ligation in neonatal mice, indicating that endothelial Ccm2l gain-of-function is not sufficient for cardiac regeneration.","method":"Endothelial-specific Ccm2l gain-of-function transgenic mouse; LAD ligation injury model; cardiomyocyte proliferation readout","journal":"Cardiovascular engineering and technology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean transgenic gain-of-function with defined phenotypic readout, but negative result; single lab, single method","pmids":["34046845"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous loss-of-function variants in CCM2L (nonsense c.741G>A and splice-site c.1263+2T>A) were identified in a fetus with Tetralogy of Fallot; minigene assay confirmed that the splice-site variant causes skipping of CCM2L exon 8, leading to frameshift and premature termination.","method":"Whole exome sequencing, Sanger sequencing, minigene splicing assay","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — minigene functional validation of splicing defect is Tier 1 quality, but single case report with no mechanistic pathway follow-up beyond splice consequence","pmids":["40521769"],"is_preprint":false}],"current_model":"CCM2L is an endothelial adaptor protein that binds CCM1 and MEKK3 (Map3k3) to suppress MEKK3 kinase activity (blocking MEK5/ERK5 and KLF signaling), acting as a competitive paralog of CCM2 that destabilizes rather than stabilizes vascular junctions during active cardiovascular growth; genetic and biochemical evidence places it as a component of the Heg-CCM pathway, and human loss-of-function variants associate it with congenital heart defects."},"narrative":{"mechanistic_narrative":"CCM2L is an endothelial adaptor protein that functions within the Heg-CCM pathway to regulate cardiovascular growth and vascular junction signaling [PMID:26540726, PMID:33657857]. It binds CCM1 in a complex that also engages the kinase MEKK3 (Map3k3), and CCM2L (like its paralog CCM2) interferes with MEKK3 activation, blocking phosphorylation of the downstream substrate MEK5; epistasis in zebrafish, where mekk3 silencing rescues ccm2l morphant phenotypes, confirms this suppression operates in vivo [PMID:26540726]. Deletion mapping defined the CCM1 regions mediating its binding to CCM2L, and ccm2 overexpression partially rescues ccm2l loss, indicating the two paralogs act on a shared CCM1-anchored module while CCM2L competitively opposes CCM2-mediated stabilizing signals during active cardiovascular growth [PMID:22898778, PMID:23328253]. Loss of CCM2L produces dilated atrium and inflow tract defects, reduces endocardial growth factor expression, and aggravates cerebral cavernous malformation through Map3k3-KLF signaling [PMID:22898778, PMID:23328253, PMID:33657857]. Compound heterozygous loss-of-function variants in CCM2L were identified in a fetus with Tetralogy of Fallot, with a minigene assay confirming exon 8 skipping and premature termination [PMID:40521769].","teleology":[{"year":2012,"claim":"Established CCM2L as an endothelial-selective, growth-phase-restricted regulator that competitively antagonizes CCM2 stabilizing signals, defining it as a functional counterpart rather than redundant paralog.","evidence":"Biochemical competition assay plus in vivo loss-of-function in developing mice with endocardial growth factor and tumor/wound-healing readouts","pmids":["22898778"],"confidence":"Medium","gaps":["Molecular basis of competition with CCM2 not resolved at structural level","Direct kinase target not yet identified in this study","Single-lab phenotypic characterization"]},{"year":2013,"claim":"Mapped the physical architecture of the CCM1-CCM2L interaction and placed CCM2L genetically within the Heg-CCM pathway via rescue, answering whether CCM2L shares the CCM1 binding interface used by CCM2 and Heg.","evidence":"Co-IP with deletion/mutational mapping; zebrafish ccm2l morpholino knockdown with ccm2 overexpression rescue","pmids":["23328253"],"confidence":"High","gaps":["Did not define the downstream effector of the CCM1-CCM2L complex","Cardiac phenotype mechanism beyond inflow tract defects unresolved"]},{"year":2015,"claim":"Identified MEKK3 as the kinase target of the CCM2L-CCM1 complex and showed CCM2L suppresses MEKK3-driven MEK5 phosphorylation, providing the molecular mechanism linking the adaptor to a signaling cascade.","evidence":"In vitro binding and kinase (MEK5 phosphorylation) assays; zebrafish genetic epistasis (mekk3 silencing rescues ccm2l morphants)","pmids":["26540726"],"confidence":"High","gaps":["Stoichiometry and structure of the CCM1-CCM2L-MEKK3 complex unresolved","Quantitative contribution of CCM2L versus CCM2 to MEKK3 suppression not separated"]},{"year":2021,"claim":"Extended the MEKK3 axis to a transcriptional output by linking CCM2L loss to KLF signaling in cerebral cavernous malformation, connecting adaptor function to disease pathology.","evidence":"CCM2L deletion model with Map3k3-KLF pathway readout","pmids":["33657857"],"confidence":"Medium","gaps":["Limited methodological detail in source","Which KLF factors mediate the phenotype not delineated","Single lab"]},{"year":2021,"claim":"Tested whether endothelial CCM2L gain-of-function could drive cardiac regeneration, establishing that CCM2L overexpression alone is insufficient to promote cardiomyocyte proliferation or repair.","evidence":"Endothelial-specific Ccm2l gain-of-function transgenic mouse, LAD ligation injury, cardiomyocyte proliferation readout","pmids":["34046845"],"confidence":"Medium","gaps":["Negative result; does not exclude effects in other contexts or doses","Single method, single lab"]},{"year":2025,"claim":"Provided the first human genetic evidence linking CCM2L loss-of-function to congenital heart disease, connecting the developmental role to clinical pathology.","evidence":"Whole exome and Sanger sequencing of a Tetralogy of Fallot fetus; minigene splicing assay confirming exon 8 skipping","pmids":["40521769"],"confidence":"Medium","gaps":["Single case report","No functional pathway follow-up beyond splice consequence","Causality not established by family segregation or model"]},{"year":null,"claim":"How CCM2L balances against CCM2 to set the threshold between vascular junction destabilization and stabilization, and whether its human variants act through the MEKK3-KLF axis, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the CCM1-CCM2L-MEKK3 complex","Mechanistic link between human CCM2L variants and MEKK3-KLF signaling untested","Quantitative competition with CCM2 not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["CCM1-CCM2L-MEKK3 complex"],"partners":["CCM1","MAP3K3","CCM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NUG4","full_name":"Cerebral cavernous malformations 2 protein-like","aliases":[],"length_aa":571,"mass_kda":62.2,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NUG4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCM2L","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/CCM2L","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":98.9}],"url":"https://www.proteinatlas.org/search/CCM2L"},"hgnc":{"alias_symbol":["dJ310O13.5"],"prev_symbol":["C20orf160"]},"alphafold":{"accession":"Q9NUG4","domains":[{"cath_id":"2.30.29.30","chopping":"54-163_297-341","consensus_level":"high","plddt":83.598,"start":54,"end":341},{"cath_id":"1.20.1160.20","chopping":"426-492","consensus_level":"medium","plddt":87.2793,"start":426,"end":492}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NUG4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NUG4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NUG4-F1-predicted_aligned_error_v6.png","plddt_mean":58.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCM2L","jax_strain_url":"https://www.jax.org/strain/search?query=CCM2L"},"sequence":{"accession":"Q9NUG4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NUG4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NUG4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NUG4"}},"corpus_meta":[{"pmid":"26540726","id":"PMC_26540726","title":"The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26540726","citation_count":62,"is_preprint":false},{"pmid":"22898778","id":"PMC_22898778","title":"Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22898778","citation_count":46,"is_preprint":false},{"pmid":"31332575","id":"PMC_31332575","title":"Genome-Wide Association Study of Growth and Body-Shape-Related Traits in Large Yellow Croaker (Larimichthys crocea) Using ddRAD Sequencing.","date":"2019","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31332575","citation_count":34,"is_preprint":false},{"pmid":"23328253","id":"PMC_23328253","title":"ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway.","date":"2013","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/23328253","citation_count":29,"is_preprint":false},{"pmid":"37372363","id":"PMC_37372363","title":"Identifying Candidate Genes for Litter Size and Three Morphological Traits in Youzhou Dark Goats Based on Genome-Wide SNP Markers.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37372363","citation_count":26,"is_preprint":false},{"pmid":"38428498","id":"PMC_38428498","title":"Genetic background of hematological parameters in Holstein cattle based on genome-wide association and RNA sequencing analyses.","date":"2024","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/38428498","citation_count":6,"is_preprint":false},{"pmid":"33657857","id":"PMC_33657857","title":"CCM2L (Cerebral Cavernous Malformation 2 Like) Deletion Aggravates Cerebral Cavernous Malformation Through Map3k3-KLF Signaling Pathway.","date":"2021","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/33657857","citation_count":5,"is_preprint":false},{"pmid":"34046845","id":"PMC_34046845","title":"Cell Cycle Withdrawal Limit the Regenerative Potential of Neonatal Cardiomyocytes.","date":"2021","source":"Cardiovascular engineering and technology","url":"https://pubmed.ncbi.nlm.nih.gov/34046845","citation_count":5,"is_preprint":false},{"pmid":"40521769","id":"PMC_40521769","title":"Compound Heterozygous Loss-of-Function Variants in CCM2L in a Fetus With Tetralogy of Fallot.","date":"2025","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40521769","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6453,"output_tokens":1556,"usd":0.02135,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8263,"output_tokens":2372,"usd":0.050307,"stage2_stop_reason":"end_turn"},"total_usd":0.071657,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"CCM2L binds MEKK3 in a complex with CCM1, and both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target.\",\n      \"method\": \"In vitro binding assay (CCM2L-MEKK3-CCM1 complex), phosphorylation assay (MEK5 as substrate), zebrafish morpholino knockdown with genetic epistasis (mekk3 silencing rescues ccm2l/ccm2 morphant phenotype)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding and kinase assay combined with in vivo genetic epistasis in zebrafish; findings corroborated by CCM2 deletion activating ERK5/MEKK3 transcriptional program in endothelial cells\",\n      \"pmids\": [\"26540726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCM2L competitively blocks CCM2-mediated stabilizing signals; it is expressed selectively in endothelial cells during active cardiovascular growth and its loss reduces endocardial growth factor expression, impairing tumor growth and wound healing.\",\n      \"method\": \"Biochemical competition assay (CCM2L blocking CCM2 interactions), cultured endothelial cell experiments, in vivo loss-of-function in developing mice\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical competition assay plus in vivo mouse loss-of-function with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"22898778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ccm2l binds Ccm1; deletion and mutational analyses defined the regions of Ccm1 that mediate its binding to Ccm2l (as well as to Ccm2 and Heg). Morpholino disruption of ccm2l causes dilated atrium and inflow tract defects, and ccm2 overexpression can partially rescue ccm2l morphant defects, placing ccm2l as a component of the Heg-CCM pathway.\",\n      \"method\": \"Co-immunoprecipitation/binding assay with deletion/mutational analysis; zebrafish morpholino knockdown; genetic rescue by ccm2 overexpression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding with deletion mapping combined with in vivo genetic rescue in zebrafish, independently consistent with findings in PMID:26540726\",\n      \"pmids\": [\"23328253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCM2L deletion aggravates cerebral cavernous malformation through the Map3k3-KLF signaling pathway, extending the mechanistic link between CCM2L and MEKK3 (Map3k3) to include KLF transcription factors as downstream effectors.\",\n      \"method\": \"CCM2L deletion model with signaling pathway analysis (Map3k3-KLF pathway readout)\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined pathway placement (Map3k3-KLF), but abstract provides limited methodological detail; single lab\",\n      \"pmids\": [\"33657857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial-specific overexpression of Ccm2l does not promote cardiomyocyte proliferation or heart repair after LAD ligation in neonatal mice, indicating that endothelial Ccm2l gain-of-function is not sufficient for cardiac regeneration.\",\n      \"method\": \"Endothelial-specific Ccm2l gain-of-function transgenic mouse; LAD ligation injury model; cardiomyocyte proliferation readout\",\n      \"journal\": \"Cardiovascular engineering and technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean transgenic gain-of-function with defined phenotypic readout, but negative result; single lab, single method\",\n      \"pmids\": [\"34046845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous loss-of-function variants in CCM2L (nonsense c.741G>A and splice-site c.1263+2T>A) were identified in a fetus with Tetralogy of Fallot; minigene assay confirmed that the splice-site variant causes skipping of CCM2L exon 8, leading to frameshift and premature termination.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, minigene splicing assay\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — minigene functional validation of splicing defect is Tier 1 quality, but single case report with no mechanistic pathway follow-up beyond splice consequence\",\n      \"pmids\": [\"40521769\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCM2L is an endothelial adaptor protein that binds CCM1 and MEKK3 (Map3k3) to suppress MEKK3 kinase activity (blocking MEK5/ERK5 and KLF signaling), acting as a competitive paralog of CCM2 that destabilizes rather than stabilizes vascular junctions during active cardiovascular growth; genetic and biochemical evidence places it as a component of the Heg-CCM pathway, and human loss-of-function variants associate it with congenital heart defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCM2L is an endothelial adaptor protein that functions within the Heg-CCM pathway to regulate cardiovascular growth and vascular junction signaling [#0, #3]. It binds CCM1 in a complex that also engages the kinase MEKK3 (Map3k3), and CCM2L (like its paralog CCM2) interferes with MEKK3 activation, blocking phosphorylation of the downstream substrate MEK5; epistasis in zebrafish, where mekk3 silencing rescues ccm2l morphant phenotypes, confirms this suppression operates in vivo [#0]. Deletion mapping defined the CCM1 regions mediating its binding to CCM2L, and ccm2 overexpression partially rescues ccm2l loss, indicating the two paralogs act on a shared CCM1-anchored module while CCM2L competitively opposes CCM2-mediated stabilizing signals during active cardiovascular growth [#1, #2]. Loss of CCM2L produces dilated atrium and inflow tract defects, reduces endocardial growth factor expression, and aggravates cerebral cavernous malformation through Map3k3-KLF signaling [#1, #2, #3]. Compound heterozygous loss-of-function variants in CCM2L were identified in a fetus with Tetralogy of Fallot, with a minigene assay confirming exon 8 skipping and premature termination [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established CCM2L as an endothelial-selective, growth-phase-restricted regulator that competitively antagonizes CCM2 stabilizing signals, defining it as a functional counterpart rather than redundant paralog.\",\n      \"evidence\": \"Biochemical competition assay plus in vivo loss-of-function in developing mice with endocardial growth factor and tumor/wound-healing readouts\",\n      \"pmids\": [\"22898778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of competition with CCM2 not resolved at structural level\", \"Direct kinase target not yet identified in this study\", \"Single-lab phenotypic characterization\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the physical architecture of the CCM1-CCM2L interaction and placed CCM2L genetically within the Heg-CCM pathway via rescue, answering whether CCM2L shares the CCM1 binding interface used by CCM2 and Heg.\",\n      \"evidence\": \"Co-IP with deletion/mutational mapping; zebrafish ccm2l morpholino knockdown with ccm2 overexpression rescue\",\n      \"pmids\": [\"23328253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream effector of the CCM1-CCM2L complex\", \"Cardiac phenotype mechanism beyond inflow tract defects unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified MEKK3 as the kinase target of the CCM2L-CCM1 complex and showed CCM2L suppresses MEKK3-driven MEK5 phosphorylation, providing the molecular mechanism linking the adaptor to a signaling cascade.\",\n      \"evidence\": \"In vitro binding and kinase (MEK5 phosphorylation) assays; zebrafish genetic epistasis (mekk3 silencing rescues ccm2l morphants)\",\n      \"pmids\": [\"26540726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the CCM1-CCM2L-MEKK3 complex unresolved\", \"Quantitative contribution of CCM2L versus CCM2 to MEKK3 suppression not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the MEKK3 axis to a transcriptional output by linking CCM2L loss to KLF signaling in cerebral cavernous malformation, connecting adaptor function to disease pathology.\",\n      \"evidence\": \"CCM2L deletion model with Map3k3-KLF pathway readout\",\n      \"pmids\": [\"33657857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited methodological detail in source\", \"Which KLF factors mediate the phenotype not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested whether endothelial CCM2L gain-of-function could drive cardiac regeneration, establishing that CCM2L overexpression alone is insufficient to promote cardiomyocyte proliferation or repair.\",\n      \"evidence\": \"Endothelial-specific Ccm2l gain-of-function transgenic mouse, LAD ligation injury, cardiomyocyte proliferation readout\",\n      \"pmids\": [\"34046845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude effects in other contexts or doses\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the first human genetic evidence linking CCM2L loss-of-function to congenital heart disease, connecting the developmental role to clinical pathology.\",\n      \"evidence\": \"Whole exome and Sanger sequencing of a Tetralogy of Fallot fetus; minigene splicing assay confirming exon 8 skipping\",\n      \"pmids\": [\"40521769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report\", \"No functional pathway follow-up beyond splice consequence\", \"Causality not established by family segregation or model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCM2L balances against CCM2 to set the threshold between vascular junction destabilization and stabilization, and whether its human variants act through the MEKK3-KLF axis, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the CCM1-CCM2L-MEKK3 complex\", \"Mechanistic link between human CCM2L variants and MEKK3-KLF signaling untested\", \"Quantitative competition with CCM2 not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"CCM1-CCM2L-MEKK3 complex\"],\n    \"partners\": [\"CCM1\", \"MAP3K3\", \"CCM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}