{"gene":"COL5A2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1995,"finding":"Type V collagen α2(V) chain is a key determinant in the assembly of tissue-specific collagen matrices: mice producing a structurally abnormal α2(V) chain exhibit disorganized type I collagen fibrils in skin and eye, demonstrating that COL5A2 regulates collagen fibril growth and organization.","method":"Targeted mutation (knock-in of structurally abnormal α2(V) chain) in mice; histological and ultrastructural analysis of collagen fibril organization","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with direct ultrastructural readout of collagen fibril disorganization, replicated across multiple tissue types in the same study","pmids":["7704020"],"is_preprint":false},{"year":1998,"finding":"A single glycine-to-arginine substitution (G934R) within the triple-helical domain of the α2(V) collagen chain causes dominant-negative disruption of type V collagen structure and results in Ehlers-Danlos syndrome type II.","method":"COL5A2 cDNA sequencing of cultured dermal fibroblasts from affected family members; haplotype analysis to exclude COL5A1; verification that mutation absent in 50 normal chromosomes","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing of patient fibroblast cDNA plus haplotype exclusion of alternate locus; single lab, single family","pmids":["9783710"],"is_preprint":false},{"year":1992,"finding":"Cell type-specific transcription of COL5A2 depends on two nuclear factor-binding sites (FP-A and FP-B) in the upstream regulatory region (~nucleotides -149 to -95); mutation of FP-B reduces promoter activity ~40-fold and FP-A ~3-fold, indicating these sites are essential positive regulators of COL5A2 expression.","method":"Transfection experiments with promoter-reporter constructs; DNA binding assays (gel shift); site-directed mutagenesis of FP-A and FP-B","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis combined with transfection/reporter assays and DNA binding assays, multiple orthogonal methods in one study","pmids":["1460034"],"is_preprint":false},{"year":2000,"finding":"Cell type-specific transcription of COL5A2 is controlled by cooperative interactions among PBX1/2, PREP1, and HOXB1 proteins binding to the bipartite FPB element (5'-ATCAATCA-3'); PBX1 (not PBX2) is required for transactivation, and cooperative heterodimer binding of PBX1/PREP1 or PBX1/HOXB1 drives promoter activity.","method":"DNA binding assays with recombinant proteins; cell transfection overexpression experiments; comparison of FPB-bound complexes from COL5A2-positive vs. COL5A2-negative cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of protein-DNA complexes with recombinant proteins combined with cell transfection functional assays, multiple orthogonal methods","pmids":["10748126"],"is_preprint":false},{"year":1999,"finding":"B-Myb represses COL5A2 promoter activity indirectly by inhibiting binding of a positively-acting matrix regulatory factor (MRF-V) to two CRE-like elements in the first exon; mutation of these elements abolishes both basal promoter activity and B-Myb-mediated repression.","method":"Reporter gene transfection; electrophoretic mobility shift assay (EMSA) with B-Myb-GST fusion protein; site-directed mutagenesis of CRE-like elements; measurement of endogenous α2(V) collagen mRNA by Northern blot","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus in vitro binding assay plus endogenous mRNA measurement; single lab, multiple orthogonal methods","pmids":["10429946"],"is_preprint":false},{"year":2015,"finding":"Homozygous null Col5a2 mice are embryonic lethal at ~E12, but unlike Col5a1-null embryos (which virtually lack fibrils), Col5a2-null embryos have detectable collagen fibrils (though thicker than wild-type), suggesting α1(V)3 homotrimers partially compensate. Heterozygous Col5a2+/- adults show marked skin hyperextensibility and reduced tensile strength at high strain, and aortas with increased compliance and reduced tensile strength.","method":"Generation of Col5a2 null mice; embryonic lethality timing; electron microscopy of collagen fibrils; biomechanical tensile testing of skin and aorta","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic null allele, multiple tissue analyses, ultrastructural and biomechanical phenotyping, comparison with Col5a1-null controls","pmids":["25987251"],"is_preprint":false},{"year":2017,"finding":"Postnatal ubiquitous Col5a2 knockdown produces pathognomonic dermal cauliflower-contoured collagen fibril aggregates (reflecting loss of collagen V's role in fibril growth control) without skin hyperextensibility (which arises separately from loss of nucleation roles), demonstrating these two cEDS hallmarks arise through distinct mechanisms. Col5a2 haploinsufficiency also caused loss of dermal and abdominal white adipose tissue and markedly increased incidence/severity of abdominal aortic aneurysms and aortic arch dissections.","method":"Ubiquitous postnatal Col5a2 knockdown in mice; electron microscopy of collagen fibrils; histological analysis of adipose tissue; assessment of aortic aneurysms and dissections","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with multiple tissue-specific phenotypic readouts and ultrastructural analysis, dissecting two mechanistically distinct cEDS hallmarks","pmids":["28734943"],"is_preprint":false},{"year":2006,"finding":"Extracellular matrix containing mutant fibrillin-1 (Fbn1) down-regulates Col5a2 mRNA steady-state levels in mouse embryonic fibroblasts, demonstrating that ECM composition (via mutant Fbn1) signals to regulate Col5a2 transcription.","method":"Mouse embryonic fibroblasts grown on matrices produced by Tsk/Tsk, Tsk/+, or +/+ cells; real-time PCR and Northern blot analysis of Col5a2 mRNA levels","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-matrix reconstitution experiment with quantitative mRNA measurement across multiple genotype combinations, single lab","pmids":["16583319"],"is_preprint":false},{"year":2021,"finding":"Knockdown of COL5A2 inhibits cell proliferation and invasion in prostate cancer PC-3 and LNCaP cell lines, demonstrating a functional role for COL5A2 in supporting these malignant behaviors.","method":"siRNA knockdown of COL5A2 in PC-3 and LNCaP cell lines; cell proliferation and invasion assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (proliferation and invasion), single lab, single gene knockdown approach","pmids":["33816226"],"is_preprint":false},{"year":2022,"finding":"Downregulation of COL5A2 expression inhibits the TGF-β signaling and Wnt/β-catenin signaling pathways in osteosarcoma cells, suppressing invasion and metastasis.","method":"CCK-8 assay, scratch assay, western blot for pathway components after COL5A2 knockdown in osteosarcoma cells; qRT-PCR and immunofluorescence for COL5A2 expression","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, western blot-based pathway inference after KD, limited mechanistic detail in abstract","pmids":["35280775"],"is_preprint":false},{"year":2023,"finding":"COL5A2 promotes malignant phenotypes in gastric cancer cells by inducing epithelial-mesenchymal transition (EMT), evidenced by upregulation of mesenchymal markers SNAI1, SNAI2, TWIST, VIM, and MMP2 upon COL5A2 expression, and inhibition of proliferation, migration, and invasion upon COL5A2 knockdown.","method":"COL5A2 knockdown in AGS and SGC-7901 gastric cancer cell lines; CCK-8, colony formation, transwell assays; qRT-PCR and western blot for EMT markers","journal":"Open medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with phenotypic readouts and western blot marker analysis, limited mechanistic depth","pmids":["36712590"],"is_preprint":false},{"year":2024,"finding":"COL5A2, aberrantly overexpressed in regorafenib-resistant hepatocellular carcinoma cells, promotes proliferation, migration, invasion, and vasculogenic mimicry by suppressing LIFR expression and activating p38/STAT3 signaling; rescue experiments confirm that LIFR silencing reverses the inhibitory effects of COL5A2 depletion on aggressive behavior.","method":"Transcriptome sequencing; genetic depletion and overexpression of COL5A2; western blot for VE-cadherin, EphA2, Twist1, p-p38, p-STAT3; LIFR overexpression rescue experiments; in vitro and in vivo assays for proliferation, migration, invasion, VM formation, and lung metastasis","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with rescue experiments, multiple phenotypic and molecular readouts in vitro and in vivo, single lab","pmids":["38818582"],"is_preprint":false},{"year":2024,"finding":"Cancer-associated fibroblast (CAF)-secreted COL5A2 activates the PI3K/AKT signaling pathway to mediate erlotinib resistance in head and neck squamous cell carcinoma cells.","method":"In vitro co-culture experiments with CAFs and HNSCC cell lines; GEO/TCGA DEG analysis; functional assays assessing erlotinib resistance; pathway analysis of PI3K/AKT activation","journal":"Oral diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro only, abstract provides limited mechanistic detail beyond pathway correlation","pmids":["39286945"],"is_preprint":false},{"year":2025,"finding":"COL5A2 overexpression in lung adenocarcinoma induces endoplasmic reticulum (ER) stress, leading to increased PD-L1 exosome secretion and macrophage uptake of PD-L1 exosomes, thereby driving M2 macrophage polarization.","method":"qPCR and western blot for COL5A2, GRP78, CHOP (ER stress markers), PD-L1; flow cytometry for CD206/CD68 M2 markers; confocal microscopy for exosome uptake; immunofluorescence; in vivo animal assays","journal":"Cell stress & chaperones","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple assays but mechanism connecting COL5A2 to ER stress is not fully established by direct experiment in the abstract","pmids":["40345640"],"is_preprint":false},{"year":2021,"finding":"COL5A2 is a downstream target of miR-1286; BZRAP1-AS1 lncRNA sequesters miR-1286 to increase COL5A2 expression, and luciferase reporter, RIP, and pull-down assays confirmed the BZRAP1-AS1/miR-1286/COL5A2 cascade, with COL5A2 suppressing RA-HFLS proliferation and inflammation.","method":"Luciferase reporter assay; RIP assay; RNA pull-down assay; COL5A2 overexpression/knockdown; CCK-8 and BrdU proliferation assays; ELISA for cytokines","journal":"Immunity, inflammation and disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter confirms miR-1286 targeting of COL5A2 3'UTR, but overall mechanistic chain relies on single lab with limited validation of COL5A2-specific downstream effects","pmids":["34766472"],"is_preprint":false},{"year":2021,"finding":"A synonymous COL5A2 variant (c.1977 G>A) causes exon 29 skipping in the RNA transcript, producing a mutant α2(V) chain and resulting in classical EDS, demonstrating that synonymous mutations can disrupt COL5A2 splicing.","method":"Whole exome sequencing; Sanger sequencing for parental validation; RT-PCR to demonstrate exon 29 skipping in patient mRNA","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RT-PCR demonstration of aberrant splicing from patient-derived material, orthogonal to sequencing, single lab","pmids":["33834621"],"is_preprint":false},{"year":2010,"finding":"True haploinsufficiency of COL5A2 (hemizygous deletion) produces a clinical phenotype consistent with classical EDS, providing evidence that one functional copy of COL5A2 is insufficient for normal connective tissue function.","method":"MLPA detection of hemizygous genomic deletion; microarray breakpoint analysis; physical and laboratory examination of patient phenotype","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genomic deletion confirmed by multiple methods (MLPA + microarray + sequencing) with clinical phenotyping; single patient/case","pmids":["20648054"],"is_preprint":false}],"current_model":"COL5A2 encodes the α2(V) chain of type V collagen, which regulates collagen fibril nucleation and growth in connective tissues (particularly controlling type I collagen fibril diameter and organization); its promoter is under positive transcriptional control of PBX/PREP/HOX cooperative complexes at the FPB element and is repressed by B-Myb; loss-of-function causes embryonic lethality when homozygous, and haploinsufficiency produces skin fragility, aortic compliance defects, and aneurysm susceptibility; missense mutations within the triple-helical domain act as dominant negatives causing classical Ehlers-Danlos syndrome; in cancer contexts, COL5A2 promotes proliferation, invasion, and EMT-related signaling, and CAF-derived COL5A2 activates PI3K/AKT to mediate drug resistance."},"narrative":{"mechanistic_narrative":"COL5A2 encodes the α2(V) chain of type V collagen, a regulatory fibrillar collagen that controls the nucleation, growth, and organization of type I collagen fibrils in connective tissues [PMID:7704020, PMID:25987251]. In vivo, a structurally abnormal α2(V) chain produces disorganized collagen fibrils in skin and eye, while homozygous Col5a2 null mice are embryonic lethal at ~E12, yet retain detectable (though abnormally thick) fibrils — distinguishing COL5A2 from COL5A1 and indicating partial compensation by α1(V) homotrimers [PMID:7704020, PMID:25987251]. Haploinsufficiency in mice produces skin hyperextensibility, reduced tensile strength, loss of dermal and abdominal adipose tissue, and a marked increase in abdominal aortic aneurysms and aortic dissections, and the two classical EDS dermal hallmarks (cauliflower-contoured fibril aggregates versus skin hyperextensibility) arise through mechanistically distinct loss of fibril-growth versus nucleation functions [PMID:25987251, PMID:28734943]. In humans, a hemizygous COL5A2 deletion and a synonymous variant causing exon 29 skipping establish that haploinsufficiency and aberrant splicing cause classical Ehlers-Danlos syndrome, while a glycine-to-arginine substitution (G934R) within the triple-helical domain acts as a dominant negative [PMID:9783710, PMID:33834621, PMID:20648054]. COL5A2 transcription is governed by upstream FP-A and FP-B regulatory sites, where cooperative PBX1/PREP1 and PBX1/HOXB1 heterodimers binding the bipartite FPB element drive cell-type-specific expression, and B-Myb represses the promoter indirectly by blocking the positive regulator MRF-V at CRE-like elements; ECM composition itself feeds back on expression, as matrix bearing mutant fibrillin-1 downregulates Col5a2 mRNA [PMID:1460034, PMID:10748126, PMID:10429946, PMID:16583319]. In cancer, COL5A2 supports proliferation, migration, invasion, and EMT-associated programs across multiple tumor types [PMID:33816226, PMID:36712590, PMID:38818582].","teleology":[{"year":1992,"claim":"Established the cis-regulatory architecture controlling cell-type-specific COL5A2 transcription, identifying which upstream elements are essential for expression.","evidence":"Promoter-reporter transfection, gel shift, and site-directed mutagenesis of FP-A and FP-B sites","pmids":["1460034"],"confidence":"High","gaps":["Did not identify the trans-acting factors binding FP-A/FP-B","No in vivo confirmation of element function"]},{"year":1995,"claim":"Demonstrated in vivo that the α2(V) chain is a determinant of collagen fibril assembly, defining COL5A2's core matrix function.","evidence":"Knock-in of a structurally abnormal α2(V) chain in mice with histological and ultrastructural analysis of fibrils in skin and eye","pmids":["7704020"],"confidence":"High","gaps":["Dominant-negative knock-in, not a clean null","Molecular mechanism of fibril growth control not resolved"]},{"year":1998,"claim":"Linked a specific triple-helical glycine substitution in COL5A2 to dominant-negative disruption and classical EDS, establishing a disease mechanism beyond loss of expression.","evidence":"cDNA sequencing of patient dermal fibroblasts with haplotype exclusion of COL5A1","pmids":["9783710"],"confidence":"Medium","gaps":["Single family","Dominant-negative effect inferred genetically, not biochemically reconstituted"]},{"year":1999,"claim":"Identified a repressive arm of COL5A2 regulation, showing B-Myb antagonizes a positive matrix regulatory factor at the promoter.","evidence":"Reporter transfection, EMSA with B-Myb-GST fusion, mutagenesis of CRE-like elements, and Northern blot of endogenous mRNA","pmids":["10429946"],"confidence":"Medium","gaps":["MRF-V identity not determined","Physiological context of B-Myb repression unclear"]},{"year":2000,"claim":"Defined the trans-acting transcription complex driving COL5A2, showing cooperative PBX/PREP/HOX heterodimers transactivate the FPB element.","evidence":"DNA binding assays with recombinant PBX1/2, PREP1, HOXB1 and transfection overexpression comparing COL5A2-positive vs -negative cells","pmids":["10748126"],"confidence":"High","gaps":["No genetic confirmation in vivo","Upstream signals selecting PBX1/PREP1 vs PBX1/HOXB1 not defined"]},{"year":2006,"claim":"Showed that ECM composition feeds back onto COL5A2 transcription, linking matrix state to collagen gene expression.","evidence":"Mouse embryonic fibroblasts grown on Tsk/Tsk mutant fibrillin-1 matrices with real-time PCR and Northern blot of Col5a2 mRNA","pmids":["16583319"],"confidence":"Medium","gaps":["Signaling pathway from mutant Fbn1 matrix to Col5a2 promoter unknown","Correlative mRNA change only"]},{"year":2010,"claim":"Provided direct human evidence that one functional COL5A2 copy is insufficient, establishing haploinsufficiency as a disease mechanism.","evidence":"MLPA and microarray detection of hemizygous genomic deletion with clinical phenotyping","pmids":["20648054"],"confidence":"Medium","gaps":["Single case","Deletion breakpoints may affect neighboring loci"]},{"year":2015,"claim":"Distinguished COL5A2 from COL5A1 by showing nulls retain fibrils via α1(V) homotrimer compensation while haploinsufficiency confers skin and aortic mechanical defects.","evidence":"Col5a2 null and heterozygous mice with embryonic lethality timing, EM of fibrils, and biomechanical tensile testing of skin and aorta","pmids":["25987251"],"confidence":"High","gaps":["Extent and tissue specificity of homotrimer compensation not quantified","Molecular basis of aortic compliance change unresolved"]},{"year":2017,"claim":"Resolved that two classical EDS dermal hallmarks arise from distinct COL5A2 functions and broadened the haploinsufficiency phenotype to adipose loss and aneurysm.","evidence":"Ubiquitous postnatal Col5a2 knockdown in mice with EM, adipose histology, and aortic aneurysm/dissection assessment","pmids":["28734943"],"confidence":"High","gaps":["Mechanism linking COL5A2 loss to adipose depletion unclear","Trigger for aneurysm/dissection progression undefined"]},{"year":2021,"claim":"Extended COL5A2 function into malignancy, showing it supports prostate cancer proliferation and invasion.","evidence":"siRNA knockdown in PC-3 and LNCaP cells with proliferation and invasion assays","pmids":["33816226"],"confidence":"Medium","gaps":["No downstream pathway identified in this model","Cell-line only"]},{"year":2021,"claim":"Defined COL5A2 as an output of a competing-endogenous-RNA axis and a regulator of synovial fibroblast behavior in rheumatoid arthritis.","evidence":"Luciferase reporter, RIP, RNA pull-down, and COL5A2 over/knockdown with proliferation and cytokine assays in RA-HFLS","pmids":["34766472"],"confidence":"Low","gaps":["COL5A2-specific downstream effects not fully validated","Single lab","Cell-line only"]},{"year":2021,"claim":"Demonstrated that synonymous coding variants can disrupt COL5A2 splicing to cause classical EDS, expanding the mutational spectrum.","evidence":"Whole exome and Sanger sequencing with RT-PCR demonstrating exon 29 skipping in patient mRNA","pmids":["33834621"],"confidence":"Medium","gaps":["Single case","Effect of truncated chain on fibril assembly not directly tested"]},{"year":2024,"claim":"Provided the most detailed cancer mechanism, linking COL5A2 to LIFR suppression and p38/STAT3 activation in regorafenib-resistant hepatocellular carcinoma.","evidence":"Transcriptome sequencing, COL5A2 depletion/overexpression, LIFR rescue, and in vitro/in vivo proliferation, invasion, VM, and metastasis assays","pmids":["38818582"],"confidence":"Medium","gaps":["Mechanism connecting COL5A2 to LIFR not biochemically defined","Single lab"]},{"year":2024,"claim":"Implicated stromal CAF-derived COL5A2 in drug resistance via PI3K/AKT signaling in head and neck cancer.","evidence":"CAF-HNSCC co-culture, DEG analysis, erlotinib resistance assays, and PI3K/AKT pathway readout","pmids":["39286945"],"confidence":"Low","gaps":["In vitro only","Pathway link largely correlative","Receptor mediating COL5A2 signaling unidentified"]},{"year":2025,"claim":"Connected COL5A2 overexpression to tumor immune evasion through ER stress, PD-L1 exosome secretion, and M2 macrophage polarization.","evidence":"qPCR/western for ER stress and PD-L1 markers, flow cytometry, exosome uptake confocal imaging, and in vivo assays in lung adenocarcinoma","pmids":["40345640"],"confidence":"Low","gaps":["Direct mechanism connecting COL5A2 to ER stress not established","Single lab"]},{"year":null,"claim":"How a secreted ECM collagen chain triggers intracellular signaling cascades (LIFR/p38/STAT3, PI3K/AKT, ER stress) in cancer cells, and the receptor(s) mediating these effects, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor for COL5A2-driven signaling identified","Cancer mechanisms rest on single-lab cell-line studies","Link between matrix function and intracellular signaling undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5,6]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,5,7]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,4]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05997","full_name":"Collagen alpha-2(V) chain","aliases":[],"length_aa":1499,"mass_kda":144.9,"function":"Type V collagen is a member of group I collagen (fibrillar forming collagen). It is a minor connective tissue component of nearly ubiquitous distribution. Type V collagen binds to DNA, heparan sulfate, thrombospondin, heparin, and insulin. Type V collagen is a key determinant in the assembly of tissue-specific matrices (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P05997/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COL5A2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COL5A2","total_profiled":1310},"omim":[{"mim_id":"612313","title":"GLASS SYNDROME; GLASS","url":"https://www.omim.org/entry/612313"},{"mim_id":"605552","title":"ABDOMINAL OBESITY-METABOLIC SYNDROME 1; AOMS1","url":"https://www.omim.org/entry/605552"},{"mim_id":"604841","title":"STICKLER SYNDROME, TYPE II; STL2","url":"https://www.omim.org/entry/604841"},{"mim_id":"601788","title":"MYOSTATIN; MSTN","url":"https://www.omim.org/entry/601788"},{"mim_id":"157700","title":"MITRAL VALVE PROLAPSE 1; MVP1","url":"https://www.omim.org/entry/157700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COL5A2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P05997","domains":[{"cath_id":"3.30.750.130","chopping":"1278-1331","consensus_level":"medium","plddt":94.522,"start":1278,"end":1331},{"cath_id":"2.60.120.1000","chopping":"1335-1499","consensus_level":"medium","plddt":93.2636,"start":1335,"end":1499}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05997","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05997-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05997-F1-predicted_aligned_error_v6.png","plddt_mean":52.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COL5A2","jax_strain_url":"https://www.jax.org/strain/search?query=COL5A2"},"sequence":{"accession":"P05997","fasta_url":"https://rest.uniprot.org/uniprotkb/P05997.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05997/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05997"}},"corpus_meta":[{"pmid":"7704020","id":"PMC_7704020","title":"Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly.","date":"1995","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7704020","citation_count":182,"is_preprint":false},{"pmid":"11375892","id":"PMC_11375892","title":"Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2.","date":"2001","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/11375892","citation_count":145,"is_preprint":false},{"pmid":"23587214","id":"PMC_23587214","title":"Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations.","date":"2013","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23587214","citation_count":97,"is_preprint":false},{"pmid":"9783710","id":"PMC_9783710","title":"A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II.","date":"1998","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9783710","citation_count":61,"is_preprint":false},{"pmid":"2930668","id":"PMC_2930668","title":"Genetic evidence that mutations in the COL1A1, COL1A2, COL3A1, or COL5A2 collagen genes are not responsible for mitral valve prolapse.","date":"1989","source":"British heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/2930668","citation_count":47,"is_preprint":false},{"pmid":"33816226","id":"PMC_33816226","title":"COL5A2 Promotes Proliferation and Invasion in Prostate Cancer and Is One of Seven Gleason-Related Genes That Predict Recurrence-Free Survival.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33816226","citation_count":42,"is_preprint":false},{"pmid":"10748126","id":"PMC_10748126","title":"Cooperative interactions between PBX, PREP, and HOX proteins modulate the activity of the alpha 2(V) collagen (COL5A2) promoter.","date":"2000","source":"The Journal of biological 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3011647","citation_count":20,"is_preprint":false},{"pmid":"33974636","id":"PMC_33974636","title":"Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33974636","citation_count":18,"is_preprint":false},{"pmid":"30210685","id":"PMC_30210685","title":"Collagen type V a2 (COL5A2) is decreased in steroid-induced necrosis of the femoral head.","date":"2018","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/30210685","citation_count":17,"is_preprint":false},{"pmid":"34447460","id":"PMC_34447460","title":"Involvement of COL5A2 and TGF-β1 in pathological scarring.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34447460","citation_count":14,"is_preprint":false},{"pmid":"10429946","id":"PMC_10429946","title":"B-Myb represses trans-activation of the Col5A2 collagen promoter indirectly via inhibition of binding of factors interacting with positive elements within the first exon.","date":"1999","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10429946","citation_count":12,"is_preprint":false},{"pmid":"36712590","id":"PMC_36712590","title":"Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial-mesenchymal transition (EMT).","date":"2023","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36712590","citation_count":11,"is_preprint":false},{"pmid":"34766472","id":"PMC_34766472","title":"lncRNA BZRAP1-AS1 alleviates rheumatoid arthritis by regulating miR-1286/COL5A2 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/42072830","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.26.609709","title":"An Integrative Study to Investigate Sex-Specific Biomarkers in Bladder Cancer Patients","date":"2024-08-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.26.609709","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21868,"output_tokens":4411,"usd":0.065884,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12393,"output_tokens":4262,"usd":0.084257,"stage2_stop_reason":"end_turn"},"total_usd":0.150141,"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\": 1995,\n      \"finding\": \"Type V collagen α2(V) chain is a key determinant in the assembly of tissue-specific collagen matrices: mice producing a structurally abnormal α2(V) chain exhibit disorganized type I collagen fibrils in skin and eye, demonstrating that COL5A2 regulates collagen fibril growth and organization.\",\n      \"method\": \"Targeted mutation (knock-in of structurally abnormal α2(V) chain) in mice; histological and ultrastructural analysis of collagen fibril organization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with direct ultrastructural readout of collagen fibril disorganization, replicated across multiple tissue types in the same study\",\n      \"pmids\": [\"7704020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A single glycine-to-arginine substitution (G934R) within the triple-helical domain of the α2(V) collagen chain causes dominant-negative disruption of type V collagen structure and results in Ehlers-Danlos syndrome type II.\",\n      \"method\": \"COL5A2 cDNA sequencing of cultured dermal fibroblasts from affected family members; haplotype analysis to exclude COL5A1; verification that mutation absent in 50 normal chromosomes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing of patient fibroblast cDNA plus haplotype exclusion of alternate locus; single lab, single family\",\n      \"pmids\": [\"9783710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Cell type-specific transcription of COL5A2 depends on two nuclear factor-binding sites (FP-A and FP-B) in the upstream regulatory region (~nucleotides -149 to -95); mutation of FP-B reduces promoter activity ~40-fold and FP-A ~3-fold, indicating these sites are essential positive regulators of COL5A2 expression.\",\n      \"method\": \"Transfection experiments with promoter-reporter constructs; DNA binding assays (gel shift); site-directed mutagenesis of FP-A and FP-B\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis combined with transfection/reporter assays and DNA binding assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"1460034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cell type-specific transcription of COL5A2 is controlled by cooperative interactions among PBX1/2, PREP1, and HOXB1 proteins binding to the bipartite FPB element (5'-ATCAATCA-3'); PBX1 (not PBX2) is required for transactivation, and cooperative heterodimer binding of PBX1/PREP1 or PBX1/HOXB1 drives promoter activity.\",\n      \"method\": \"DNA binding assays with recombinant proteins; cell transfection overexpression experiments; comparison of FPB-bound complexes from COL5A2-positive vs. COL5A2-negative cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of protein-DNA complexes with recombinant proteins combined with cell transfection functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"10748126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"B-Myb represses COL5A2 promoter activity indirectly by inhibiting binding of a positively-acting matrix regulatory factor (MRF-V) to two CRE-like elements in the first exon; mutation of these elements abolishes both basal promoter activity and B-Myb-mediated repression.\",\n      \"method\": \"Reporter gene transfection; electrophoretic mobility shift assay (EMSA) with B-Myb-GST fusion protein; site-directed mutagenesis of CRE-like elements; measurement of endogenous α2(V) collagen mRNA by Northern blot\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus in vitro binding assay plus endogenous mRNA measurement; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10429946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homozygous null Col5a2 mice are embryonic lethal at ~E12, but unlike Col5a1-null embryos (which virtually lack fibrils), Col5a2-null embryos have detectable collagen fibrils (though thicker than wild-type), suggesting α1(V)3 homotrimers partially compensate. Heterozygous Col5a2+/- adults show marked skin hyperextensibility and reduced tensile strength at high strain, and aortas with increased compliance and reduced tensile strength.\",\n      \"method\": \"Generation of Col5a2 null mice; embryonic lethality timing; electron microscopy of collagen fibrils; biomechanical tensile testing of skin and aorta\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic null allele, multiple tissue analyses, ultrastructural and biomechanical phenotyping, comparison with Col5a1-null controls\",\n      \"pmids\": [\"25987251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Postnatal ubiquitous Col5a2 knockdown produces pathognomonic dermal cauliflower-contoured collagen fibril aggregates (reflecting loss of collagen V's role in fibril growth control) without skin hyperextensibility (which arises separately from loss of nucleation roles), demonstrating these two cEDS hallmarks arise through distinct mechanisms. Col5a2 haploinsufficiency also caused loss of dermal and abdominal white adipose tissue and markedly increased incidence/severity of abdominal aortic aneurysms and aortic arch dissections.\",\n      \"method\": \"Ubiquitous postnatal Col5a2 knockdown in mice; electron microscopy of collagen fibrils; histological analysis of adipose tissue; assessment of aortic aneurysms and dissections\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with multiple tissue-specific phenotypic readouts and ultrastructural analysis, dissecting two mechanistically distinct cEDS hallmarks\",\n      \"pmids\": [\"28734943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Extracellular matrix containing mutant fibrillin-1 (Fbn1) down-regulates Col5a2 mRNA steady-state levels in mouse embryonic fibroblasts, demonstrating that ECM composition (via mutant Fbn1) signals to regulate Col5a2 transcription.\",\n      \"method\": \"Mouse embryonic fibroblasts grown on matrices produced by Tsk/Tsk, Tsk/+, or +/+ cells; real-time PCR and Northern blot analysis of Col5a2 mRNA levels\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-matrix reconstitution experiment with quantitative mRNA measurement across multiple genotype combinations, single lab\",\n      \"pmids\": [\"16583319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of COL5A2 inhibits cell proliferation and invasion in prostate cancer PC-3 and LNCaP cell lines, demonstrating a functional role for COL5A2 in supporting these malignant behaviors.\",\n      \"method\": \"siRNA knockdown of COL5A2 in PC-3 and LNCaP cell lines; cell proliferation and invasion assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (proliferation and invasion), single lab, single gene knockdown approach\",\n      \"pmids\": [\"33816226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Downregulation of COL5A2 expression inhibits the TGF-β signaling and Wnt/β-catenin signaling pathways in osteosarcoma cells, suppressing invasion and metastasis.\",\n      \"method\": \"CCK-8 assay, scratch assay, western blot for pathway components after COL5A2 knockdown in osteosarcoma cells; qRT-PCR and immunofluorescence for COL5A2 expression\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, western blot-based pathway inference after KD, limited mechanistic detail in abstract\",\n      \"pmids\": [\"35280775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COL5A2 promotes malignant phenotypes in gastric cancer cells by inducing epithelial-mesenchymal transition (EMT), evidenced by upregulation of mesenchymal markers SNAI1, SNAI2, TWIST, VIM, and MMP2 upon COL5A2 expression, and inhibition of proliferation, migration, and invasion upon COL5A2 knockdown.\",\n      \"method\": \"COL5A2 knockdown in AGS and SGC-7901 gastric cancer cell lines; CCK-8, colony formation, transwell assays; qRT-PCR and western blot for EMT markers\",\n      \"journal\": \"Open medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with phenotypic readouts and western blot marker analysis, limited mechanistic depth\",\n      \"pmids\": [\"36712590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL5A2, aberrantly overexpressed in regorafenib-resistant hepatocellular carcinoma cells, promotes proliferation, migration, invasion, and vasculogenic mimicry by suppressing LIFR expression and activating p38/STAT3 signaling; rescue experiments confirm that LIFR silencing reverses the inhibitory effects of COL5A2 depletion on aggressive behavior.\",\n      \"method\": \"Transcriptome sequencing; genetic depletion and overexpression of COL5A2; western blot for VE-cadherin, EphA2, Twist1, p-p38, p-STAT3; LIFR overexpression rescue experiments; in vitro and in vivo assays for proliferation, migration, invasion, VM formation, and lung metastasis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with rescue experiments, multiple phenotypic and molecular readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"38818582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cancer-associated fibroblast (CAF)-secreted COL5A2 activates the PI3K/AKT signaling pathway to mediate erlotinib resistance in head and neck squamous cell carcinoma cells.\",\n      \"method\": \"In vitro co-culture experiments with CAFs and HNSCC cell lines; GEO/TCGA DEG analysis; functional assays assessing erlotinib resistance; pathway analysis of PI3K/AKT activation\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro only, abstract provides limited mechanistic detail beyond pathway correlation\",\n      \"pmids\": [\"39286945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COL5A2 overexpression in lung adenocarcinoma induces endoplasmic reticulum (ER) stress, leading to increased PD-L1 exosome secretion and macrophage uptake of PD-L1 exosomes, thereby driving M2 macrophage polarization.\",\n      \"method\": \"qPCR and western blot for COL5A2, GRP78, CHOP (ER stress markers), PD-L1; flow cytometry for CD206/CD68 M2 markers; confocal microscopy for exosome uptake; immunofluorescence; in vivo animal assays\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple assays but mechanism connecting COL5A2 to ER stress is not fully established by direct experiment in the abstract\",\n      \"pmids\": [\"40345640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COL5A2 is a downstream target of miR-1286; BZRAP1-AS1 lncRNA sequesters miR-1286 to increase COL5A2 expression, and luciferase reporter, RIP, and pull-down assays confirmed the BZRAP1-AS1/miR-1286/COL5A2 cascade, with COL5A2 suppressing RA-HFLS proliferation and inflammation.\",\n      \"method\": \"Luciferase reporter assay; RIP assay; RNA pull-down assay; COL5A2 overexpression/knockdown; CCK-8 and BrdU proliferation assays; ELISA for cytokines\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter confirms miR-1286 targeting of COL5A2 3'UTR, but overall mechanistic chain relies on single lab with limited validation of COL5A2-specific downstream effects\",\n      \"pmids\": [\"34766472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A synonymous COL5A2 variant (c.1977 G>A) causes exon 29 skipping in the RNA transcript, producing a mutant α2(V) chain and resulting in classical EDS, demonstrating that synonymous mutations can disrupt COL5A2 splicing.\",\n      \"method\": \"Whole exome sequencing; Sanger sequencing for parental validation; RT-PCR to demonstrate exon 29 skipping in patient mRNA\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RT-PCR demonstration of aberrant splicing from patient-derived material, orthogonal to sequencing, single lab\",\n      \"pmids\": [\"33834621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"True haploinsufficiency of COL5A2 (hemizygous deletion) produces a clinical phenotype consistent with classical EDS, providing evidence that one functional copy of COL5A2 is insufficient for normal connective tissue function.\",\n      \"method\": \"MLPA detection of hemizygous genomic deletion; microarray breakpoint analysis; physical and laboratory examination of patient phenotype\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic deletion confirmed by multiple methods (MLPA + microarray + sequencing) with clinical phenotyping; single patient/case\",\n      \"pmids\": [\"20648054\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COL5A2 encodes the α2(V) chain of type V collagen, which regulates collagen fibril nucleation and growth in connective tissues (particularly controlling type I collagen fibril diameter and organization); its promoter is under positive transcriptional control of PBX/PREP/HOX cooperative complexes at the FPB element and is repressed by B-Myb; loss-of-function causes embryonic lethality when homozygous, and haploinsufficiency produces skin fragility, aortic compliance defects, and aneurysm susceptibility; missense mutations within the triple-helical domain act as dominant negatives causing classical Ehlers-Danlos syndrome; in cancer contexts, COL5A2 promotes proliferation, invasion, and EMT-related signaling, and CAF-derived COL5A2 activates PI3K/AKT to mediate drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COL5A2 encodes the α2(V) chain of type V collagen, a regulatory fibrillar collagen that controls the nucleation, growth, and organization of type I collagen fibrils in connective tissues [#0, #5]. In vivo, a structurally abnormal α2(V) chain produces disorganized collagen fibrils in skin and eye, while homozygous Col5a2 null mice are embryonic lethal at ~E12, yet retain detectable (though abnormally thick) fibrils — distinguishing COL5A2 from COL5A1 and indicating partial compensation by α1(V) homotrimers [#0, #5]. Haploinsufficiency in mice produces skin hyperextensibility, reduced tensile strength, loss of dermal and abdominal adipose tissue, and a marked increase in abdominal aortic aneurysms and aortic dissections, and the two classical EDS dermal hallmarks (cauliflower-contoured fibril aggregates versus skin hyperextensibility) arise through mechanistically distinct loss of fibril-growth versus nucleation functions [#5, #6]. In humans, a hemizygous COL5A2 deletion and a synonymous variant causing exon 29 skipping establish that haploinsufficiency and aberrant splicing cause classical Ehlers-Danlos syndrome, while a glycine-to-arginine substitution (G934R) within the triple-helical domain acts as a dominant negative [#1, #15, #16]. COL5A2 transcription is governed by upstream FP-A and FP-B regulatory sites, where cooperative PBX1/PREP1 and PBX1/HOXB1 heterodimers binding the bipartite FPB element drive cell-type-specific expression, and B-Myb represses the promoter indirectly by blocking the positive regulator MRF-V at CRE-like elements; ECM composition itself feeds back on expression, as matrix bearing mutant fibrillin-1 downregulates Col5a2 mRNA [#2, #3, #4, #7]. In cancer, COL5A2 supports proliferation, migration, invasion, and EMT-associated programs across multiple tumor types [#8, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the cis-regulatory architecture controlling cell-type-specific COL5A2 transcription, identifying which upstream elements are essential for expression.\",\n      \"evidence\": \"Promoter-reporter transfection, gel shift, and site-directed mutagenesis of FP-A and FP-B sites\",\n      \"pmids\": [\"1460034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trans-acting factors binding FP-A/FP-B\", \"No in vivo confirmation of element function\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated in vivo that the α2(V) chain is a determinant of collagen fibril assembly, defining COL5A2's core matrix function.\",\n      \"evidence\": \"Knock-in of a structurally abnormal α2(V) chain in mice with histological and ultrastructural analysis of fibrils in skin and eye\",\n      \"pmids\": [\"7704020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative knock-in, not a clean null\", \"Molecular mechanism of fibril growth control not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked a specific triple-helical glycine substitution in COL5A2 to dominant-negative disruption and classical EDS, establishing a disease mechanism beyond loss of expression.\",\n      \"evidence\": \"cDNA sequencing of patient dermal fibroblasts with haplotype exclusion of COL5A1\",\n      \"pmids\": [\"9783710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"Dominant-negative effect inferred genetically, not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified a repressive arm of COL5A2 regulation, showing B-Myb antagonizes a positive matrix regulatory factor at the promoter.\",\n      \"evidence\": \"Reporter transfection, EMSA with B-Myb-GST fusion, mutagenesis of CRE-like elements, and Northern blot of endogenous mRNA\",\n      \"pmids\": [\"10429946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MRF-V identity not determined\", \"Physiological context of B-Myb repression unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the trans-acting transcription complex driving COL5A2, showing cooperative PBX/PREP/HOX heterodimers transactivate the FPB element.\",\n      \"evidence\": \"DNA binding assays with recombinant PBX1/2, PREP1, HOXB1 and transfection overexpression comparing COL5A2-positive vs -negative cells\",\n      \"pmids\": [\"10748126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genetic confirmation in vivo\", \"Upstream signals selecting PBX1/PREP1 vs PBX1/HOXB1 not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that ECM composition feeds back onto COL5A2 transcription, linking matrix state to collagen gene expression.\",\n      \"evidence\": \"Mouse embryonic fibroblasts grown on Tsk/Tsk mutant fibrillin-1 matrices with real-time PCR and Northern blot of Col5a2 mRNA\",\n      \"pmids\": [\"16583319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from mutant Fbn1 matrix to Col5a2 promoter unknown\", \"Correlative mRNA change only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided direct human evidence that one functional COL5A2 copy is insufficient, establishing haploinsufficiency as a disease mechanism.\",\n      \"evidence\": \"MLPA and microarray detection of hemizygous genomic deletion with clinical phenotyping\",\n      \"pmids\": [\"20648054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case\", \"Deletion breakpoints may affect neighboring loci\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguished COL5A2 from COL5A1 by showing nulls retain fibrils via α1(V) homotrimer compensation while haploinsufficiency confers skin and aortic mechanical defects.\",\n      \"evidence\": \"Col5a2 null and heterozygous mice with embryonic lethality timing, EM of fibrils, and biomechanical tensile testing of skin and aorta\",\n      \"pmids\": [\"25987251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent and tissue specificity of homotrimer compensation not quantified\", \"Molecular basis of aortic compliance change unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved that two classical EDS dermal hallmarks arise from distinct COL5A2 functions and broadened the haploinsufficiency phenotype to adipose loss and aneurysm.\",\n      \"evidence\": \"Ubiquitous postnatal Col5a2 knockdown in mice with EM, adipose histology, and aortic aneurysm/dissection assessment\",\n      \"pmids\": [\"28734943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking COL5A2 loss to adipose depletion unclear\", \"Trigger for aneurysm/dissection progression undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended COL5A2 function into malignancy, showing it supports prostate cancer proliferation and invasion.\",\n      \"evidence\": \"siRNA knockdown in PC-3 and LNCaP cells with proliferation and invasion assays\",\n      \"pmids\": [\"33816226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No downstream pathway identified in this model\", \"Cell-line only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined COL5A2 as an output of a competing-endogenous-RNA axis and a regulator of synovial fibroblast behavior in rheumatoid arthritis.\",\n      \"evidence\": \"Luciferase reporter, RIP, RNA pull-down, and COL5A2 over/knockdown with proliferation and cytokine assays in RA-HFLS\",\n      \"pmids\": [\"34766472\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"COL5A2-specific downstream effects not fully validated\", \"Single lab\", \"Cell-line only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that synonymous coding variants can disrupt COL5A2 splicing to cause classical EDS, expanding the mutational spectrum.\",\n      \"evidence\": \"Whole exome and Sanger sequencing with RT-PCR demonstrating exon 29 skipping in patient mRNA\",\n      \"pmids\": [\"33834621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case\", \"Effect of truncated chain on fibril assembly not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the most detailed cancer mechanism, linking COL5A2 to LIFR suppression and p38/STAT3 activation in regorafenib-resistant hepatocellular carcinoma.\",\n      \"evidence\": \"Transcriptome sequencing, COL5A2 depletion/overexpression, LIFR rescue, and in vitro/in vivo proliferation, invasion, VM, and metastasis assays\",\n      \"pmids\": [\"38818582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting COL5A2 to LIFR not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated stromal CAF-derived COL5A2 in drug resistance via PI3K/AKT signaling in head and neck cancer.\",\n      \"evidence\": \"CAF-HNSCC co-culture, DEG analysis, erlotinib resistance assays, and PI3K/AKT pathway readout\",\n      \"pmids\": [\"39286945\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"In vitro only\", \"Pathway link largely correlative\", \"Receptor mediating COL5A2 signaling unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected COL5A2 overexpression to tumor immune evasion through ER stress, PD-L1 exosome secretion, and M2 macrophage polarization.\",\n      \"evidence\": \"qPCR/western for ER stress and PD-L1 markers, flow cytometry, exosome uptake confocal imaging, and in vivo assays in lung adenocarcinoma\",\n      \"pmids\": [\"40345640\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct mechanism connecting COL5A2 to ER stress not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a secreted ECM collagen chain triggers intracellular signaling cascades (LIFR/p38/STAT3, PI3K/AKT, ER stress) in cancer cells, and the receptor(s) mediating these effects, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No receptor for COL5A2-driven signaling identified\", \"Cancer mechanisms rest on single-lab cell-line studies\", \"Link between matrix function and intracellular signaling undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}