{"gene":"FRAS1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2003,"finding":"FRAS1 encodes a protein with N-terminal cysteine-rich repeat motifs related to an ECM blastocoelar protein found in sea urchin, and loss-of-function mutations in FRAS1/Fras1 cause Fraser syndrome in humans and the blebbed phenotype in mice, establishing its role in epithelial integrity via disrupted ECM function.","method":"Autozygosity mapping, mutation analysis (frameshift mutations in patients), identification of premature termination in bl/bl mice, protein domain analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in two simultaneous papers (PMIDs 12766769 and 12766770), mutation identification in both human patients and mouse model with phenotypic validation","pmids":["12766769"],"is_preprint":false},{"year":2003,"finding":"Fras1 protein localizes specifically in a linear fashion underlying the epidermis and basal surface of other epithelia in mouse embryos; loss of Fras1 results in subepidermal hemorrhagic blisters and renal agenesis, and bl/bl embryos are devoid of Fras1 protein.","method":"Immunolocalization in embryonic mouse tissues, Fras1 knockout mouse generation, immunostaining of bl/bl mutant embryos","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein localization by immunostaining plus knockout phenotype, replicated across two independent papers","pmids":["12766770"],"is_preprint":false},{"year":2004,"finding":"GRIP1 (a cytoplasmic multi-PDZ scaffolding protein) physically interacts with Fras1 and is required for the localization of Fras1 to the basal side of cells; loss of GRIP1 causes Fraser syndrome-like defects, and the eye-blebs (eb) mouse has a deletion of two coding exons of Grip1.","method":"Co-immunoprecipitation/physical interaction assay between GRIP1 and Fras1, genetic analysis of eb mouse (coding exon deletion in Grip1), loss-of-function mouse phenotype analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct physical interaction demonstrated, genetic epistasis confirmed in vivo, mechanism (localization dependence) validated by loss-of-function","pmids":["14730302"],"is_preprint":false},{"year":2006,"finding":"Fras1, QBRICK/Frem1, and Frem2 form a ternary complex in the basement membrane and reciprocally stabilize each other's basement membrane localization; loss of any single protein (Fras1, Frem1, or Frem2) depletes all three from the basement membrane zone.","method":"Immunofluorescence localization in Fraser syndrome model mice (Frem2 mutant, GRIP1 mutant, Frem1/QBRICK knockout), transfection-based secretion assay showing ternary complex formation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent mouse mutant models tested, ternary complex formation confirmed by transfection/secretion assay, reciprocal stabilization demonstrated across three proteins","pmids":["16880404"],"is_preprint":false},{"year":2007,"finding":"The crystal structure of GRIP1 PDZ12 tandem in complex with the Fras1 C-terminal peptide reveals that PDZ1 and PDZ2 form a supramodule, with only the peptide-binding groove of PDZ1 binding the Fras1 C-terminal peptide; PDZ1 folding strictly depends on covalent attachment to PDZ2.","method":"Crystal structure determination of GRIP1 PDZ12/Fras1 C-terminal peptide complex; domain interaction/folding analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation of domain requirements, single lab but structural resolution provides mechanistic clarity","pmids":["18155042"],"is_preprint":false},{"year":2007,"finding":"Fras1 is ultrastructurally localized within the sublamina densa of embryonic mouse epithelial basement membranes, forming clustered depositions attached to anchoring fibrils and frequently detected in close proximity to mesenchymal cells, suggesting a direct link between sublamina densa and mesenchyme.","method":"Pre-embedding immunocytochemistry with electron microscopy (immunogold/silver enhancement) in multiple embryonic mouse epithelia","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ultrastructural localization by immunoelectron microscopy across multiple tissue types, single lab","pmids":["17576586"],"is_preprint":false},{"year":2007,"finding":"Loss of Fras1 results in the accumulation of Frem2 within epithelial cells, demonstrating that Fras1 is required not only as a complex component for extracellular stabilization of Frem2 but also for its proper intracellular trafficking and export from embryonic epithelial cells. Frem3 basement membrane localization remains unaffected in Fras1-null mice, demonstrating it is anchored independently of the Fras1/Frem1/Frem2 complex.","method":"Immunofluorescence localization of Frem2 and Frem3 in Fras1-null embryos; comparison of basement membrane protein retention in wild-type vs. Fras1-/- skin","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function experiment with subcellular localization readout, single lab with two distinct mechanistic findings","pmids":["17596926"],"is_preprint":false},{"year":2008,"finding":"Fras1 is expressed in the branching ureteric bud (UB) epithelium; in Fras1-null (bl/bl) mice, the ureteric bud fails to invade metanephric mesenchyme (replicated in organ culture), correlating with defective GDNF and GDF11 expression in renal primordia; addition of either growth factor restored bud invasion in culture. Fras1 also localizes in a glomerular basement membrane-like pattern in podocytes.","method":"In vivo analysis of bl/bl mouse kidney primordia, organ culture rescue experiment with GDNF/GDF11, immunolocalization of Fras1 in glomeruli, expression analysis of nephrogenic molecules (Hoxd11, Six2, BMP4) in mutant vs. wild-type","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and organ culture rescue experiment with defined growth factor pathways, single lab","pmids":["18787044"],"is_preprint":false},{"year":2006,"finding":"Frem1 colocalizes with Fras1 in diverse epithelial basement membranes; in Fras1-/- embryos, Frem1 is lost from the basement membrane but retained in periderm cells, indicating partial functional dependence on Fras1 for basement membrane localization.","method":"Immunofluorescence colocalization of Frem1 and Fras1 in wild-type and Fras1-/- embryonic tissues; electron microscopy showing clustered Frem1 arrangement in sublamina densa","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization in loss-of-function background with functional implications, single lab","pmids":["17240369"],"is_preprint":false},{"year":2016,"finding":"FRAS1 knockdown in A549 lung cancer cells reduces migration and invasion through downregulation of FAK signaling (but not Src signaling), as shown by shRNA knockdown followed by Western blot analysis.","method":"shRNA knockdown of FRAS1 in A549 cells, migration/invasion assays, Western blot for FAK and Src pathway components","journal":"International journal of clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot) for pathway identification, cancer cell line context may not reflect canonical FRAS1 function","pmids":["25126166"],"is_preprint":false},{"year":2016,"finding":"In Fras1(rdf) loss-of-function mice, syndactyly arises from loss of interdigital cell death (ICD); despite normal BMP ligand and receptor expression, the BMP downstream target Msx2 is downregulated in interdigital regions, suggesting Fras1-dependent epithelial-mesenchymal adhesion is required for BMP signal transmission to promote ICD.","method":"ENU-derived Fras1(rdf) nonsense allele mouse, histological analysis of interdigital cell death, in situ hybridization/immunostaining for BMP ligands, receptors, and Msx2 in limb buds","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular pathway (BMP/Msx2) and cellular phenotype (ICD), single lab","pmids":["26813283"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, fras1 acts in endoderm (confirmed by transplantation studies) to shape pharyngeal pouch 1 and stabilize pharyngeal skeletal development; fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1, and skeletal defects arise during late-p1 morphogenesis.","method":"Zebrafish fras1 mutant analysis, cell transplantation experiments to determine tissue of origin, temporal analysis of skeletal defects","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell transplantation establishes tissue-autonomous function; single lab with multiple phenotypic analyses","pmids":["22782724"],"is_preprint":false},{"year":2016,"finding":"Fras1 and Itga8 (integrin alpha-8, expressed in complementary facial mesenchyme) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; fras1 and itga8 single and double mutants show similar craniofacial phenotypes, and using a revertible fras1 allele the critical window for fras1 function was determined to be 1.5–3 days post fertilization.","method":"Zebrafish genetics (fras1 mutant, CRISPR itga8 alleles, double mutants), revertible allele temporal analysis, expression analysis of fras1/itga8/npnt/fbn2b","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with CRISPR validation, temporal revertible allele experiment, single lab","pmids":["27265864"],"is_preprint":false},{"year":2012,"finding":"Conditional podocyte-specific deletion of Fras1 leads to downregulation of FRAS1 in maturing glomeruli followed by glomerulosclerosis, demonstrating a locally required role of FRAS1 in glomerular maturation and integrity independent of skin blistering.","method":"Conditional Fras1 null allele with Cre-mediated podocyte-specific deletion in mice, histological analysis of glomeruli","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with tissue-specific phenotype, single lab","pmids":["22730198"],"is_preprint":false},{"year":2024,"finding":"CRL4-DCAF13 E3 ubiquitin ligase complex targets FRAS1 for polyubiquitination and proteasomal degradation; FRAS1 in turn promotes proliferation and migration of ovarian cancer cells through FAK signaling pathway activation.","method":"CRISPR/Cas9 knockout of DCAF13, polyubiquitination assay, proteasomal degradation assay, cell proliferation/migration assays, Western blot for FAK pathway","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polyubiquitination assay with CRISPR KO and proteasomal degradation demonstrated, but single lab and cancer cell line context","pmids":["39367995"],"is_preprint":false},{"year":2023,"finding":"Fraser complex proteins (Fras1, Frem1, Frem2) form anchoring cords at the dermal-epidermal junction in mouse skin; AMACO (VWA2) associates with these anchoring cords but is not required for their formation or the mutual basement membrane deposition of Fraser complex proteins.","method":"AMACO-deficient mouse generation and characterization, immunofluorescence analysis of Fraser complex protein localization in AMACO KO mice","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with direct protein localization analysis, confirms complex formation is AMACO-independent, single lab","pmids":["37047755"],"is_preprint":false},{"year":2020,"finding":"Fras1 is expressed in choroid plexuses and specific brain regions (cortical, hippocampal, amygdalar areas) in juvenile mice; Fras1-/- mice exhibit impaired egocentric spatial memory, aberrant olfactory learning/memory, reduced fear memory, and reduced anxiety, accompanied by severely disrupted extracellular matrix organization in cortical and subcortical areas (shown by WFA immunolabeling).","method":"RT-PCR and immunostaining for Fras1 expression in brain regions, behavioral testing of Fras1-/- mice, Wisteria floribunda agglutinin (WFA) immunolabeling for ECM organization","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mice with multiple behavioral readouts and ECM structural analysis, single lab","pmids":["32333816"],"is_preprint":false},{"year":2013,"finding":"A novel missense mutation in Fras1 (bfb allele) causes the classic blebs phenotype (epithelial-mesenchymal adhesion defects, subepidermal blistering) without embryonic lethality typical of other blebs mutants, and also produces novel palate and sternal defects, supporting a role for Fras1 in regulating signaling during organogenesis beyond adhesion.","method":"ENU mutagenesis screen, positional mapping and sequencing identifying Fras1 missense mutation, histological and phenotypic analysis of bfb mice","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — novel allele characterization with phenotypic analysis, no direct molecular mechanism identified for the novel defects, single lab","pmids":["24143185"],"is_preprint":false}],"current_model":"FRAS1 encodes a large extracellular matrix protein that localizes to the sublamina densa of epithelial basement membranes, where it forms a mutually stabilizing ternary complex with FREM1 and FREM2 (anchoring cords); its trafficking to the basal cell surface requires intracellular interaction with the PDZ scaffolding protein GRIP1 (which binds the FRAS1 C-terminus via its PDZ1-PDZ2 supramodule), and loss of any complex member depletes all three from the basement membrane, disrupting epithelial-mesenchymal adhesion and causing Fraser syndrome phenotypes including subepidermal blistering, renal agenesis, cryptophthalmos, and syndactyly; additionally, FRAS1 is subject to polyubiquitination and proteasomal degradation by the CRL4-DCAF13 E3 ligase, and can activate FAK signaling to regulate cell migration."},"narrative":{"mechanistic_narrative":"FRAS1 encodes a large extracellular matrix protein essential for epithelial-mesenchymal adhesion, whose loss causes Fraser syndrome in humans and the blebbed phenotype in mice [PMID:12766769]. The protein localizes in a linear pattern to the basal surface of epithelia, specifically within the sublamina densa of basement membranes where it forms clustered depositions attached to anchoring fibrils [PMID:12766770, PMID:17576586]. There it assembles a mutually stabilizing ternary complex with FREM1 and FREM2 (anchoring cords): loss of any single member depletes all three from the basement membrane zone, and FRAS1 is additionally required for the intracellular trafficking and export of FREM2 from epithelial cells [PMID:16880404, PMID:17596926, PMID:37047755]. Correct delivery of FRAS1 to the basal cell surface depends on the cytoplasmic multi-PDZ scaffold GRIP1, which binds the FRAS1 C-terminal peptide through a PDZ1-PDZ2 supramodule in which only the PDZ1 groove engages the ligand and PDZ1 folding requires covalent linkage to PDZ2 [PMID:14730302, PMID:18155042]. Through this adhesive function FRAS1 supports organogenesis across multiple systems—ureteric bud invasion in kidney development via GDNF/GDF11 [PMID:18787044], glomerular maturation [PMID:22730198], interdigital cell death and digit separation through BMP/Msx2 signaling [PMID:26813283], and pharyngeal pouch and craniofacial morphogenesis acting with integrin alpha-8 (ITGA8) [PMID:22782724, PMID:27265864]. FRAS1 protein abundance is controlled by CRL4-DCAF13-mediated polyubiquitination and proteasomal degradation, and FRAS1 can activate FAK signaling to promote cancer cell migration and proliferation [PMID:39367995].","teleology":[{"year":2003,"claim":"Established the molecular cause of Fraser syndrome and the murine blebbed phenotype, defining FRAS1 as an ECM-related protein required for epithelial integrity.","evidence":"Autozygosity mapping and mutation analysis in human patients plus identification of premature termination in bl/bl mice, with protein domain analysis","pmids":["12766769"],"confidence":"High","gaps":["Did not resolve subcellular/ultrastructural localization","Did not identify molecular partners or trafficking machinery"]},{"year":2003,"claim":"Localized Fras1 protein to the basal epithelial surface and tied its loss directly to subepidermal blistering and renal agenesis, linking molecular site to phenotype.","evidence":"Immunolocalization in embryonic mouse tissues and knockout/bl-mutant phenotype analysis","pmids":["12766770"],"confidence":"High","gaps":["Mechanism of basal targeting unknown","Whether Fras1 acts alone or in a complex not addressed"]},{"year":2004,"claim":"Identified GRIP1 as the cytoplasmic scaffold required to deliver Fras1 to the basal cell surface, explaining a genetically distinct route to Fraser-like phenotypes.","evidence":"Co-immunoprecipitation of GRIP1 with Fras1, genetic analysis of the eb mouse, and loss-of-function phenotyping","pmids":["14730302"],"confidence":"High","gaps":["Structural basis of the interaction not defined","Trafficking step (export vs. surface retention) not pinpointed"]},{"year":2006,"claim":"Defined the Fras1/Frem1/Frem2 ternary complex and its reciprocal stabilization, establishing that the three proteins act as an interdependent unit in the basement membrane.","evidence":"Immunofluorescence across multiple Fraser-model mouse mutants and transfection/secretion assays demonstrating complex formation","pmids":["16880404","17240369"],"confidence":"High","gaps":["Stoichiometry and binding interfaces of the complex not determined","Extracellular receptor/anchor on the mesenchymal side unknown"]},{"year":2007,"claim":"Resolved the atomic basis of FRAS1 recognition by GRIP1, showing PDZ1-PDZ2 act as a single supramodule with PDZ1 dependent on PDZ2 for folding and ligand binding.","evidence":"Crystal structure of GRIP1 PDZ12 in complex with the Fras1 C-terminal peptide plus domain folding analysis","pmids":["18155042"],"confidence":"High","gaps":["Does not address how the complex transits to the cell surface","In vivo consequence of disrupting the specific interface not tested"]},{"year":2007,"claim":"Placed FRAS1 ultrastructurally in the sublamina densa attached to anchoring fibrils and near mesenchyme, providing a physical model for epithelial-mesenchymal linkage.","evidence":"Pre-embedding immunoelectron microscopy in multiple embryonic mouse epithelia","pmids":["17576586"],"confidence":"Medium","gaps":["Single lab","Molecular identity of the mesenchymal anchoring partner not established"]},{"year":2007,"claim":"Showed FRAS1 is needed for intracellular export of FREM2 and that FREM3 anchors independently, separating Fras1-dependent from Fras1-independent basement membrane assembly.","evidence":"Immunofluorescence of Frem2 and Frem3 in Fras1-null versus wild-type embryonic skin","pmids":["17596926"],"confidence":"Medium","gaps":["Trafficking mechanism by which Fras1 promotes Frem2 export unresolved","Single lab"]},{"year":2008,"claim":"Linked FRAS1 adhesive function to kidney organogenesis, showing ureteric bud invasion failure correlates with reduced GDNF/GDF11 and is rescued by these growth factors.","evidence":"bl/bl mouse and organ-culture rescue with GDNF/GDF11, plus expression and immunolocalization analysis","pmids":["18787044"],"confidence":"Medium","gaps":["How adhesion defects feed into growth factor expression not mechanistically defined","Single lab"]},{"year":2012,"claim":"Demonstrated tissue-autonomous and locally required roles for fras1 in endoderm-driven pharyngeal morphogenesis and in glomerular maturation, broadening its organogenetic reach.","evidence":"Zebrafish mutant analysis with cell transplantation, and podocyte-specific conditional Fras1 deletion in mice","pmids":["22782724","22730198"],"confidence":"Medium","gaps":["Downstream effectors in pharyngeal/glomerular contexts not fully resolved","Single labs"]},{"year":2016,"claim":"Connected FRAS1-dependent adhesion to developmental signaling, showing syndactyly arises from failed BMP/Msx2-driven interdigital cell death and that fras1 cooperates with itga8 in craniofacial morphogenesis within a defined time window.","evidence":"Fras1(rdf) mouse with BMP/Msx2 in situ analysis, and zebrafish fras1/itga8 double-mutant and revertible-allele genetics","pmids":["26813283","27265864"],"confidence":"Medium","gaps":["Direct molecular bridge from adhesion to BMP signal transmission not established","ITGA8-FRAS1 physical interaction not demonstrated"]},{"year":2020,"claim":"Extended FRAS1 function beyond classical Fraser phenotypes to brain ECM organization and cognition, implicating it in perineuronal-net-type matrix integrity and behavior.","evidence":"Expression mapping, behavioral testing of Fras1-/- mice, and WFA immunolabeling of cortical/subcortical ECM","pmids":["32333816"],"confidence":"Medium","gaps":["Molecular role of Fras1 in brain ECM not defined","Single lab"]},{"year":2024,"claim":"Identified post-translational control of FRAS1 by CRL4-DCAF13-mediated ubiquitination/degradation and a pro-tumorigenic FAK-activating output in cancer cells.","evidence":"DCAF13 CRISPR knockout, polyubiquitination and proteasomal degradation assays, and migration/proliferation assays with FAK Western blots","pmids":["39367995","25126166"],"confidence":"Medium","gaps":["FAK activation mechanism by an ECM protein not detailed","Cancer cell-line context may not reflect canonical developmental function"]},{"year":null,"claim":"How the FRAS1/FREM ternary complex physically bridges the sublamina densa to mesenchymal receptors, and how FRAS1 abundance and signaling are integrated to control adhesion versus migration, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Mesenchymal receptor for the anchoring cords unidentified","No structural model of the full Fras1/Frem1/Frem2 complex","Mechanistic basis of FRAS1-driven FAK activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,3,5,16]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,5,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,10,11,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14]}],"complexes":["Fras1/Frem1/Frem2 ternary complex (Fraser complex / anchoring cords)"],"partners":["FREM1","FREM2","GRIP1","DCAF13","ITGA8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86XX4","full_name":"Extracellular matrix organizing protein FRAS1","aliases":["Fraser syndrome 1 protein"],"length_aa":4008,"mass_kda":443.2,"function":"Involved in extracellular matrix organization (By similarity). Required for the regulation of epidermal-basement membrane adhesion responsible for proper organogenesis during embryonic development (By similarity). Involved in brain organization and function (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86XX4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRAS1","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/FRAS1","total_profiled":1310},"omim":[{"mim_id":"618281","title":"VON WILLEBRAND FACTOR A DOMAIN-CONTAINING PROTEIN 2; VWA2","url":"https://www.omim.org/entry/618281"},{"mim_id":"617667","title":"FRASER SYNDROME 3; FRASRS3","url":"https://www.omim.org/entry/617667"},{"mim_id":"617666","title":"FRASER SYNDROME 2; FRASRS2","url":"https://www.omim.org/entry/617666"},{"mim_id":"614485","title":"TRIGONOCEPHALY 2; TRIGNO2","url":"https://www.omim.org/entry/614485"},{"mim_id":"608980","title":"BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES; BNAR","url":"https://www.omim.org/entry/608980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"thyroid gland","ntpm":11.2}],"url":"https://www.proteinatlas.org/search/FRAS1"},"hgnc":{"alias_symbol":["FLJ22031","FLJ14927","KIAA1500"],"prev_symbol":[]},"alphafold":{"accession":"Q86XX4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XX4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XX4-6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XX4-6-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRAS1","jax_strain_url":"https://www.jax.org/strain/search?query=FRAS1"},"sequence":{"accession":"Q86XX4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86XX4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86XX4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XX4"}},"corpus_meta":[{"pmid":"12766769","id":"PMC_12766769","title":"Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12766769","citation_count":190,"is_preprint":false},{"pmid":"14730302","id":"PMC_14730302","title":"A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14730302","citation_count":120,"is_preprint":false},{"pmid":"16880404","id":"PMC_16880404","title":"Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16880404","citation_count":110,"is_preprint":false},{"pmid":"12766770","id":"PMC_12766770","title":"Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12766770","citation_count":107,"is_preprint":false},{"pmid":"21182980","id":"PMC_21182980","title":"The role of Fras1/Frem proteins in the structure and function of basement membrane.","date":"2010","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21182980","citation_count":76,"is_preprint":false},{"pmid":"18787044","id":"PMC_18787044","title":"Fras1, a basement membrane-associated protein mutated in Fraser syndrome, mediates both the initiation of the mammalian kidney and the integrity of renal glomeruli.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18787044","citation_count":56,"is_preprint":false},{"pmid":"18661360","id":"PMC_18661360","title":"The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype.","date":"2008","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/18661360","citation_count":44,"is_preprint":false},{"pmid":"17240369","id":"PMC_17240369","title":"Overlapping and divergent localization of Frem1 and Fras1 and its functional implications during mouse embryonic development.","date":"2006","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17240369","citation_count":40,"is_preprint":false},{"pmid":"23221805","id":"PMC_23221805","title":"Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23221805","citation_count":38,"is_preprint":false},{"pmid":"17251066","id":"PMC_17251066","title":"Spatiotemporal distribution of Fras1/Frem proteins during mouse embryonic development.","date":"2006","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/17251066","citation_count":34,"is_preprint":false},{"pmid":"18155042","id":"PMC_18155042","title":"Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18155042","citation_count":34,"is_preprint":false},{"pmid":"17596926","id":"PMC_17596926","title":"Basement membrane localization of Frem3 is independent of the Fras1/Frem1/Frem2 protein complex within the sublamina densa.","date":"2007","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17596926","citation_count":25,"is_preprint":false},{"pmid":"16894541","id":"PMC_16894541","title":"Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome.","date":"2006","source":"American journal of medical genetics. 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loss of Fras1 results in subepidermal hemorrhagic blisters and renal agenesis, and bl/bl embryos are devoid of Fras1 protein.\",\n      \"method\": \"Immunolocalization in embryonic mouse tissues, Fras1 knockout mouse generation, immunostaining of bl/bl mutant embryos\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein localization by immunostaining plus knockout phenotype, replicated across two independent papers\",\n      \"pmids\": [\"12766770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GRIP1 (a cytoplasmic multi-PDZ scaffolding protein) physically interacts with Fras1 and is required for the localization of Fras1 to the basal side of cells; loss of GRIP1 causes Fraser syndrome-like defects, and the eye-blebs (eb) mouse has a deletion of two coding exons of Grip1.\",\n      \"method\": \"Co-immunoprecipitation/physical interaction assay between GRIP1 and Fras1, genetic analysis of eb mouse (coding exon deletion in Grip1), loss-of-function mouse phenotype analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct physical interaction demonstrated, genetic epistasis confirmed in vivo, mechanism (localization dependence) validated by loss-of-function\",\n      \"pmids\": [\"14730302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fras1, QBRICK/Frem1, and Frem2 form a ternary complex in the basement membrane and reciprocally stabilize each other's basement membrane localization; loss of any single protein (Fras1, Frem1, or Frem2) depletes all three from the basement membrane zone.\",\n      \"method\": \"Immunofluorescence localization in Fraser syndrome model mice (Frem2 mutant, GRIP1 mutant, Frem1/QBRICK knockout), transfection-based secretion assay showing ternary complex formation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent mouse mutant models tested, ternary complex formation confirmed by transfection/secretion assay, reciprocal stabilization demonstrated across three proteins\",\n      \"pmids\": [\"16880404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The crystal structure of GRIP1 PDZ12 tandem in complex with the Fras1 C-terminal peptide reveals that PDZ1 and PDZ2 form a supramodule, with only the peptide-binding groove of PDZ1 binding the Fras1 C-terminal peptide; PDZ1 folding strictly depends on covalent attachment to PDZ2.\",\n      \"method\": \"Crystal structure determination of GRIP1 PDZ12/Fras1 C-terminal peptide complex; domain interaction/folding analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation of domain requirements, single lab but structural resolution provides mechanistic clarity\",\n      \"pmids\": [\"18155042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fras1 is ultrastructurally localized within the sublamina densa of embryonic mouse epithelial basement membranes, forming clustered depositions attached to anchoring fibrils and frequently detected in close proximity to mesenchymal cells, suggesting a direct link between sublamina densa and mesenchyme.\",\n      \"method\": \"Pre-embedding immunocytochemistry with electron microscopy (immunogold/silver enhancement) in multiple embryonic mouse epithelia\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ultrastructural localization by immunoelectron microscopy across multiple tissue types, single lab\",\n      \"pmids\": [\"17576586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of Fras1 results in the accumulation of Frem2 within epithelial cells, demonstrating that Fras1 is required not only as a complex component for extracellular stabilization of Frem2 but also for its proper intracellular trafficking and export from embryonic epithelial cells. Frem3 basement membrane localization remains unaffected in Fras1-null mice, demonstrating it is anchored independently of the Fras1/Frem1/Frem2 complex.\",\n      \"method\": \"Immunofluorescence localization of Frem2 and Frem3 in Fras1-null embryos; comparison of basement membrane protein retention in wild-type vs. Fras1-/- skin\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function experiment with subcellular localization readout, single lab with two distinct mechanistic findings\",\n      \"pmids\": [\"17596926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fras1 is expressed in the branching ureteric bud (UB) epithelium; in Fras1-null (bl/bl) mice, the ureteric bud fails to invade metanephric mesenchyme (replicated in organ culture), correlating with defective GDNF and GDF11 expression in renal primordia; addition of either growth factor restored bud invasion in culture. Fras1 also localizes in a glomerular basement membrane-like pattern in podocytes.\",\n      \"method\": \"In vivo analysis of bl/bl mouse kidney primordia, organ culture rescue experiment with GDNF/GDF11, immunolocalization of Fras1 in glomeruli, expression analysis of nephrogenic molecules (Hoxd11, Six2, BMP4) in mutant vs. wild-type\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and organ culture rescue experiment with defined growth factor pathways, single lab\",\n      \"pmids\": [\"18787044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Frem1 colocalizes with Fras1 in diverse epithelial basement membranes; in Fras1-/- embryos, Frem1 is lost from the basement membrane but retained in periderm cells, indicating partial functional dependence on Fras1 for basement membrane localization.\",\n      \"method\": \"Immunofluorescence colocalization of Frem1 and Fras1 in wild-type and Fras1-/- embryonic tissues; electron microscopy showing clustered Frem1 arrangement in sublamina densa\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization in loss-of-function background with functional implications, single lab\",\n      \"pmids\": [\"17240369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FRAS1 knockdown in A549 lung cancer cells reduces migration and invasion through downregulation of FAK signaling (but not Src signaling), as shown by shRNA knockdown followed by Western blot analysis.\",\n      \"method\": \"shRNA knockdown of FRAS1 in A549 cells, migration/invasion assays, Western blot for FAK and Src pathway components\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot) for pathway identification, cancer cell line context may not reflect canonical FRAS1 function\",\n      \"pmids\": [\"25126166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Fras1(rdf) loss-of-function mice, syndactyly arises from loss of interdigital cell death (ICD); despite normal BMP ligand and receptor expression, the BMP downstream target Msx2 is downregulated in interdigital regions, suggesting Fras1-dependent epithelial-mesenchymal adhesion is required for BMP signal transmission to promote ICD.\",\n      \"method\": \"ENU-derived Fras1(rdf) nonsense allele mouse, histological analysis of interdigital cell death, in situ hybridization/immunostaining for BMP ligands, receptors, and Msx2 in limb buds\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular pathway (BMP/Msx2) and cellular phenotype (ICD), single lab\",\n      \"pmids\": [\"26813283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, fras1 acts in endoderm (confirmed by transplantation studies) to shape pharyngeal pouch 1 and stabilize pharyngeal skeletal development; fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1, and skeletal defects arise during late-p1 morphogenesis.\",\n      \"method\": \"Zebrafish fras1 mutant analysis, cell transplantation experiments to determine tissue of origin, temporal analysis of skeletal defects\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell transplantation establishes tissue-autonomous function; single lab with multiple phenotypic analyses\",\n      \"pmids\": [\"22782724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fras1 and Itga8 (integrin alpha-8, expressed in complementary facial mesenchyme) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; fras1 and itga8 single and double mutants show similar craniofacial phenotypes, and using a revertible fras1 allele the critical window for fras1 function was determined to be 1.5–3 days post fertilization.\",\n      \"method\": \"Zebrafish genetics (fras1 mutant, CRISPR itga8 alleles, double mutants), revertible allele temporal analysis, expression analysis of fras1/itga8/npnt/fbn2b\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with CRISPR validation, temporal revertible allele experiment, single lab\",\n      \"pmids\": [\"27265864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional podocyte-specific deletion of Fras1 leads to downregulation of FRAS1 in maturing glomeruli followed by glomerulosclerosis, demonstrating a locally required role of FRAS1 in glomerular maturation and integrity independent of skin blistering.\",\n      \"method\": \"Conditional Fras1 null allele with Cre-mediated podocyte-specific deletion in mice, histological analysis of glomeruli\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with tissue-specific phenotype, single lab\",\n      \"pmids\": [\"22730198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRL4-DCAF13 E3 ubiquitin ligase complex targets FRAS1 for polyubiquitination and proteasomal degradation; FRAS1 in turn promotes proliferation and migration of ovarian cancer cells through FAK signaling pathway activation.\",\n      \"method\": \"CRISPR/Cas9 knockout of DCAF13, polyubiquitination assay, proteasomal degradation assay, cell proliferation/migration assays, Western blot for FAK pathway\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polyubiquitination assay with CRISPR KO and proteasomal degradation demonstrated, but single lab and cancer cell line context\",\n      \"pmids\": [\"39367995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fraser complex proteins (Fras1, Frem1, Frem2) form anchoring cords at the dermal-epidermal junction in mouse skin; AMACO (VWA2) associates with these anchoring cords but is not required for their formation or the mutual basement membrane deposition of Fraser complex proteins.\",\n      \"method\": \"AMACO-deficient mouse generation and characterization, immunofluorescence analysis of Fraser complex protein localization in AMACO KO mice\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with direct protein localization analysis, confirms complex formation is AMACO-independent, single lab\",\n      \"pmids\": [\"37047755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fras1 is expressed in choroid plexuses and specific brain regions (cortical, hippocampal, amygdalar areas) in juvenile mice; Fras1-/- mice exhibit impaired egocentric spatial memory, aberrant olfactory learning/memory, reduced fear memory, and reduced anxiety, accompanied by severely disrupted extracellular matrix organization in cortical and subcortical areas (shown by WFA immunolabeling).\",\n      \"method\": \"RT-PCR and immunostaining for Fras1 expression in brain regions, behavioral testing of Fras1-/- mice, Wisteria floribunda agglutinin (WFA) immunolabeling for ECM organization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mice with multiple behavioral readouts and ECM structural analysis, single lab\",\n      \"pmids\": [\"32333816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel missense mutation in Fras1 (bfb allele) causes the classic blebs phenotype (epithelial-mesenchymal adhesion defects, subepidermal blistering) without embryonic lethality typical of other blebs mutants, and also produces novel palate and sternal defects, supporting a role for Fras1 in regulating signaling during organogenesis beyond adhesion.\",\n      \"method\": \"ENU mutagenesis screen, positional mapping and sequencing identifying Fras1 missense mutation, histological and phenotypic analysis of bfb mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — novel allele characterization with phenotypic analysis, no direct molecular mechanism identified for the novel defects, single lab\",\n      \"pmids\": [\"24143185\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRAS1 encodes a large extracellular matrix protein that localizes to the sublamina densa of epithelial basement membranes, where it forms a mutually stabilizing ternary complex with FREM1 and FREM2 (anchoring cords); its trafficking to the basal cell surface requires intracellular interaction with the PDZ scaffolding protein GRIP1 (which binds the FRAS1 C-terminus via its PDZ1-PDZ2 supramodule), and loss of any complex member depletes all three from the basement membrane, disrupting epithelial-mesenchymal adhesion and causing Fraser syndrome phenotypes including subepidermal blistering, renal agenesis, cryptophthalmos, and syndactyly; additionally, FRAS1 is subject to polyubiquitination and proteasomal degradation by the CRL4-DCAF13 E3 ligase, and can activate FAK signaling to regulate cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRAS1 encodes a large extracellular matrix protein essential for epithelial-mesenchymal adhesion, whose loss causes Fraser syndrome in humans and the blebbed phenotype in mice [#0]. The protein localizes in a linear pattern to the basal surface of epithelia, specifically within the sublamina densa of basement membranes where it forms clustered depositions attached to anchoring fibrils [#1, #5]. There it assembles a mutually stabilizing ternary complex with FREM1 and FREM2 (anchoring cords): loss of any single member depletes all three from the basement membrane zone, and FRAS1 is additionally required for the intracellular trafficking and export of FREM2 from epithelial cells [#3, #6, #15]. Correct delivery of FRAS1 to the basal cell surface depends on the cytoplasmic multi-PDZ scaffold GRIP1, which binds the FRAS1 C-terminal peptide through a PDZ1-PDZ2 supramodule in which only the PDZ1 groove engages the ligand and PDZ1 folding requires covalent linkage to PDZ2 [#2, #4]. Through this adhesive function FRAS1 supports organogenesis across multiple systems—ureteric bud invasion in kidney development via GDNF/GDF11 [#7], glomerular maturation [#13], interdigital cell death and digit separation through BMP/Msx2 signaling [#10], and pharyngeal pouch and craniofacial morphogenesis acting with integrin alpha-8 (ITGA8) [#11, #12]. FRAS1 protein abundance is controlled by CRL4-DCAF13-mediated polyubiquitination and proteasomal degradation, and FRAS1 can activate FAK signaling to promote cancer cell migration and proliferation [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the molecular cause of Fraser syndrome and the murine blebbed phenotype, defining FRAS1 as an ECM-related protein required for epithelial integrity.\",\n      \"evidence\": \"Autozygosity mapping and mutation analysis in human patients plus identification of premature termination in bl/bl mice, with protein domain analysis\",\n      \"pmids\": [\"12766769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve subcellular/ultrastructural localization\", \"Did not identify molecular partners or trafficking machinery\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Localized Fras1 protein to the basal epithelial surface and tied its loss directly to subepidermal blistering and renal agenesis, linking molecular site to phenotype.\",\n      \"evidence\": \"Immunolocalization in embryonic mouse tissues and knockout/bl-mutant phenotype analysis\",\n      \"pmids\": [\"12766770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of basal targeting unknown\", \"Whether Fras1 acts alone or in a complex not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified GRIP1 as the cytoplasmic scaffold required to deliver Fras1 to the basal cell surface, explaining a genetically distinct route to Fraser-like phenotypes.\",\n      \"evidence\": \"Co-immunoprecipitation of GRIP1 with Fras1, genetic analysis of the eb mouse, and loss-of-function phenotyping\",\n      \"pmids\": [\"14730302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction not defined\", \"Trafficking step (export vs. surface retention) not pinpointed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the Fras1/Frem1/Frem2 ternary complex and its reciprocal stabilization, establishing that the three proteins act as an interdependent unit in the basement membrane.\",\n      \"evidence\": \"Immunofluorescence across multiple Fraser-model mouse mutants and transfection/secretion assays demonstrating complex formation\",\n      \"pmids\": [\"16880404\", \"17240369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and binding interfaces of the complex not determined\", \"Extracellular receptor/anchor on the mesenchymal side unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the atomic basis of FRAS1 recognition by GRIP1, showing PDZ1-PDZ2 act as a single supramodule with PDZ1 dependent on PDZ2 for folding and ligand binding.\",\n      \"evidence\": \"Crystal structure of GRIP1 PDZ12 in complex with the Fras1 C-terminal peptide plus domain folding analysis\",\n      \"pmids\": [\"18155042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how the complex transits to the cell surface\", \"In vivo consequence of disrupting the specific interface not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed FRAS1 ultrastructurally in the sublamina densa attached to anchoring fibrils and near mesenchyme, providing a physical model for epithelial-mesenchymal linkage.\",\n      \"evidence\": \"Pre-embedding immunoelectron microscopy in multiple embryonic mouse epithelia\",\n      \"pmids\": [\"17576586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular identity of the mesenchymal anchoring partner not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed FRAS1 is needed for intracellular export of FREM2 and that FREM3 anchors independently, separating Fras1-dependent from Fras1-independent basement membrane assembly.\",\n      \"evidence\": \"Immunofluorescence of Frem2 and Frem3 in Fras1-null versus wild-type embryonic skin\",\n      \"pmids\": [\"17596926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking mechanism by which Fras1 promotes Frem2 export unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked FRAS1 adhesive function to kidney organogenesis, showing ureteric bud invasion failure correlates with reduced GDNF/GDF11 and is rescued by these growth factors.\",\n      \"evidence\": \"bl/bl mouse and organ-culture rescue with GDNF/GDF11, plus expression and immunolocalization analysis\",\n      \"pmids\": [\"18787044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How adhesion defects feed into growth factor expression not mechanistically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated tissue-autonomous and locally required roles for fras1 in endoderm-driven pharyngeal morphogenesis and in glomerular maturation, broadening its organogenetic reach.\",\n      \"evidence\": \"Zebrafish mutant analysis with cell transplantation, and podocyte-specific conditional Fras1 deletion in mice\",\n      \"pmids\": [\"22782724\", \"22730198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors in pharyngeal/glomerular contexts not fully resolved\", \"Single labs\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected FRAS1-dependent adhesion to developmental signaling, showing syndactyly arises from failed BMP/Msx2-driven interdigital cell death and that fras1 cooperates with itga8 in craniofacial morphogenesis within a defined time window.\",\n      \"evidence\": \"Fras1(rdf) mouse with BMP/Msx2 in situ analysis, and zebrafish fras1/itga8 double-mutant and revertible-allele genetics\",\n      \"pmids\": [\"26813283\", \"27265864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular bridge from adhesion to BMP signal transmission not established\", \"ITGA8-FRAS1 physical interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FRAS1 function beyond classical Fraser phenotypes to brain ECM organization and cognition, implicating it in perineuronal-net-type matrix integrity and behavior.\",\n      \"evidence\": \"Expression mapping, behavioral testing of Fras1-/- mice, and WFA immunolabeling of cortical/subcortical ECM\",\n      \"pmids\": [\"32333816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role of Fras1 in brain ECM not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-translational control of FRAS1 by CRL4-DCAF13-mediated ubiquitination/degradation and a pro-tumorigenic FAK-activating output in cancer cells.\",\n      \"evidence\": \"DCAF13 CRISPR knockout, polyubiquitination and proteasomal degradation assays, and migration/proliferation assays with FAK Western blots\",\n      \"pmids\": [\"39367995\", \"25126166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FAK activation mechanism by an ECM protein not detailed\", \"Cancer cell-line context may not reflect canonical developmental function\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the FRAS1/FREM ternary complex physically bridges the sublamina densa to mesenchymal receptors, and how FRAS1 abundance and signaling are integrated to control adhesion versus migration, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mesenchymal receptor for the anchoring cords unidentified\", \"No structural model of the full Fras1/Frem1/Frem2 complex\", \"Mechanistic basis of FRAS1-driven FAK activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 3, 5, 16]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 5, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"Fras1/Frem1/Frem2 ternary complex (Fraser complex / anchoring cords)\"],\n    \"partners\": [\"FREM1\", \"FREM2\", \"GRIP1\", \"DCAF13\", \"ITGA8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}