{"gene":"TMIGD1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"TMIGD1 is a cell adhesion molecule expressed in renal tubular epithelial cells whose extracellular domain mediates self-dimerization (homophilic interaction); it regulates transepithelial electric resistance, paracellular permeability, cell migration, and cell morphology, and protects renal epithelial cells from oxidative- and nutrient-deprivation-induced cell injury. Hydrogen peroxide-induced oxidative stress downregulates TMIGD1 expression and targets it for ubiquitination.","method":"Cell-based adhesion assays, transepithelial electrical resistance (TEER) measurements, permeability assays, migration assays, overexpression/knockdown in renal epithelial cell lines, ubiquitination assays, acute kidney injury and hypertensive kidney disease mouse models","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cell-based assays and in vivo models in a single lab; no in vitro reconstitution or structural validation of dimerization","pmids":["26342724"],"is_preprint":false},{"year":2017,"finding":"TMIGD1 acts as a tumor suppressor in renal cancer. C/EBPβ/LAP is a key transcriptional regulator that physically interacts with the TMIGD1 promoter and drives its expression; loss of C/EBPβ/LAP is responsible for TMIGD1 downregulation in RCC. Re-expression of TMIGD1 in renal tumor cells stimulates p38 MAPK phosphorylation and induces expression of cell-cycle inhibitors p21CIP1 and p27KIP1, inhibiting tumor growth and metastatic behaviors.","method":"Promoter activity assays, co-immunoprecipitation of C/EBPβ with TMIGD1 promoter, overexpression of TMIGD1 in renal tumor cell lines, Western blot for p38/p21/p27, migration and morphogenic branching assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (promoter assay, Co-IP, functional cell assays) in single lab; no structural or in vitro reconstitution data","pmids":["29515762"],"is_preprint":false},{"year":2020,"finding":"TMIGD1 localizes to mitochondria in subconfluent renal epithelial cells and to cell-cell contacts in confluent cells; this cell-confluency-regulated localization is modulated by N-glycosylation. Both the extracellular and cytoplasmic domains contribute to cell-cell contact localization. SYNJ2BP (a PDZ-domain-containing mitochondrial outer membrane protein) is a direct interaction partner of TMIGD1; the interaction is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1, and SYNJ2BP can actively recruit TMIGD1 to mitochondria.","method":"Subcellular fractionation, immunofluorescence/confocal microscopy, glycosylation inhibition, co-immunoprecipitation, domain-deletion/mutation analysis, confocal co-localization","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and domain mutagenesis, direct localization experiments, single lab with multiple orthogonal methods","pmids":["32303178"],"is_preprint":false},{"year":2021,"finding":"TMIGD1 binds directly to ERM family proteins moesin and ezrin via an evolutionarily conserved RRKK motif on its C-terminus interacting with the N-terminal ERM domains. TMIGD1 governs the apical localization of moesin and ezrin in epithelial cells (loss of TMIGD1 in mice alters this localization). TMIGD1 inhibits moesin-induced filopodia-like protrusions and cell migration. TMIGD1 stimulates Lys40 acetylation of α-tubulin and promotes mitotic spindle organization; CRISPR/Cas9 knockout of moesin impairs TMIGD1-mediated α-tubulin acetylation and F-actin organization.","method":"Co-immunoprecipitation, domain-deletion/mutagenesis (RRKK motif), in vivo mouse knockout of TMIGD1, CRISPR/Cas9 knockout of moesin, immunofluorescence for moesin/ezrin localization, acetylated α-tubulin Western blot, migration assays, filopodia quantification","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with mutagenesis of binding motif, CRISPR KO functional epistasis, in vivo mouse localization data, and multiple orthogonal readouts in a single study","pmids":["34503512"],"is_preprint":false},{"year":2021,"finding":"TMIGD1 overexpression in peritoneal mesothelial cells protects against H2O2-induced oxidative stress injury by preserving mitochondrial function (assessed by JC-1 mitochondrial membrane potential, ROS/MDA levels, and transmission electron microscopy), reduces mesothelial cell apoptosis, and enhances mesothelial cell adhesion, thereby inhibiting postoperative abdominal adhesion formation in mice.","method":"TMIGD1-overexpressing cell line, MTT/apoptosis assays, ROS/MDA assays, JC-1 mitochondrial staining, immunofluorescence, transmission electron microscopy, scratch-wound/adhesion assays, in vivo mouse adhesion model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional, mitochondrial, in vivo), single lab","pmids":["34426761"],"is_preprint":false},{"year":2022,"finding":"TMIGD1 forms an intermicrovillar adhesion complex at the proximal base region of intestinal microvilli (distinct from the protocadherin-based tip complex). TMIGD1 directly interacts with microvillar scaffolding proteins EBP50 and E3KARP. Complex formation with EBP50 requires ezrin-mediated EBP50 activation and is enhanced by dephosphorylation of Ser162 in the PDZ2 domain of EBP50 by phosphatase PP1α. Binding of the EBP50-ezrin complex to TMIGD1 enhances the dynamic turnover of EBP50 at microvilli. Enterocyte-specific inactivation of Tmigd1 in mice causes microvillar blebbing, loss of intermicrovillar adhesion, and perturbed brush border formation.","method":"Co-immunoprecipitation, pulldown assays, phosphatase (PP1α) treatment, FRAP for EBP50 dynamics, enterocyte-specific Tmigd1 knockout mice, confocal and electron microscopy","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assays, phosphorylation-state manipulation, FRAP, enterocyte-specific KO mouse with defined ultrastructural phenotype; multiple orthogonal methods","pmids":["36099341"],"is_preprint":false},{"year":2023,"finding":"TMIGD1 directly interacts with cytoplasmic BAF nuclear assembly factor 1 (BANF1) and inhibits NF-κB activation. Knockdown of TMIGD1 in intestinal epithelial cells increases paracellular permeability, reduces TEER and apical junction complex expression, and induces pro-inflammatory cytokine production. Exogenous expression of TMIGD1 and BANF1 restores intestinal barrier function and inhibits inflammation both in vitro and in vivo. Intestinal-specific Tmigd1 knockout mice are more susceptible to chemically induced colitis.","method":"Co-immunoprecipitation, GST pull-down assays, mass spectrometry, TEER/permeability assays, organoid cultures, intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice, cytokine measurements, transcriptome/proteomics analysis","journal":"BMC medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding confirmed by Co-IP and GST pulldown, in vivo KO mouse, organoids, multiple orthogonal methods in a single study","pmids":["37542259"],"is_preprint":false},{"year":2023,"finding":"TMIGD1 directly interacts with the polarity protein Scribble (Scrib) through a PDZ domain-mediated interaction and recruits Scrib to the lateral membrane domain in epithelial cells. The crystal structure of the TMIGD1 C-terminal peptide complexed with PDZ domain 1 of Scrib was determined, defining the structural basis of the interaction. TMIGD1 thus serves as a membrane anchor for Scrib.","method":"Co-immunoprecipitation, direct binding assays characterizing all four Scrib PDZ domains, X-ray crystallography (crystal structure of TMIGD1 C-terminal peptide with Scrib PDZ1), confocal immunofluorescence of membrane localization","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation of PDZ domain specificity and membrane recruitment, multiple orthogonal methods","pmids":["37430142"],"is_preprint":false},{"year":2023,"finding":"Macrophage-derived exosomal miR-223 targets TMIGD1 mRNA and inhibits its expression, promoting intestinal barrier dysfunction in DSS-induced colitis. Upregulated exosomal miR-223 from LPS-stimulated macrophages exacerbates colitis in vivo; this was verified using mouse and human colon organoids co-cultured with macrophages.","method":"miRNA sequencing of macrophage-derived exosomes, lentiviral miR-223 overexpression/inhibition, DSS-induced mouse colitis model, mouse and human organoid co-culture with macrophages in Transwell system, qPCR/Western blot for TMIGD1","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA target validated in vivo and in organoids, multiple systems, single lab","pmids":["37301121"],"is_preprint":false},{"year":2020,"finding":"TMIGD1 localizes to the apical microvilli of well-differentiated enterocytes (but not intestinal crypt cells), and this apical localization is reduced in noninflamed and nearly absent in inflamed CD mucosa. Hypoxia decreases TMIGD1 expression in enterocyte-like cells in vitro.","method":"Immunofluorescence on surgical resection tissue and enterocyte-like cell cultures, whole transcriptome gene expression analysis, in vitro hypoxia experiments","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunofluorescence localization and hypoxia experiment in single study without mechanistic follow-up","pmids":["32508154"],"is_preprint":false}],"current_model":"TMIGD1 is an immunoglobulin superfamily cell adhesion molecule expressed in renal tubular and intestinal epithelial cells that forms a PDZ-domain-dependent intermicrovillar adhesion complex with EBP50/E3KARP and ezrin (regulated by PP1α-mediated dephosphorylation) to organize the intestinal brush border; its cytoplasmic RRKK motif binds ERM proteins moesin and ezrin to regulate their apical localization, suppress filopodia and cell migration, and promote α-tubulin K40 acetylation and mitotic spindle organization; its C-terminal PDZ-binding motif recruits polarity protein Scribble to the lateral membrane (crystal structure resolved) and engages mitochondria-associated SYNJ2BP; TMIGD1 directly binds BANF1 to suppress NF-κB-driven inflammation and barrier dysfunction; it is transcriptionally driven by C/EBPβ/LAP and suppresses tumor growth via p38 MAPK/p21CIP1/p27KIP1 signaling; oxidative stress ubiquitinates and degrades TMIGD1, and macrophage exosomal miR-223 targets TMIGD1 mRNA to exacerbate intestinal barrier dysfunction."},"narrative":{"mechanistic_narrative":"TMIGD1 is an immunoglobulin-superfamily cell adhesion molecule of renal tubular and intestinal epithelial cells that organizes the apical brush border and stabilizes epithelial barrier integrity through homophilic adhesion and PDZ/ERM-dependent scaffolding [PMID:26342724, PMID:36099341]. Its extracellular domain mediates self-dimerization and supports transepithelial resistance, paracellular barrier function, and resistance to oxidative and nutrient-deprivation injury [PMID:26342724]. At the proximal base of intestinal microvilli, TMIGD1 nucleates an intermicrovillar adhesion complex by binding the scaffolding proteins EBP50 and E3KARP, a complex whose assembly requires ezrin-mediated EBP50 activation and PP1α-dependent dephosphorylation of EBP50 Ser162; loss of TMIGD1 in enterocytes causes microvillar blebbing and defective brush border formation [PMID:36099341]. Independently, a conserved cytoplasmic RRKK motif binds the N-terminal domains of the ERM proteins moesin and ezrin to direct their apical localization, suppress filopodia and migration, and promote α-tubulin Lys40 acetylation and mitotic spindle organization [PMID:34503512]. The C-terminal PDZ-binding motif recruits the polarity protein Scribble to the lateral membrane—an interaction defined at atomic resolution with Scrib PDZ1—and also engages the mitochondrial outer-membrane protein SYNJ2BP, consistent with confluency-dependent partitioning of TMIGD1 between cell-cell contacts and mitochondria [PMID:37430142, PMID:32303178]. In barrier defense, TMIGD1 binds BANF1 to suppress NF-κB activation and inflammation, and its enterocyte-specific deletion sensitizes mice to colitis [PMID:37542259]. TMIGD1 acts as a tumor suppressor downstream of the transcription factor C/EBPβ/LAP, driving p38 MAPK signaling and induction of the cell-cycle inhibitors p21CIP1 and p27KIP1 [PMID:29515762]. Its abundance is negatively controlled by oxidative-stress-induced ubiquitination and by macrophage exosomal miR-223 targeting its mRNA [PMID:26342724, PMID:37301121].","teleology":[{"year":2015,"claim":"Established TMIGD1 as a functional epithelial adhesion molecule rather than an orphan Ig-domain protein by showing it self-dimerizes and controls barrier and migratory properties.","evidence":"Adhesion, TEER, permeability, and migration assays with overexpression/knockdown plus ubiquitination assays and kidney injury mouse models","pmids":["26342724"],"confidence":"Medium","gaps":["Homophilic dimerization not validated by in vitro reconstitution or structure","Ubiquitination machinery (E3 ligase) not identified"]},{"year":2017,"claim":"Placed TMIGD1 in a growth-suppressive program by identifying its upstream transcriptional driver C/EBPβ/LAP and downstream p38 MAPK/p21/p27 axis in renal cancer.","evidence":"Promoter activity and Co-IP at the TMIGD1 promoter, re-expression in RCC cell lines, p38/p21/p27 Western blots, migration and branching assays","pmids":["29515762"],"confidence":"Medium","gaps":["Mechanistic link between adhesion function and p38 signaling unresolved","No in vivo tumor genetics"]},{"year":2020,"claim":"Revealed confluency- and glycosylation-dependent dual targeting of TMIGD1 to mitochondria and cell-cell contacts and identified SYNJ2BP as the mitochondrial anchor.","evidence":"Subcellular fractionation, glycosylation inhibition, reciprocal Co-IP, domain mutagenesis, confocal co-localization","pmids":["32303178"],"confidence":"Medium","gaps":["Functional consequence of mitochondrial localization not defined","How confluency triggers relocalization unknown"]},{"year":2020,"claim":"Connected TMIGD1 to human disease by showing its apical enterocyte localization is lost in inflamed Crohn's disease mucosa and downregulated by hypoxia.","evidence":"Immunofluorescence on resection tissue, whole-transcriptome analysis, in vitro hypoxia","pmids":["32508154"],"confidence":"Low","gaps":["Descriptive localization without mechanistic follow-up","Causality between TMIGD1 loss and inflammation not tested here"]},{"year":2021,"claim":"Defined the cytoplasmic effector mechanism: TMIGD1 binds moesin/ezrin via an RRKK motif to control apical ERM localization, suppress filopodia/migration, and drive α-tubulin acetylation and spindle organization.","evidence":"Reciprocal Co-IP with RRKK mutagenesis, TMIGD1 mouse knockout localization, moesin CRISPR knockout epistasis, acetylated tubulin and migration readouts","pmids":["34503512"],"confidence":"High","gaps":["Mechanism linking ERM binding to tubulin acetylation not resolved","Relevant tubulin acetyltransferase not identified"]},{"year":2021,"claim":"Extended TMIGD1's cytoprotective role beyond kidney by showing it preserves mitochondrial function and reduces apoptosis under oxidative stress in mesothelial cells.","evidence":"Overexpression with JC-1, ROS/MDA, TEM, apoptosis and adhesion assays, in vivo abdominal adhesion model","pmids":["34426761"],"confidence":"Medium","gaps":["Molecular pathway linking TMIGD1 to mitochondrial protection unclear","Whether SYNJ2BP mediates this effect untested"]},{"year":2022,"claim":"Resolved the brush-border assembly mechanism: TMIGD1 forms a basal intermicrovillar adhesion complex with EBP50/E3KARP requiring ezrin activation and PP1α-mediated EBP50 dephosphorylation.","evidence":"Co-IP, pulldowns, PP1α phosphatase treatment, FRAP, enterocyte-specific Tmigd1 knockout mice with ultrastructural phenotype","pmids":["36099341"],"confidence":"High","gaps":["Spatial coupling between basal TMIGD1 complex and tip protocadherin complex unknown","Upstream signals controlling PP1α activity here undefined"]},{"year":2023,"claim":"Provided the structural basis for TMIGD1 as a lateral-membrane anchor for the polarity machinery via its PDZ-binding motif engaging Scribble PDZ1.","evidence":"Co-IP, binding assays across all four Scrib PDZ domains, X-ray crystallography of the TMIGD1 peptide–Scrib PDZ1 complex, confocal localization","pmids":["37430142"],"confidence":"High","gaps":["Functional consequence of Scrib mislocalization in TMIGD1-null cells not quantified","Competition between SYNJ2BP and Scrib for the same C-terminal motif not addressed"]},{"year":2023,"claim":"Identified an anti-inflammatory mechanism: TMIGD1 binds BANF1 to inhibit NF-κB and maintain barrier integrity, with knockout mice sensitized to colitis.","evidence":"Co-IP, GST pulldown, mass spectrometry, TEER/permeability, organoids, intestinal-specific Tmigd1 knockout mice, cytokine and omics profiling","pmids":["37542259"],"confidence":"High","gaps":["How cytoplasmic BANF1 interaction translates to NF-κB suppression mechanistically unclear","Relationship to its junctional adhesion role not integrated"]},{"year":2023,"claim":"Showed TMIGD1 is post-transcriptionally repressed by macrophage exosomal miR-223, linking immune signaling to epithelial barrier loss in colitis.","evidence":"Exosomal miRNA sequencing, lentiviral miR-223 manipulation, DSS colitis model, mouse and human organoid–macrophage co-culture","pmids":["37301121"],"confidence":"Medium","gaps":["Direct miR-223 binding site on TMIGD1 mRNA not mapped","Quantitative contribution relative to transcriptional and ubiquitin control unknown"]},{"year":null,"claim":"How TMIGD1's distinct interaction modules (homophilic adhesion, EBP50/ERM scaffolding, Scribble/SYNJ2BP PDZ engagement, BANF1/NF-κB control) are coordinated within a single cell, and whether any human Mendelian phenotype results from TMIGD1 loss, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model of how one C-terminal PDZ motif partitions among competing partners","No germline human genetic disease association in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]}],"complexes":["intermicrovillar adhesion complex (TMIGD1-EBP50/E3KARP-ezrin)"],"partners":["EBP50","E3KARP","EZR","MSN","SCRIB","SYNJ2BP","BANF1","CEBPB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXZ0","full_name":"Transmembrane and immunoglobulin domain-containing protein 1","aliases":[],"length_aa":262,"mass_kda":29.2,"function":"May control cell-cell adhesion, cell migration and proliferation, cell morphology, and protects renal epithelial cells from oxidative cell injury to promote cell survival","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6UXZ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMIGD1","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMIGD1","total_profiled":1310},"omim":[{"mim_id":"621206","title":"TRANSMEMBRANE AND IMMUNOGLOBULIN DOMAINS-CONTAINING PROTEIN 1; TMIGD1","url":"https://www.omim.org/entry/621206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitochondria","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":132.3}],"url":"https://www.proteinatlas.org/search/TMIGD1"},"hgnc":{"alias_symbol":["UNQ9372"],"prev_symbol":["TMIGD"]},"alphafold":{"accession":"Q6UXZ0","domains":[{"cath_id":"2.60.40.10","chopping":"29-120","consensus_level":"high","plddt":92.9636,"start":29,"end":120},{"cath_id":"2.60.40.10","chopping":"123-214","consensus_level":"high","plddt":94.8455,"start":123,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXZ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXZ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXZ0-F1-predicted_aligned_error_v6.png","plddt_mean":87.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMIGD1","jax_strain_url":"https://www.jax.org/strain/search?query=TMIGD1"},"sequence":{"accession":"Q6UXZ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXZ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXZ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXZ0"}},"corpus_meta":[{"pmid":"37301121","id":"PMC_37301121","title":"Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37301121","citation_count":29,"is_preprint":false},{"pmid":"26342724","id":"PMC_26342724","title":"TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury.","date":"2015","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26342724","citation_count":28,"is_preprint":false},{"pmid":"37542259","id":"PMC_37542259","title":"Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease.","date":"2023","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37542259","citation_count":22,"is_preprint":false},{"pmid":"32303178","id":"PMC_32303178","title":"The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria.","date":"2020","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32303178","citation_count":21,"is_preprint":false},{"pmid":"29515762","id":"PMC_29515762","title":"TMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29515762","citation_count":18,"is_preprint":false},{"pmid":"32508154","id":"PMC_32508154","title":"Transcriptomic identification of TMIGD1 and its relationship with the ileal epithelial cell differentiation in Crohn's disease.","date":"2020","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32508154","citation_count":14,"is_preprint":false},{"pmid":"36099341","id":"PMC_36099341","title":"Intestinal brush border formation requires a TMIGD1-based intermicrovillar adhesion complex.","date":"2022","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/36099341","citation_count":14,"is_preprint":false},{"pmid":"34426761","id":"PMC_34426761","title":"TMIGD1 Inhibited Abdominal Adhesion Formation by Alleviating Oxidative Stress in the Mitochondria of Peritoneal Mesothelial Cells.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34426761","citation_count":13,"is_preprint":false},{"pmid":"34503512","id":"PMC_34503512","title":"The cell adhesion molecule TMIGD1 binds to moesin and regulates tubulin acetylation and cell migration.","date":"2021","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/34503512","citation_count":11,"is_preprint":false},{"pmid":"37087524","id":"PMC_37087524","title":"TMIGD1: Emerging functions of a tumor supressor and adhesion receptor.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37087524","citation_count":5,"is_preprint":false},{"pmid":"35481970","id":"PMC_35481970","title":"The Role of TMIGD1 as a Tumor Suppressor in Colorectal Cancer.","date":"2022","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/35481970","citation_count":5,"is_preprint":false},{"pmid":"37430142","id":"PMC_37430142","title":"Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37430142","citation_count":3,"is_preprint":false},{"pmid":"30305481","id":"PMC_30305481","title":"A new DNA marker of the TMIGD1 gene used to identify high fertilization rates in Tsaiya ducks (Anas platyrhynchos).","date":"2018","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/30305481","citation_count":2,"is_preprint":false},{"pmid":"29945164","id":"PMC_29945164","title":"A new method for detection of single nucleotide polymorphism in a female reproduction-associated gene, tmigd1, of Anas platyrhynchos using a strip biosensor with gold nanoparticles.","date":"2018","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/29945164","citation_count":1,"is_preprint":false},{"pmid":"41439483","id":"PMC_41439483","title":"Human TMIGD1 Promoter Exhibits Robust Activity in Prokaryotic Cells.","date":"2025","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41439483","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9758,"output_tokens":3438,"usd":0.040422,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11073,"output_tokens":3975,"usd":0.07737,"stage2_stop_reason":"end_turn"},"total_usd":0.117792,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"TMIGD1 is a cell adhesion molecule expressed in renal tubular epithelial cells whose extracellular domain mediates self-dimerization (homophilic interaction); it regulates transepithelial electric resistance, paracellular permeability, cell migration, and cell morphology, and protects renal epithelial cells from oxidative- and nutrient-deprivation-induced cell injury. Hydrogen peroxide-induced oxidative stress downregulates TMIGD1 expression and targets it for ubiquitination.\",\n      \"method\": \"Cell-based adhesion assays, transepithelial electrical resistance (TEER) measurements, permeability assays, migration assays, overexpression/knockdown in renal epithelial cell lines, ubiquitination assays, acute kidney injury and hypertensive kidney disease mouse models\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cell-based assays and in vivo models in a single lab; no in vitro reconstitution or structural validation of dimerization\",\n      \"pmids\": [\"26342724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMIGD1 acts as a tumor suppressor in renal cancer. C/EBPβ/LAP is a key transcriptional regulator that physically interacts with the TMIGD1 promoter and drives its expression; loss of C/EBPβ/LAP is responsible for TMIGD1 downregulation in RCC. Re-expression of TMIGD1 in renal tumor cells stimulates p38 MAPK phosphorylation and induces expression of cell-cycle inhibitors p21CIP1 and p27KIP1, inhibiting tumor growth and metastatic behaviors.\",\n      \"method\": \"Promoter activity assays, co-immunoprecipitation of C/EBPβ with TMIGD1 promoter, overexpression of TMIGD1 in renal tumor cell lines, Western blot for p38/p21/p27, migration and morphogenic branching assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (promoter assay, Co-IP, functional cell assays) in single lab; no structural or in vitro reconstitution data\",\n      \"pmids\": [\"29515762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMIGD1 localizes to mitochondria in subconfluent renal epithelial cells and to cell-cell contacts in confluent cells; this cell-confluency-regulated localization is modulated by N-glycosylation. Both the extracellular and cytoplasmic domains contribute to cell-cell contact localization. SYNJ2BP (a PDZ-domain-containing mitochondrial outer membrane protein) is a direct interaction partner of TMIGD1; the interaction is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1, and SYNJ2BP can actively recruit TMIGD1 to mitochondria.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence/confocal microscopy, glycosylation inhibition, co-immunoprecipitation, domain-deletion/mutation analysis, confocal co-localization\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and domain mutagenesis, direct localization experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32303178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMIGD1 binds directly to ERM family proteins moesin and ezrin via an evolutionarily conserved RRKK motif on its C-terminus interacting with the N-terminal ERM domains. TMIGD1 governs the apical localization of moesin and ezrin in epithelial cells (loss of TMIGD1 in mice alters this localization). TMIGD1 inhibits moesin-induced filopodia-like protrusions and cell migration. TMIGD1 stimulates Lys40 acetylation of α-tubulin and promotes mitotic spindle organization; CRISPR/Cas9 knockout of moesin impairs TMIGD1-mediated α-tubulin acetylation and F-actin organization.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion/mutagenesis (RRKK motif), in vivo mouse knockout of TMIGD1, CRISPR/Cas9 knockout of moesin, immunofluorescence for moesin/ezrin localization, acetylated α-tubulin Western blot, migration assays, filopodia quantification\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with mutagenesis of binding motif, CRISPR KO functional epistasis, in vivo mouse localization data, and multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"34503512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMIGD1 overexpression in peritoneal mesothelial cells protects against H2O2-induced oxidative stress injury by preserving mitochondrial function (assessed by JC-1 mitochondrial membrane potential, ROS/MDA levels, and transmission electron microscopy), reduces mesothelial cell apoptosis, and enhances mesothelial cell adhesion, thereby inhibiting postoperative abdominal adhesion formation in mice.\",\n      \"method\": \"TMIGD1-overexpressing cell line, MTT/apoptosis assays, ROS/MDA assays, JC-1 mitochondrial staining, immunofluorescence, transmission electron microscopy, scratch-wound/adhesion assays, in vivo mouse adhesion model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional, mitochondrial, in vivo), single lab\",\n      \"pmids\": [\"34426761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMIGD1 forms an intermicrovillar adhesion complex at the proximal base region of intestinal microvilli (distinct from the protocadherin-based tip complex). TMIGD1 directly interacts with microvillar scaffolding proteins EBP50 and E3KARP. Complex formation with EBP50 requires ezrin-mediated EBP50 activation and is enhanced by dephosphorylation of Ser162 in the PDZ2 domain of EBP50 by phosphatase PP1α. Binding of the EBP50-ezrin complex to TMIGD1 enhances the dynamic turnover of EBP50 at microvilli. Enterocyte-specific inactivation of Tmigd1 in mice causes microvillar blebbing, loss of intermicrovillar adhesion, and perturbed brush border formation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, phosphatase (PP1α) treatment, FRAP for EBP50 dynamics, enterocyte-specific Tmigd1 knockout mice, confocal and electron microscopy\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assays, phosphorylation-state manipulation, FRAP, enterocyte-specific KO mouse with defined ultrastructural phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"36099341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMIGD1 directly interacts with cytoplasmic BAF nuclear assembly factor 1 (BANF1) and inhibits NF-κB activation. Knockdown of TMIGD1 in intestinal epithelial cells increases paracellular permeability, reduces TEER and apical junction complex expression, and induces pro-inflammatory cytokine production. Exogenous expression of TMIGD1 and BANF1 restores intestinal barrier function and inhibits inflammation both in vitro and in vivo. Intestinal-specific Tmigd1 knockout mice are more susceptible to chemically induced colitis.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down assays, mass spectrometry, TEER/permeability assays, organoid cultures, intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice, cytokine measurements, transcriptome/proteomics analysis\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding confirmed by Co-IP and GST pulldown, in vivo KO mouse, organoids, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"37542259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMIGD1 directly interacts with the polarity protein Scribble (Scrib) through a PDZ domain-mediated interaction and recruits Scrib to the lateral membrane domain in epithelial cells. The crystal structure of the TMIGD1 C-terminal peptide complexed with PDZ domain 1 of Scrib was determined, defining the structural basis of the interaction. TMIGD1 thus serves as a membrane anchor for Scrib.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays characterizing all four Scrib PDZ domains, X-ray crystallography (crystal structure of TMIGD1 C-terminal peptide with Scrib PDZ1), confocal immunofluorescence of membrane localization\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation of PDZ domain specificity and membrane recruitment, multiple orthogonal methods\",\n      \"pmids\": [\"37430142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Macrophage-derived exosomal miR-223 targets TMIGD1 mRNA and inhibits its expression, promoting intestinal barrier dysfunction in DSS-induced colitis. Upregulated exosomal miR-223 from LPS-stimulated macrophages exacerbates colitis in vivo; this was verified using mouse and human colon organoids co-cultured with macrophages.\",\n      \"method\": \"miRNA sequencing of macrophage-derived exosomes, lentiviral miR-223 overexpression/inhibition, DSS-induced mouse colitis model, mouse and human organoid co-culture with macrophages in Transwell system, qPCR/Western blot for TMIGD1\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA target validated in vivo and in organoids, multiple systems, single lab\",\n      \"pmids\": [\"37301121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMIGD1 localizes to the apical microvilli of well-differentiated enterocytes (but not intestinal crypt cells), and this apical localization is reduced in noninflamed and nearly absent in inflamed CD mucosa. Hypoxia decreases TMIGD1 expression in enterocyte-like cells in vitro.\",\n      \"method\": \"Immunofluorescence on surgical resection tissue and enterocyte-like cell cultures, whole transcriptome gene expression analysis, in vitro hypoxia experiments\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunofluorescence localization and hypoxia experiment in single study without mechanistic follow-up\",\n      \"pmids\": [\"32508154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMIGD1 is an immunoglobulin superfamily cell adhesion molecule expressed in renal tubular and intestinal epithelial cells that forms a PDZ-domain-dependent intermicrovillar adhesion complex with EBP50/E3KARP and ezrin (regulated by PP1α-mediated dephosphorylation) to organize the intestinal brush border; its cytoplasmic RRKK motif binds ERM proteins moesin and ezrin to regulate their apical localization, suppress filopodia and cell migration, and promote α-tubulin K40 acetylation and mitotic spindle organization; its C-terminal PDZ-binding motif recruits polarity protein Scribble to the lateral membrane (crystal structure resolved) and engages mitochondria-associated SYNJ2BP; TMIGD1 directly binds BANF1 to suppress NF-κB-driven inflammation and barrier dysfunction; it is transcriptionally driven by C/EBPβ/LAP and suppresses tumor growth via p38 MAPK/p21CIP1/p27KIP1 signaling; oxidative stress ubiquitinates and degrades TMIGD1, and macrophage exosomal miR-223 targets TMIGD1 mRNA to exacerbate intestinal barrier dysfunction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMIGD1 is an immunoglobulin-superfamily cell adhesion molecule of renal tubular and intestinal epithelial cells that organizes the apical brush border and stabilizes epithelial barrier integrity through homophilic adhesion and PDZ/ERM-dependent scaffolding [#0, #5]. Its extracellular domain mediates self-dimerization and supports transepithelial resistance, paracellular barrier function, and resistance to oxidative and nutrient-deprivation injury [#0]. At the proximal base of intestinal microvilli, TMIGD1 nucleates an intermicrovillar adhesion complex by binding the scaffolding proteins EBP50 and E3KARP, a complex whose assembly requires ezrin-mediated EBP50 activation and PP1\\u03b1-dependent dephosphorylation of EBP50 Ser162; loss of TMIGD1 in enterocytes causes microvillar blebbing and defective brush border formation [#5]. Independently, a conserved cytoplasmic RRKK motif binds the N-terminal domains of the ERM proteins moesin and ezrin to direct their apical localization, suppress filopodia and migration, and promote \\u03b1-tubulin Lys40 acetylation and mitotic spindle organization [#3]. The C-terminal PDZ-binding motif recruits the polarity protein Scribble to the lateral membrane\\u2014an interaction defined at atomic resolution with Scrib PDZ1\\u2014and also engages the mitochondrial outer-membrane protein SYNJ2BP, consistent with confluency-dependent partitioning of TMIGD1 between cell-cell contacts and mitochondria [#7, #2]. In barrier defense, TMIGD1 binds BANF1 to suppress NF-\\u03baB activation and inflammation, and its enterocyte-specific deletion sensitizes mice to colitis [#6]. TMIGD1 acts as a tumor suppressor downstream of the transcription factor C/EBP\\u03b2/LAP, driving p38 MAPK signaling and induction of the cell-cycle inhibitors p21CIP1 and p27KIP1 [#1]. Its abundance is negatively controlled by oxidative-stress-induced ubiquitination and by macrophage exosomal miR-223 targeting its mRNA [#0, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established TMIGD1 as a functional epithelial adhesion molecule rather than an orphan Ig-domain protein by showing it self-dimerizes and controls barrier and migratory properties.\",\n      \"evidence\": \"Adhesion, TEER, permeability, and migration assays with overexpression/knockdown plus ubiquitination assays and kidney injury mouse models\",\n      \"pmids\": [\"26342724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homophilic dimerization not validated by in vitro reconstitution or structure\", \"Ubiquitination machinery (E3 ligase) not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TMIGD1 in a growth-suppressive program by identifying its upstream transcriptional driver C/EBP\\u03b2/LAP and downstream p38 MAPK/p21/p27 axis in renal cancer.\",\n      \"evidence\": \"Promoter activity and Co-IP at the TMIGD1 promoter, re-expression in RCC cell lines, p38/p21/p27 Western blots, migration and branching assays\",\n      \"pmids\": [\"29515762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between adhesion function and p38 signaling unresolved\", \"No in vivo tumor genetics\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed confluency- and glycosylation-dependent dual targeting of TMIGD1 to mitochondria and cell-cell contacts and identified SYNJ2BP as the mitochondrial anchor.\",\n      \"evidence\": \"Subcellular fractionation, glycosylation inhibition, reciprocal Co-IP, domain mutagenesis, confocal co-localization\",\n      \"pmids\": [\"32303178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of mitochondrial localization not defined\", \"How confluency triggers relocalization unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected TMIGD1 to human disease by showing its apical enterocyte localization is lost in inflamed Crohn's disease mucosa and downregulated by hypoxia.\",\n      \"evidence\": \"Immunofluorescence on resection tissue, whole-transcriptome analysis, in vitro hypoxia\",\n      \"pmids\": [\"32508154\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Descriptive localization without mechanistic follow-up\", \"Causality between TMIGD1 loss and inflammation not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the cytoplasmic effector mechanism: TMIGD1 binds moesin/ezrin via an RRKK motif to control apical ERM localization, suppress filopodia/migration, and drive \\u03b1-tubulin acetylation and spindle organization.\",\n      \"evidence\": \"Reciprocal Co-IP with RRKK mutagenesis, TMIGD1 mouse knockout localization, moesin CRISPR knockout epistasis, acetylated tubulin and migration readouts\",\n      \"pmids\": [\"34503512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ERM binding to tubulin acetylation not resolved\", \"Relevant tubulin acetyltransferase not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TMIGD1's cytoprotective role beyond kidney by showing it preserves mitochondrial function and reduces apoptosis under oxidative stress in mesothelial cells.\",\n      \"evidence\": \"Overexpression with JC-1, ROS/MDA, TEM, apoptosis and adhesion assays, in vivo abdominal adhesion model\",\n      \"pmids\": [\"34426761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking TMIGD1 to mitochondrial protection unclear\", \"Whether SYNJ2BP mediates this effect untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the brush-border assembly mechanism: TMIGD1 forms a basal intermicrovillar adhesion complex with EBP50/E3KARP requiring ezrin activation and PP1\\u03b1-mediated EBP50 dephosphorylation.\",\n      \"evidence\": \"Co-IP, pulldowns, PP1\\u03b1 phosphatase treatment, FRAP, enterocyte-specific Tmigd1 knockout mice with ultrastructural phenotype\",\n      \"pmids\": [\"36099341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial coupling between basal TMIGD1 complex and tip protocadherin complex unknown\", \"Upstream signals controlling PP1\\u03b1 activity here undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural basis for TMIGD1 as a lateral-membrane anchor for the polarity machinery via its PDZ-binding motif engaging Scribble PDZ1.\",\n      \"evidence\": \"Co-IP, binding assays across all four Scrib PDZ domains, X-ray crystallography of the TMIGD1 peptide\\u2013Scrib PDZ1 complex, confocal localization\",\n      \"pmids\": [\"37430142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Scrib mislocalization in TMIGD1-null cells not quantified\", \"Competition between SYNJ2BP and Scrib for the same C-terminal motif not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an anti-inflammatory mechanism: TMIGD1 binds BANF1 to inhibit NF-\\u03baB and maintain barrier integrity, with knockout mice sensitized to colitis.\",\n      \"evidence\": \"Co-IP, GST pulldown, mass spectrometry, TEER/permeability, organoids, intestinal-specific Tmigd1 knockout mice, cytokine and omics profiling\",\n      \"pmids\": [\"37542259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cytoplasmic BANF1 interaction translates to NF-\\u03baB suppression mechanistically unclear\", \"Relationship to its junctional adhesion role not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TMIGD1 is post-transcriptionally repressed by macrophage exosomal miR-223, linking immune signaling to epithelial barrier loss in colitis.\",\n      \"evidence\": \"Exosomal miRNA sequencing, lentiviral miR-223 manipulation, DSS colitis model, mouse and human organoid\\u2013macrophage co-culture\",\n      \"pmids\": [\"37301121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-223 binding site on TMIGD1 mRNA not mapped\", \"Quantitative contribution relative to transcriptional and ubiquitin control unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMIGD1's distinct interaction modules (homophilic adhesion, EBP50/ERM scaffolding, Scribble/SYNJ2BP PDZ engagement, BANF1/NF-\\u03baB control) are coordinated within a single cell, and whether any human Mendelian phenotype results from TMIGD1 loss, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated model of how one C-terminal PDZ motif partitions among competing partners\", \"No germline human genetic disease association in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\"intermicrovillar adhesion complex (TMIGD1-EBP50/E3KARP-ezrin)\"],\n    \"partners\": [\"EBP50\", \"E3KARP\", \"EZR\", \"MSN\", \"SCRIB\", \"SYNJ2BP\", \"BANF1\", \"CEBPB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}