{"gene":"LLGL1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2017,"finding":"LLGL1 directly binds N-cadherin and promotes its internalization; this interaction is inhibited by aPKC-mediated phosphorylation of LLGL1, restricting accumulation of apical junctional complexes to the basolateral-apical boundary. Disruption of the N-cadherin–LLGL1 interaction during cortical development in vivo is sufficient to cause periventricular heterotopia.","method":"Co-immunoprecipitation, live cortical imaging, in vivo conditional knockout (Nestin-Cre/Llgl1fl/fl), rescue experiments with N-cadherin interaction mutants","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct binding, in vivo KO with defined cellular phenotype, and point-mutation disruption of interaction; multiple orthogonal methods in one rigorous study","pmids":["28552558"],"is_preprint":false},{"year":2024,"finding":"Human aPKCι-Par6α forms a stable tripartite complex with full-length LLGL1, captured via an aPKCι docking site and a Par6 PDZ contact. A phospho-S663 LLGL1 intermediate bridges aPKC and Par6, impeding phosphorylation progression. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation; disrupting the Lgl-Par6 PDZ contact promotes complex dissociation and completion of the Lgl phosphorylation cycle. Cdc42-GTP binding and the apical partner Crumbs drive complex disassembly.","method":"Cryo-EM/structural determination of tripartite complex, mutagenesis of docking and PDZ contact sites, in vitro phosphorylation assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure determination plus mutagenesis plus in vitro kinase assay; single preprint but multiple orthogonal methods","pmids":["bio_10.1101_2024.09.26.615224"],"is_preprint":true},{"year":2004,"finding":"Human HUGL-1 (LLGL1) functionally substitutes for Drosophila Lgl in vivo: expression in homozygous lgl Drosophila mutants rescues larval lethality, restores correct localization of Dlg and Scrib, and prevents neoplastic tissue features, demonstrating functional conservation within the Lgl-Dlg-Scrib tumor suppressor pathway.","method":"Transgenic rescue of Drosophila lgl homozygous mutants with human HUGL-1; immunolocalization of Dlg and Scrib","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic complementation in Drosophila with pathway marker localization; replicated conceptually across multiple labs","pmids":["15467749"],"is_preprint":false},{"year":2008,"finding":"LLGL1 (Hugl-1) is a component of the hScrib/hDlg/Hugl-1 complex; hScrib is required in part for correct localization of hDlg and Hugl-1. Under osmotic stress, hDlg and Hugl-1 can localize to cell membranes independently of hScrib. The complex interacts with the t-SNARE syntaxin 4, and correct localization of the Scrib complex is partially dependent on this t-SNARE, linking the complex to vesicle transport pathways.","method":"shRNA knockdown of hScrib, co-localization immunofluorescence, co-immunoprecipitation with syntaxin 4","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and KD with localization readout, two orthogonal methods, single lab","pmids":["18793635"],"is_preprint":false},{"year":2016,"finding":"Loss of Llgl1 causes EGFR mislocalization; an EGFR mislocalization point mutation (P667A) recapitulates Llgl1-loss phenotypes including AKT activation and TAZ nuclear translocation. Llgl1 loss drives EGFR-dependent mammosphere formation and survival, and Llgl1 regulates nuclear translocation of TAZ and Slug.","method":"Stable Llgl1 knockout cell lines, EGFR point mutation (P667A), mammosphere assay, soft-agar growth, orthotopic transplant, lineage tracing","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and point-mutation epistasis; single lab, multiple assays","pmids":["27542214"],"is_preprint":false},{"year":2020,"finding":"In zebrafish cardiomyocytes, Llgl1 depletion decreases Yap protein levels and blunts Yap target gene transcription without affecting Yap transcript abundance, indicating Llgl1 promotes Yap protein stability. Cardiomyocyte-specific overexpression of Yap in Llgl1-depleted embryos rescues pericardial effusion and blood flow, placing Llgl1 upstream of Yap in cardiomyocytes.","method":"Morpholino knockdown in zebrafish, Yap protein quantification by Western blot, cardiomyocyte-specific Yap overexpression rescue","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined phenotype, genetic rescue experiment placing Llgl1 upstream of Yap; single lab","pmids":["32843528"],"is_preprint":false},{"year":2020,"finding":"LLGL1 loss promotes oncostatin M receptor (OSMR) expression via phosphorylation of ERK2 and Sp1, with phosphorylated Sp1 (pThr453) binding the OSMR promoter to enhance transcription. Knockdown of OSMR rescues the gemcitabine-resistance phenotype caused by LLGL1 silencing.","method":"Genome-wide RNAi screen, gene-expression microarray, ChIP for Sp1 at OSMR promoter, OSMR knockdown rescue, cell proliferation and tumor formation assays","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, rescue KD, microarray) in single lab establishing pathway order","pmids":["32615164"],"is_preprint":false},{"year":2016,"finding":"USP11 deubiquitinates and stabilizes Mgl-1 (LLGL1) protein, preventing its proteasomal degradation. This stabilization requires RanBPM; USP11-mediated Mgl-1 stabilization is abolished in RanBPM-knockdown cells. USP11-mediated regulation of Mgl-1 also requires RanBPM for control of cancer cell migration.","method":"Ubiquitination assay (deubiquitinating activity of USP11), RanBPM knockdown, Western blot for Mgl-1 stability, cell migration assay, in vivo tumor formation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct deubiquitination assay plus epistasis via RanBPM KD; single lab, two orthogonal approaches","pmids":["26919101"],"is_preprint":false},{"year":2012,"finding":"Loss of Llgl1 in retinal neuroepithelia expands apical domains and increases Notch activity, reducing neurogenesis. Blocking Notch by depleting Rbpj restores normal neurogenesis. Experimental expansion of the apical domain via Shroom3 inhibition similarly increases Notch activity, placing Llgl1-controlled apical domain size upstream of Notch-dependent neurogenesis.","method":"Conditional Llgl1 knockout in zebrafish retina, Rbpj depletion epistasis, Shroom3 inhibition, interkinetic nuclear migration analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Rbpj rescue) plus pharmacological epistasis, single lab with multiple orthogonal approaches","pmids":["22492354"],"is_preprint":false},{"year":2006,"finding":"The WD-40 repeat motif of Mgl-1/LLGL1 is required for protein-protein interactions essential for cellular function: deletion mutants at conserved residues G450 and D453 within the WD-40 domain fail to complement yeast Sop1/Sop2 double mutants at restrictive temperature and high salt, while other deletion mutants in this region retain complementation ability.","method":"Site-directed mutagenesis of WD-40 residues, yeast complementation assay (temperature sensitivity and salt tolerance)","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional readout; single lab, single assay system","pmids":["16969496"],"is_preprint":false},{"year":2003,"finding":"Mouse Mgl-1 (ortholog of LLGL1) can partially restore salt tolerance in yeast lacking Sop1 and Sop2 (yeast lgl homologs), demonstrating evolutionary conservation of lgl family function.","method":"Yeast complementation assay (salt tolerance rescue)","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single heterologous complementation assay, single lab","pmids":["14612921"],"is_preprint":false},{"year":2023,"finding":"LLGL1 inactivation in AML results in loss of stemness-associated gene expression including HoxA genes and induces a GMP-like phenotype in leukemia stem cells; re-expression of HoxA9 functionally and phenotypically rescues LLGL1 loss, placing LLGL1 upstream of HoxA9 in AML stem cell maintenance.","method":"CRISPR/Cas9-based genetic screening, murine and human AML models, gene expression analysis, HoxA9 re-expression rescue","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined phenotype plus genetic rescue establishing pathway epistasis; conserved in human and murine models","pmids":["37587260"],"is_preprint":false},{"year":2023,"finding":"Combined ablation of Llgl1 and Llgl2 in mouse skin epidermis cooperates with Trp53 loss to cause squamous cell carcinoma, and is associated with activation of aPKC and upregulation of NF-κB signaling, placing Lgl signaling upstream of aPKC-NF-κB in epidermal tumor suppression.","method":"Conditional double knockout (K14-Cre/Llgl1fl/fl/Llgl2fl/fl) in mice, crossed with Trp53 cKO; aPKC activity assay, NF-κB pathway analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo double KO with cancer phenotype plus pathway activation analysis; preprint, single lab","pmids":["36945368"],"is_preprint":true},{"year":2024,"finding":"In zebrafish, Llgl1 is required for timely epicardial emergence and for correct deposition of laminin on the apical ventricular surface; llgl1 mutants show aberrant apical extrusion of cardiomyocytes and delayed epicardial cell emergence, resulting in delayed apical laminin deposition.","method":"Zebrafish llgl1 mutant analysis, epicardial lineage imaging, laminin immunofluorescence, epicardium-ablation experiments","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype; single lab, multiple tissue-level assays","pmids":["38940292"],"is_preprint":false},{"year":2005,"finding":"Re-expression of HUGL-1 in colorectal cancer cell lines increases cell adhesion and decreases cell migration, establishing a direct functional role for LLGL1 in these cellular processes.","method":"Ecdysone-inducible Hugl-1 expression in cancer cell lines, cell adhesion assay, cell migration assay","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with functional readouts; single lab, no pathway placement","pmids":["15735678"],"is_preprint":false},{"year":2006,"finding":"Re-expression of Hugl-1 in melanoma cells increases cell adhesion, decreases cell migration, downregulates MMP2 and MMP14, and induces re-expression of E-cadherin, supporting a role for LLGL1 in suppressing epithelial-mesenchymal transition.","method":"Stable Hugl-1 transfection in melanoma cell lines, adhesion and migration assays, Western blot for MMP2/MMP14/E-cadherin","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with functional readouts; single lab, limited mechanistic depth","pmids":["16170365"],"is_preprint":false}],"current_model":"LLGL1 is a basolateral polarity scaffold that is phosphorylated at multiple serine residues (including S663) by the apical aPKCι-Par6α complex, forming a transient tripartite capture complex whose release requires Cdc42-GTP and Crumbs; unphosphorylated LLGL1 binds N-cadherin to promote its internalization and restrict apical junctional complexes to the basolateral-apical boundary, while its WD-40 repeat domain mediates protein–protein interactions, its ubiquitination is countered by the deubiquitinase USP11 in a RanBPM-dependent manner, and in specific cellular contexts it stabilizes Yap protein in cardiomyocytes, maintains HoxA9-dependent stemness in AML, and suppresses EGFR/RAS/MAPK and NF-κB signaling to enforce epithelial identity and suppress tumorigenesis."},"narrative":{"mechanistic_narrative":"LLGL1 is an evolutionarily conserved basolateral polarity scaffold that enforces epithelial architecture and acts as a tumor suppressor within the Lgl-Dlg-Scrib polarity module, as established by its ability to functionally substitute for Drosophila Lgl in vivo to restore Dlg/Scrib localization and prevent neoplastic overgrowth [PMID:15467749]. Its activity is governed by a phospho-regulatory cycle: the apical aPKCι-Par6α complex captures full-length LLGL1 into a tripartite assembly via an aPKCι docking site and a Par6 PDZ contact, generating a phospho-S663 intermediate, with Cdc42-GTP and the apical determinant Crumbs driving complex disassembly to complete the phosphorylation cycle [PMID:bio_10.1101_2024.09.26.615224]. Phosphorylation by aPKC inhibits the direct binding of LLGL1 to N-cadherin, which in the unphosphorylated state drives N-cadherin internalization and restricts apical junctional complexes to the basolateral-apical boundary; disrupting this interaction during cortical development causes periventricular heterotopia [PMID:28552558]. LLGL1 functions through its WD-40 repeat domain, which mediates the protein-protein interactions required for its cellular function [PMID:16969496], and operates within a hScrib/hDlg/Hugl-1 complex that engages the t-SNARE syntaxin 4, linking polarity to vesicle transport [PMID:18793635]. LLGL1 protein levels are set post-translationally by USP11, which deubiquitinates and stabilizes LLGL1 in a RanBPM-dependent manner [PMID:26919101]. Loss of LLGL1 unleashes oncogenic signaling—EGFR mislocalization with downstream AKT and TAZ/Slug nuclear translocation [PMID:27542214], ERK2/Sp1-driven OSMR transcription conferring drug resistance [PMID:32615164], and aPKC-NF-κB activation cooperating with Trp53 loss to drive carcinoma [PMID:36945368]—while in context-specific roles it stabilizes Yap protein in cardiomyocytes [PMID:32843528] and sustains HoxA9-dependent stemness in AML [PMID:37587260].","teleology":[{"year":2003,"claim":"Establishing whether mammalian Lgl-family genes retain the ancestral function of their yeast and fly counterparts was the first step in attributing any conserved cellular role to LLGL1.","evidence":"Yeast complementation rescuing salt tolerance in Sop1/Sop2-deficient cells with mouse Mgl-1","pmids":["14612921"],"confidence":"Low","gaps":["Single heterologous complementation assay only","No molecular mechanism for the complemented function","Does not address mammalian-specific roles"]},{"year":2004,"claim":"It was unknown whether human LLGL1 operates in the same tumor-suppressive polarity pathway as Drosophila Lgl; cross-species genetic complementation placed it firmly within the Lgl-Dlg-Scrib module.","evidence":"Transgenic rescue of Drosophila lgl-null mutants with human HUGL-1, scoring lethality and Dlg/Scrib localization","pmids":["15467749"],"confidence":"High","gaps":["Does not identify the direct molecular partners of LLGL1 in mammals","Pathway placement inferred from fly markers, not mammalian biochemistry"]},{"year":2005,"claim":"Whether re-expressing LLGL1 in carcinoma cells reverses malignant behavior was tested to validate its tumor-suppressor function at the cellular level.","evidence":"Inducible HUGL-1 expression in colorectal cancer lines with adhesion and migration assays","pmids":["15735678"],"confidence":"Low","gaps":["Single overexpression experiment without pathway placement","No mechanism linking adhesion/migration change to a molecular target"]},{"year":2006,"claim":"The structural basis for LLGL1's protein interactions and its capacity to suppress EMT markers were addressed to connect domain architecture and phenotype.","evidence":"WD-40 residue mutagenesis with yeast complementation, and melanoma re-expression scoring E-cadherin/MMP levels","pmids":["16969496","16170365"],"confidence":"Medium","gaps":["WD-40 partners not identified","EMT marker changes are correlative, no direct binding shown","Melanoma data is overexpression-based, single lab"]},{"year":2008,"claim":"Defining the composition and dependencies of the mammalian Scrib polarity complex clarified how LLGL1 is positioned and linked it to membrane trafficking.","evidence":"hScrib shRNA knockdown with co-localization and syntaxin 4 co-immunoprecipitation","pmids":["18793635"],"confidence":"Medium","gaps":["Direct vs indirect LLGL1-syntaxin 4 contact not resolved","Functional consequence of the t-SNARE link not tested","Single lab"]},{"year":2012,"claim":"How LLGL1-controlled apical domain size feeds into developmental signaling was unknown; epistasis placed it upstream of Notch-dependent neurogenesis.","evidence":"Conditional Llgl1 knockout in zebrafish retina with Rbpj-depletion and Shroom3-inhibition epistasis","pmids":["22492354"],"confidence":"Medium","gaps":["Molecular link between apical domain expansion and Notch activation unresolved","Tissue-specific to retinal neuroepithelium"]},{"year":2016,"claim":"Two complementary mechanisms of LLGL1 regulation were defined: how its loss activates oncogenic EGFR signaling, and how its protein abundance is controlled post-translationally.","evidence":"Llgl1 knockout cells with EGFR P667A point mutant and mammosphere/transplant assays; USP11 deubiquitination assay with RanBPM knockdown epistasis","pmids":["27542214","26919101"],"confidence":"Medium","gaps":["Mechanism by which LLGL1 controls EGFR localization not defined","How RanBPM enables USP11 access to LLGL1 unknown","Single lab for each finding"]},{"year":2017,"claim":"The direct molecular substrate of LLGL1 polarity activity was identified, linking aPKC phosphorylation to N-cadherin trafficking and a defined developmental disease.","evidence":"Reciprocal Co-IP, live cortical imaging, conditional knockout, and N-cadherin interaction point mutants causing periventricular heterotopia","pmids":["28552558"],"confidence":"High","gaps":["Internalization machinery downstream of LLGL1-N-cadherin not detailed","Whether this mechanism operates in non-neural epithelia not tested"]},{"year":2020,"claim":"Context-specific signaling outputs of LLGL1 were established: Yap protein stabilization in cardiomyocytes and ERK2/Sp1-driven OSMR transcription conferring drug resistance.","evidence":"Zebrafish morpholino knockdown with cardiomyocyte Yap rescue; genome-wide RNAi screen with Sp1 ChIP at the OSMR promoter and OSMR knockdown rescue","pmids":["32843528","32615164"],"confidence":"Medium","gaps":["Mechanism by which LLGL1 stabilizes Yap protein unknown","How LLGL1 loss triggers ERK2/Sp1 phosphorylation not defined","Both context-specific, single lab each"]},{"year":2023,"claim":"LLGL1 was shown to have a stemness-maintaining role beyond classical polarity, and its loss to cooperate with Trp53 in carcinogenesis via aPKC-NF-κB.","evidence":"CRISPR screening in AML models with HoxA9 re-expression rescue; conditional Llgl1/Llgl2 double knockout crossed with Trp53 cKO in mouse epidermis","pmids":["37587260","36945368"],"confidence":"Medium","gaps":["Mechanism linking LLGL1 to HoxA gene expression unknown","Redundancy with Llgl2 complicates single-gene attribution","Epidermal study is a preprint"]},{"year":2024,"claim":"The atomic basis of LLGL1's phospho-regulatory cycle was resolved, and a new tissue-morphogenesis role in epicardial emergence and apical laminin deposition was defined.","evidence":"Cryo-EM of the aPKCι-Par6α-LLGL1 tripartite complex with docking/PDZ mutagenesis and in vitro kinase assays; zebrafish llgl1 mutant epicardial lineage imaging and laminin immunofluorescence","pmids":["bio_10.1101_2024.09.26.615224","38940292"],"confidence":"High","gaps":["Structural work is a preprint","Precise role of Cdc42-GTP/Crumbs in disassembly defined biochemically but not in tissue","Link between LLGL1 and laminin deposition mechanism unresolved"]},{"year":null,"claim":"How a single basolateral scaffold integrates its conserved polarity/N-cadherin function with the diverse downstream outputs (Yap, HoxA9, EGFR, OSMR, NF-κB) remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connecting polarity scaffolding to transcriptional/signaling outputs","Direct WD-40 domain interactome largely uncharacterized","Whether outputs are direct or secondary to polarity loss unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,8,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,6,12]}],"complexes":["aPKCι-Par6α-LLGL1 tripartite complex","hScrib/hDlg/Hugl-1 complex"],"partners":["PRKCI","PARD6A","CDH2","SCRIB","DLG1","STX4","USP11","RANBP9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15334","full_name":"Lethal(2) giant larvae protein homolog 1","aliases":["DLG4","Hugl-1","Human homolog to the D-lgl gene protein"],"length_aa":1064,"mass_kda":115.4,"function":"Cortical cytoskeleton protein found in a complex involved in maintaining cell polarity and epithelial integrity. Involved in the regulation of mitotic spindle orientation, proliferation, differentiation and tissue organization of neuroepithelial cells. Involved in axonogenesis through RAB10 activation thereby regulating vesicular membrane trafficking toward the axonal plasma membrane","subcellular_location":"Early endosome membrane; Golgi apparatus, trans-Golgi network membrane; Golgi apparatus membrane; Cell projection, axon; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q15334/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LLGL1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKCI","stoichiometry":10.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"VCL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LLGL1","total_profiled":1310},"omim":[{"mim_id":"620915","title":"MYOSIN XVB; MYO15B","url":"https://www.omim.org/entry/620915"},{"mim_id":"616062","title":"ANKYRIN REPEAT- AND LEM DOMAIN-CONTAINING PROTEIN 2; ANKLE2","url":"https://www.omim.org/entry/616062"},{"mim_id":"609381","title":"SYNTAXIN-BINDING PROTEIN 5-LIKE; STXBP5L","url":"https://www.omim.org/entry/609381"},{"mim_id":"601014","title":"DISCS LARGE MAGUK SCAFFOLD PROTEIN 1; DLG1","url":"https://www.omim.org/entry/601014"},{"mim_id":"600966","title":"LLGL SCRIBBLE CELL POLARITY COMPLEX COMPONENT 1; LLGL1","url":"https://www.omim.org/entry/600966"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":64.9}],"url":"https://www.proteinatlas.org/search/LLGL1"},"hgnc":{"alias_symbol":["Lgl1","Mgl1"],"prev_symbol":["DLG4","LLGL","HUGL","HUGL-1"]},"alphafold":{"accession":"Q15334","domains":[{"cath_id":"-","chopping":"15-34_855-951","consensus_level":"medium","plddt":95.1939,"start":15,"end":951},{"cath_id":"2.130.10.10","chopping":"136-254","consensus_level":"medium","plddt":90.6676,"start":136,"end":254},{"cath_id":"2.40.128","chopping":"35-121","consensus_level":"medium","plddt":93.9243,"start":35,"end":121},{"cath_id":"2.40.128","chopping":"293-310_321-386","consensus_level":"medium","plddt":93.0993,"start":293,"end":386}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15334","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15334-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15334-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LLGL1","jax_strain_url":"https://www.jax.org/strain/search?query=LLGL1"},"sequence":{"accession":"Q15334","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15334.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15334/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15334"}},"corpus_meta":[{"pmid":"15735678","id":"PMC_15735678","title":"Reduced 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journal of experimental and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26662669","citation_count":10,"is_preprint":false},{"pmid":"31906385","id":"PMC_31906385","title":"MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31906385","citation_count":10,"is_preprint":false},{"pmid":"33677516","id":"PMC_33677516","title":"Intestinal lamina propria macrophages upregulate interleukin-10 mRNA in response to signals from commensal bacteria recognized by MGL1/CD301a.","date":"2021","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/33677516","citation_count":10,"is_preprint":false},{"pmid":"32843528","id":"PMC_32843528","title":"Llgl1 regulates zebrafish cardiac development by mediating Yap stability in cardiomyocytes.","date":"2020","source":"Development (Cambridge, 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32222154","citation_count":5,"is_preprint":false},{"pmid":"37587260","id":"PMC_37587260","title":"Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia.","date":"2023","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/37587260","citation_count":3,"is_preprint":false},{"pmid":"14612921","id":"PMC_14612921","title":"Functional and expression analyses of mgl-1, a mouse orthologue of lethal giant larvae recessive oncogene.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/14612921","citation_count":3,"is_preprint":false},{"pmid":"36945368","id":"PMC_36945368","title":"Lethal giant larvae gene family ( Llgl1 and Llgl2 ) functions as a tumor suppressor in mouse skin epidermis.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36945368","citation_count":2,"is_preprint":false},{"pmid":"30083817","id":"PMC_30083817","title":"Diverging impact of cell fate determinants Scrib and Llgl1 on adhesion and migration of hematopoietic stem cells.","date":"2018","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30083817","citation_count":2,"is_preprint":false},{"pmid":"38940292","id":"PMC_38940292","title":"Llgl1 mediates timely epicardial emergence and establishment of an apical laminin sheath around the trabeculating cardiac ventricle.","date":"2024","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38940292","citation_count":1,"is_preprint":false},{"pmid":"16969496","id":"PMC_16969496","title":"Disruption of protein-protein interaction in the Mgl-1 oncoprotein.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16969496","citation_count":1,"is_preprint":false},{"pmid":"41977148","id":"PMC_41977148","title":"Loss of LLGL1 Elevates EGFR/RAS/MAPK Signaling and Remodels EMT Markers in Huh-7 Hepatocellular Carcinoma Cells.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41977148","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.26.615224","title":"Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multi-site polarity substrate Lgl","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.615224","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18885,"output_tokens":4119,"usd":0.05922,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11934,"output_tokens":4112,"usd":0.081235,"stage2_stop_reason":"end_turn"},"total_usd":0.140455,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"LLGL1 directly binds N-cadherin and promotes its internalization; this interaction is inhibited by aPKC-mediated phosphorylation of LLGL1, restricting accumulation of apical junctional complexes to the basolateral-apical boundary. Disruption of the N-cadherin–LLGL1 interaction during cortical development in vivo is sufficient to cause periventricular heterotopia.\",\n      \"method\": \"Co-immunoprecipitation, live cortical imaging, in vivo conditional knockout (Nestin-Cre/Llgl1fl/fl), rescue experiments with N-cadherin interaction mutants\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct binding, in vivo KO with defined cellular phenotype, and point-mutation disruption of interaction; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"28552558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human aPKCι-Par6α forms a stable tripartite complex with full-length LLGL1, captured via an aPKCι docking site and a Par6 PDZ contact. A phospho-S663 LLGL1 intermediate bridges aPKC and Par6, impeding phosphorylation progression. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation; disrupting the Lgl-Par6 PDZ contact promotes complex dissociation and completion of the Lgl phosphorylation cycle. Cdc42-GTP binding and the apical partner Crumbs drive complex disassembly.\",\n      \"method\": \"Cryo-EM/structural determination of tripartite complex, mutagenesis of docking and PDZ contact sites, in vitro phosphorylation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure determination plus mutagenesis plus in vitro kinase assay; single preprint but multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2024.09.26.615224\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human HUGL-1 (LLGL1) functionally substitutes for Drosophila Lgl in vivo: expression in homozygous lgl Drosophila mutants rescues larval lethality, restores correct localization of Dlg and Scrib, and prevents neoplastic tissue features, demonstrating functional conservation within the Lgl-Dlg-Scrib tumor suppressor pathway.\",\n      \"method\": \"Transgenic rescue of Drosophila lgl homozygous mutants with human HUGL-1; immunolocalization of Dlg and Scrib\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic complementation in Drosophila with pathway marker localization; replicated conceptually across multiple labs\",\n      \"pmids\": [\"15467749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LLGL1 (Hugl-1) is a component of the hScrib/hDlg/Hugl-1 complex; hScrib is required in part for correct localization of hDlg and Hugl-1. Under osmotic stress, hDlg and Hugl-1 can localize to cell membranes independently of hScrib. The complex interacts with the t-SNARE syntaxin 4, and correct localization of the Scrib complex is partially dependent on this t-SNARE, linking the complex to vesicle transport pathways.\",\n      \"method\": \"shRNA knockdown of hScrib, co-localization immunofluorescence, co-immunoprecipitation with syntaxin 4\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and KD with localization readout, two orthogonal methods, single lab\",\n      \"pmids\": [\"18793635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Llgl1 causes EGFR mislocalization; an EGFR mislocalization point mutation (P667A) recapitulates Llgl1-loss phenotypes including AKT activation and TAZ nuclear translocation. Llgl1 loss drives EGFR-dependent mammosphere formation and survival, and Llgl1 regulates nuclear translocation of TAZ and Slug.\",\n      \"method\": \"Stable Llgl1 knockout cell lines, EGFR point mutation (P667A), mammosphere assay, soft-agar growth, orthotopic transplant, lineage tracing\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and point-mutation epistasis; single lab, multiple assays\",\n      \"pmids\": [\"27542214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish cardiomyocytes, Llgl1 depletion decreases Yap protein levels and blunts Yap target gene transcription without affecting Yap transcript abundance, indicating Llgl1 promotes Yap protein stability. Cardiomyocyte-specific overexpression of Yap in Llgl1-depleted embryos rescues pericardial effusion and blood flow, placing Llgl1 upstream of Yap in cardiomyocytes.\",\n      \"method\": \"Morpholino knockdown in zebrafish, Yap protein quantification by Western blot, cardiomyocyte-specific Yap overexpression rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined phenotype, genetic rescue experiment placing Llgl1 upstream of Yap; single lab\",\n      \"pmids\": [\"32843528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LLGL1 loss promotes oncostatin M receptor (OSMR) expression via phosphorylation of ERK2 and Sp1, with phosphorylated Sp1 (pThr453) binding the OSMR promoter to enhance transcription. Knockdown of OSMR rescues the gemcitabine-resistance phenotype caused by LLGL1 silencing.\",\n      \"method\": \"Genome-wide RNAi screen, gene-expression microarray, ChIP for Sp1 at OSMR promoter, OSMR knockdown rescue, cell proliferation and tumor formation assays\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, rescue KD, microarray) in single lab establishing pathway order\",\n      \"pmids\": [\"32615164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP11 deubiquitinates and stabilizes Mgl-1 (LLGL1) protein, preventing its proteasomal degradation. This stabilization requires RanBPM; USP11-mediated Mgl-1 stabilization is abolished in RanBPM-knockdown cells. USP11-mediated regulation of Mgl-1 also requires RanBPM for control of cancer cell migration.\",\n      \"method\": \"Ubiquitination assay (deubiquitinating activity of USP11), RanBPM knockdown, Western blot for Mgl-1 stability, cell migration assay, in vivo tumor formation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct deubiquitination assay plus epistasis via RanBPM KD; single lab, two orthogonal approaches\",\n      \"pmids\": [\"26919101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of Llgl1 in retinal neuroepithelia expands apical domains and increases Notch activity, reducing neurogenesis. Blocking Notch by depleting Rbpj restores normal neurogenesis. Experimental expansion of the apical domain via Shroom3 inhibition similarly increases Notch activity, placing Llgl1-controlled apical domain size upstream of Notch-dependent neurogenesis.\",\n      \"method\": \"Conditional Llgl1 knockout in zebrafish retina, Rbpj depletion epistasis, Shroom3 inhibition, interkinetic nuclear migration analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Rbpj rescue) plus pharmacological epistasis, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"22492354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The WD-40 repeat motif of Mgl-1/LLGL1 is required for protein-protein interactions essential for cellular function: deletion mutants at conserved residues G450 and D453 within the WD-40 domain fail to complement yeast Sop1/Sop2 double mutants at restrictive temperature and high salt, while other deletion mutants in this region retain complementation ability.\",\n      \"method\": \"Site-directed mutagenesis of WD-40 residues, yeast complementation assay (temperature sensitivity and salt tolerance)\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional readout; single lab, single assay system\",\n      \"pmids\": [\"16969496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Mgl-1 (ortholog of LLGL1) can partially restore salt tolerance in yeast lacking Sop1 and Sop2 (yeast lgl homologs), demonstrating evolutionary conservation of lgl family function.\",\n      \"method\": \"Yeast complementation assay (salt tolerance rescue)\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single heterologous complementation assay, single lab\",\n      \"pmids\": [\"14612921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LLGL1 inactivation in AML results in loss of stemness-associated gene expression including HoxA genes and induces a GMP-like phenotype in leukemia stem cells; re-expression of HoxA9 functionally and phenotypically rescues LLGL1 loss, placing LLGL1 upstream of HoxA9 in AML stem cell maintenance.\",\n      \"method\": \"CRISPR/Cas9-based genetic screening, murine and human AML models, gene expression analysis, HoxA9 re-expression rescue\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined phenotype plus genetic rescue establishing pathway epistasis; conserved in human and murine models\",\n      \"pmids\": [\"37587260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Combined ablation of Llgl1 and Llgl2 in mouse skin epidermis cooperates with Trp53 loss to cause squamous cell carcinoma, and is associated with activation of aPKC and upregulation of NF-κB signaling, placing Lgl signaling upstream of aPKC-NF-κB in epidermal tumor suppression.\",\n      \"method\": \"Conditional double knockout (K14-Cre/Llgl1fl/fl/Llgl2fl/fl) in mice, crossed with Trp53 cKO; aPKC activity assay, NF-κB pathway analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo double KO with cancer phenotype plus pathway activation analysis; preprint, single lab\",\n      \"pmids\": [\"36945368\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, Llgl1 is required for timely epicardial emergence and for correct deposition of laminin on the apical ventricular surface; llgl1 mutants show aberrant apical extrusion of cardiomyocytes and delayed epicardial cell emergence, resulting in delayed apical laminin deposition.\",\n      \"method\": \"Zebrafish llgl1 mutant analysis, epicardial lineage imaging, laminin immunofluorescence, epicardium-ablation experiments\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype; single lab, multiple tissue-level assays\",\n      \"pmids\": [\"38940292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Re-expression of HUGL-1 in colorectal cancer cell lines increases cell adhesion and decreases cell migration, establishing a direct functional role for LLGL1 in these cellular processes.\",\n      \"method\": \"Ecdysone-inducible Hugl-1 expression in cancer cell lines, cell adhesion assay, cell migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with functional readouts; single lab, no pathway placement\",\n      \"pmids\": [\"15735678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Re-expression of Hugl-1 in melanoma cells increases cell adhesion, decreases cell migration, downregulates MMP2 and MMP14, and induces re-expression of E-cadherin, supporting a role for LLGL1 in suppressing epithelial-mesenchymal transition.\",\n      \"method\": \"Stable Hugl-1 transfection in melanoma cell lines, adhesion and migration assays, Western blot for MMP2/MMP14/E-cadherin\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with functional readouts; single lab, limited mechanistic depth\",\n      \"pmids\": [\"16170365\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LLGL1 is a basolateral polarity scaffold that is phosphorylated at multiple serine residues (including S663) by the apical aPKCι-Par6α complex, forming a transient tripartite capture complex whose release requires Cdc42-GTP and Crumbs; unphosphorylated LLGL1 binds N-cadherin to promote its internalization and restrict apical junctional complexes to the basolateral-apical boundary, while its WD-40 repeat domain mediates protein–protein interactions, its ubiquitination is countered by the deubiquitinase USP11 in a RanBPM-dependent manner, and in specific cellular contexts it stabilizes Yap protein in cardiomyocytes, maintains HoxA9-dependent stemness in AML, and suppresses EGFR/RAS/MAPK and NF-κB signaling to enforce epithelial identity and suppress tumorigenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LLGL1 is an evolutionarily conserved basolateral polarity scaffold that enforces epithelial architecture and acts as a tumor suppressor within the Lgl-Dlg-Scrib polarity module, as established by its ability to functionally substitute for Drosophila Lgl in vivo to restore Dlg/Scrib localization and prevent neoplastic overgrowth [#2]. Its activity is governed by a phospho-regulatory cycle: the apical aPKC\\u03b9-Par6\\u03b1 complex captures full-length LLGL1 into a tripartite assembly via an aPKC\\u03b9 docking site and a Par6 PDZ contact, generating a phospho-S663 intermediate, with Cdc42-GTP and the apical determinant Crumbs driving complex disassembly to complete the phosphorylation cycle [#1]. Phosphorylation by aPKC inhibits the direct binding of LLGL1 to N-cadherin, which in the unphosphorylated state drives N-cadherin internalization and restricts apical junctional complexes to the basolateral-apical boundary; disrupting this interaction during cortical development causes periventricular heterotopia [#0]. LLGL1 functions through its WD-40 repeat domain, which mediates the protein-protein interactions required for its cellular function [#9], and operates within a hScrib/hDlg/Hugl-1 complex that engages the t-SNARE syntaxin 4, linking polarity to vesicle transport [#3]. LLGL1 protein levels are set post-translationally by USP11, which deubiquitinates and stabilizes LLGL1 in a RanBPM-dependent manner [#7]. Loss of LLGL1 unleashes oncogenic signaling\\u2014EGFR mislocalization with downstream AKT and TAZ/Slug nuclear translocation [#4], ERK2/Sp1-driven OSMR transcription conferring drug resistance [#6], and aPKC-NF-\\u03baB activation cooperating with Trp53 loss to drive carcinoma [#12]\\u2014while in context-specific roles it stabilizes Yap protein in cardiomyocytes [#5] and sustains HoxA9-dependent stemness in AML [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing whether mammalian Lgl-family genes retain the ancestral function of their yeast and fly counterparts was the first step in attributing any conserved cellular role to LLGL1.\",\n      \"evidence\": \"Yeast complementation rescuing salt tolerance in Sop1/Sop2-deficient cells with mouse Mgl-1\",\n      \"pmids\": [\"14612921\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single heterologous complementation assay only\", \"No molecular mechanism for the complemented function\", \"Does not address mammalian-specific roles\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"It was unknown whether human LLGL1 operates in the same tumor-suppressive polarity pathway as Drosophila Lgl; cross-species genetic complementation placed it firmly within the Lgl-Dlg-Scrib module.\",\n      \"evidence\": \"Transgenic rescue of Drosophila lgl-null mutants with human HUGL-1, scoring lethality and Dlg/Scrib localization\",\n      \"pmids\": [\"15467749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the direct molecular partners of LLGL1 in mammals\", \"Pathway placement inferred from fly markers, not mammalian biochemistry\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Whether re-expressing LLGL1 in carcinoma cells reverses malignant behavior was tested to validate its tumor-suppressor function at the cellular level.\",\n      \"evidence\": \"Inducible HUGL-1 expression in colorectal cancer lines with adhesion and migration assays\",\n      \"pmids\": [\"15735678\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression experiment without pathway placement\", \"No mechanism linking adhesion/migration change to a molecular target\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The structural basis for LLGL1's protein interactions and its capacity to suppress EMT markers were addressed to connect domain architecture and phenotype.\",\n      \"evidence\": \"WD-40 residue mutagenesis with yeast complementation, and melanoma re-expression scoring E-cadherin/MMP levels\",\n      \"pmids\": [\"16969496\", \"16170365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WD-40 partners not identified\", \"EMT marker changes are correlative, no direct binding shown\", \"Melanoma data is overexpression-based, single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining the composition and dependencies of the mammalian Scrib polarity complex clarified how LLGL1 is positioned and linked it to membrane trafficking.\",\n      \"evidence\": \"hScrib shRNA knockdown with co-localization and syntaxin 4 co-immunoprecipitation\",\n      \"pmids\": [\"18793635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect LLGL1-syntaxin 4 contact not resolved\", \"Functional consequence of the t-SNARE link not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"How LLGL1-controlled apical domain size feeds into developmental signaling was unknown; epistasis placed it upstream of Notch-dependent neurogenesis.\",\n      \"evidence\": \"Conditional Llgl1 knockout in zebrafish retina with Rbpj-depletion and Shroom3-inhibition epistasis\",\n      \"pmids\": [\"22492354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between apical domain expansion and Notch activation unresolved\", \"Tissue-specific to retinal neuroepithelium\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two complementary mechanisms of LLGL1 regulation were defined: how its loss activates oncogenic EGFR signaling, and how its protein abundance is controlled post-translationally.\",\n      \"evidence\": \"Llgl1 knockout cells with EGFR P667A point mutant and mammosphere/transplant assays; USP11 deubiquitination assay with RanBPM knockdown epistasis\",\n      \"pmids\": [\"27542214\", \"26919101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LLGL1 controls EGFR localization not defined\", \"How RanBPM enables USP11 access to LLGL1 unknown\", \"Single lab for each finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The direct molecular substrate of LLGL1 polarity activity was identified, linking aPKC phosphorylation to N-cadherin trafficking and a defined developmental disease.\",\n      \"evidence\": \"Reciprocal Co-IP, live cortical imaging, conditional knockout, and N-cadherin interaction point mutants causing periventricular heterotopia\",\n      \"pmids\": [\"28552558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Internalization machinery downstream of LLGL1-N-cadherin not detailed\", \"Whether this mechanism operates in non-neural epithelia not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Context-specific signaling outputs of LLGL1 were established: Yap protein stabilization in cardiomyocytes and ERK2/Sp1-driven OSMR transcription conferring drug resistance.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with cardiomyocyte Yap rescue; genome-wide RNAi screen with Sp1 ChIP at the OSMR promoter and OSMR knockdown rescue\",\n      \"pmids\": [\"32843528\", \"32615164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LLGL1 stabilizes Yap protein unknown\", \"How LLGL1 loss triggers ERK2/Sp1 phosphorylation not defined\", \"Both context-specific, single lab each\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"LLGL1 was shown to have a stemness-maintaining role beyond classical polarity, and its loss to cooperate with Trp53 in carcinogenesis via aPKC-NF-\\u03baB.\",\n      \"evidence\": \"CRISPR screening in AML models with HoxA9 re-expression rescue; conditional Llgl1/Llgl2 double knockout crossed with Trp53 cKO in mouse epidermis\",\n      \"pmids\": [\"37587260\", \"36945368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LLGL1 to HoxA gene expression unknown\", \"Redundancy with Llgl2 complicates single-gene attribution\", \"Epidermal study is a preprint\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The atomic basis of LLGL1's phospho-regulatory cycle was resolved, and a new tissue-morphogenesis role in epicardial emergence and apical laminin deposition was defined.\",\n      \"evidence\": \"Cryo-EM of the aPKC\\u03b9-Par6\\u03b1-LLGL1 tripartite complex with docking/PDZ mutagenesis and in vitro kinase assays; zebrafish llgl1 mutant epicardial lineage imaging and laminin immunofluorescence\",\n      \"pmids\": [\"bio_10.1101_2024.09.26.615224\", \"38940292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural work is a preprint\", \"Precise role of Cdc42-GTP/Crumbs in disassembly defined biochemically but not in tissue\", \"Link between LLGL1 and laminin deposition mechanism unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single basolateral scaffold integrates its conserved polarity/N-cadherin function with the diverse downstream outputs (Yap, HoxA9, EGFR, OSMR, NF-\\u03baB) remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism connecting polarity scaffolding to transcriptional/signaling outputs\", \"Direct WD-40 domain interactome largely uncharacterized\", \"Whether outputs are direct or secondary to polarity loss unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 8, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 6, 12]}\n    ],\n    \"complexes\": [\n      \"aPKC\\u03b9-Par6\\u03b1-LLGL1 tripartite complex\",\n      \"hScrib/hDlg/Hugl-1 complex\"\n    ],\n    \"partners\": [\n      \"PRKCI\",\n      \"PARD6A\",\n      \"CDH2\",\n      \"SCRIB\",\n      \"DLG1\",\n      \"STX4\",\n      \"USP11\",\n      \"RANBP9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}