{"gene":"LLGL1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1995,"finding":"Human LLGL1 (HUGL) encodes a cytoskeletal protein of ~115 kDa that physically associates with nonmuscle myosin II heavy chain; the protein is phosphorylated at serine residues by an associated kinase, establishing its identity as a cortical cytoskeleton component.","method":"Affinity-purified polyclonal antibodies against HUGL peptides; co-immunoprecipitation/co-purification with nonmuscle myosin II heavy chain; in vitro kinase assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal biochemical association plus kinase assay, foundational paper replicated by subsequent studies","pmids":["7542763"],"is_preprint":false},{"year":2003,"finding":"Mammalian Lgl (mLgl/LLGL1) competes with PAR-3 to form an independent complex with PAR-6 and aPKC. During cell polarization, mLgl initially colocalizes with PAR-6/aPKC at cell-cell contacts and is phosphorylated by aPKC, causing its segregation to the basolateral membrane. Overexpression of the mLgl/PAR-6/aPKC complex suppresses epithelial junction formation, in contrast to the PAR-3/PAR-6/aPKC complex which promotes it.","method":"Co-immunoprecipitation; overexpression studies in epithelial cells; immunofluorescence localization; in vitro aPKC phosphorylation assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, localization, functional overexpression, in vitro phosphorylation), replicated in subsequent studies","pmids":["12725730"],"is_preprint":false},{"year":2004,"finding":"Loss of Lgl1 in mice causes failure of asymmetric localization of the Notch inhibitor Numb during cell division of neural progenitor cells, leading to symmetric divisions, hyperproliferation, lack of differentiation, and severe brain dysplasia including neuroepithelial rosette-like structures resembling neuroblastic rosettes.","method":"Lgl1 knockout mouse (Lgl1−/−); immunostaining for Numb localization; BrdU incorporation; TUNEL apoptosis assay; histopathology","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple specific phenotypic readouts including Numb asymmetry, widely cited foundational study","pmids":["15037549"],"is_preprint":false},{"year":2004,"finding":"Human LLGL1 (Hugl-1) can functionally substitute for Drosophila lgl in vivo: expression of Hugl-1 in homozygous lgl Drosophila mutants rescues larval lethality, restores correct localization of Dlg and Scrib, and permits normal metamorphosis, demonstrating functional conservation of the lgl/dlg/scrib tumor suppressor pathway.","method":"Transgenic rescue in Drosophila lgl homozygous mutants; immunostaining for Dlg and Scrib localization; developmental phenotype scoring","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic rescue with localization readouts, strong functional conservation evidence","pmids":["15467749"],"is_preprint":false},{"year":2006,"finding":"Re-expression of LLGL1 (Hugl-1) in melanoma cell lines increases cell adhesion and decreases cell migration, and is associated with downregulation of MMP2 and MMP14 and re-expression of E-cadherin, supporting a role for LLGL1 in suppressing epithelial-mesenchymal transition (EMT).","method":"Stable transfection of Hugl-1 into melanoma cell lines; cell adhesion and migration functional assays; RT-PCR and western blot for MMP2, MMP14, E-cadherin","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — functional gain-of-function with multiple molecular readouts but single lab","pmids":["16170365"],"is_preprint":false},{"year":2008,"finding":"LLGL1 (Hugl-1) forms a complex with hDlg and hScrib in mammalian cells; correct localization of hDlg and Hugl-1 is partially dependent on hScrib under normal conditions, but both can localize to cell membranes independently of hScrib under osmotic stress. The hScrib complex interacts with the t-SNARE syntaxin 4, linking the Scrib polarity complex to vesicle transport pathways.","method":"shRNA ablation of hScrib; co-localization by immunofluorescence; co-immunoprecipitation with syntaxin 4; osmotic stress treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional localization experiments, single lab","pmids":["18793635"],"is_preprint":false},{"year":2009,"finding":"LLGL1 (Hugl-1) mRNA undergoes frequent aberrant splicing in hepatocellular carcinoma, generating truncated proteins lacking WD-40 repeat motifs. Overexpression of two HCC-derived aberrant Hugl-1 variants promotes HCC cell migration, invasion, and tumorigenicity in nude mice, acting as dominant-negative or gain-of-function variants.","method":"RT-PCR and sequencing of 80 HCC specimens; western blot; wound healing, Boyden chamber migration/invasion assays; nude mouse tumorigenicity assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with multiple readouts in vitro and in vivo, single lab","pmids":["19447873"],"is_preprint":false},{"year":2011,"finding":"Lgl1 (mouse LLGL1) associates with plasmalemmal precursor vesicles, is enriched in developing axons, and directly interacts with Rab10 GTPase. Lgl1 activates Rab10 by releasing GDP dissociation inhibitor (GDI) from Rab10, thereby promoting membrane protein trafficking. Rab10 acts downstream of Lgl1 in axon development and directional membrane insertion, and both are required for neocortical neuronal polarization in vivo.","method":"Co-immunoprecipitation; GDI release assay; overexpression/knockdown of Lgl1 and Rab10 in neurons; live imaging of membrane insertion; in vivo electroporation into neocortex","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including biochemical interaction, functional GDI assay, in vitro and in vivo epistasis","pmids":["21856246"],"is_preprint":false},{"year":2012,"finding":"Loss of Llgl1 in vertebrate retinal neuroepithelia results in expansion of the apical domain and increased Notch activity, which reduces neurogenesis. Blocking Notch signaling by depleting Rbpj restores normal neurogenesis. Experimental expansion of the apical domain via Shroom3 inhibition phenocopies Llgl1 loss (increased Notch, reduced neurogenesis), establishing that Llgl1 controls neurogenesis through regulation of apical domain size and downstream Notch signaling.","method":"Morpholino knockdown of Llgl1 in zebrafish retina; genetic epistasis (Rbpj depletion); Shroom3 inhibition; Notch activity reporters; interkinetic nuclear migration analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with rescue experiment plus multiple phenotypic readouts","pmids":["22492354"],"is_preprint":false},{"year":2012,"finding":"Lgl1 (mammalian LLGL1) directly interacts with nonmuscle myosin IIA (NMII-A) and inhibits NMII-A filament assembly in vitro. Depletion of Lgl1 causes aberrant NMII-A localization to the leading edge, alters focal adhesion size and number, and impairs cell polarity and directional migration.","method":"Co-immunoprecipitation in vivo; in vitro filament assembly inhibition assay; Lgl1 siRNA knockdown; immunofluorescence of NMII-A localization and focal adhesions; migration assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro filament assembly assay plus Co-IP and functional knockdown with defined readouts","pmids":["22219375"],"is_preprint":false},{"year":2013,"finding":"Lgl1 forms two distinct complexes in vivo: Lgl1-NMII-A and Lgl1-Par6α-aPKCζ. Phosphorylation of Lgl1 by aPKCζ prevents Lgl1 interaction with NMII-A both in vitro and in vivo, affects NMII-A filament assembly inhibition, and alters Lgl1 cellular localization. aPKCζ and NMII-A compete to bind the same domain of Lgl1. The Lgl1-Par6α-aPKCζ complex localizes to the leading edge.","method":"Co-immunoprecipitation; in vitro phosphorylation and filament assembly assays; phosphomimetic/non-phosphorylatable Lgl1 mutants; immunofluorescence localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro biochemical assays plus mutagenesis plus reciprocal Co-IPs","pmids":["24213535"],"is_preprint":false},{"year":2013,"finding":"PTEN loss leads to aberrant aPKC activation, which phosphorylates and inactivates Lgl1 in glioblastoma cells. Re-expression of PTEN promotes differentiation along a neuronal lineage, as does aPKC knockdown or expression of a non-phosphorylatable Lgl1 (Lgl3SA). Thus, the PTEN→PI3K→aPKC→Lgl1 pathway controls glioblastoma tumor-initiating cell differentiation.","method":"PTEN re-expression; aPKC siRNA knockdown; non-phosphorylatable Lgl3SA expression; neuronal differentiation assays; phospho-Lgl1 western blot","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple interventions converging on same pathway and phenotype","pmids":["23907540"],"is_preprint":false},{"year":2014,"finding":"Constitutively active non-phosphorylatable Lgl1 (Lgl3SA) inhibits glioblastoma cell motility in vitro and markedly reduces in vivo invasion of primary glioblastoma cells in intracerebral xenografts. Lgl3SA also induces differentiation along the neuronal lineage in vitro and in vivo, confirming that Lgl1's tumor suppressor functions require its non-phosphorylated (active) state.","method":"Doxycycline-inducible Lgl3SA expression system; in vitro motility assay; intracerebral xenograft model; differentiation markers by immunostaining","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — doxycycline-inducible system with non-phosphorylatable mutant, in vitro and in vivo readouts","pmids":["25426552"],"is_preprint":false},{"year":2016,"finding":"miR-652-3p directly targets the 3'UTR of LLGL1, reducing LLGL1 protein expression. Overexpression of Lgl1 partially attenuates miR-652-3p-driven promotion of NSCLC cell proliferation, migration, invasion, and inhibition of apoptosis, confirming LLGL1 as a direct functional target of miR-652-3p.","method":"Luciferase reporter with LLGL1 3'UTR; 3'UTR binding-site mutation; miR-652-3p overexpression/knockdown; western blot; proliferation/migration/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct 3'UTR luciferase validation with mutation plus functional rescue, single lab","pmids":["26934648"],"is_preprint":false},{"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 (AJCs) to the basolateral-apical boundary. Disruption of the N-cadherin–LLGL1 interaction in vivo is sufficient to cause periventricular heterotopia (PH) resembling severe cortical malformation in mice.","method":"Co-immunoprecipitation; endocytosis/internalization assay; phosphomimetic/non-phosphorylatable LLGL1 mutants; Nestin-Cre/Llgl1fl/fl conditional KO; live cortical imaging; in utero electroporation to disrupt N-cadherin-LLGL1 interaction","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, endocytosis assay, mutagenesis, conditional KO, and in vivo rescue/disruption","pmids":["28552558"],"is_preprint":false},{"year":2017,"finding":"Mosaic analysis with double markers (MADM) reveals Lgl1 has distinct sequential functions: tissue-wide (community effect) Lgl1-dependent mechanisms are required for embryonic cortical neurogenesis, while cell-autonomous Lgl1 functions control radial glial progenitor-mediated gliogenesis and postnatal neural stem cell behavior.","method":"MADM-based sparse and global conditional knockout at single-cell resolution; clonal analysis; BrdU/EdU labeling; immunostaining for progenitor/glia markers","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — MADM genetic paradigm enabling cell-autonomous vs. non-autonomous dissection with single-cell resolution","pmids":["28472654"],"is_preprint":false},{"year":2018,"finding":"Conditional deletion of Lgl1 in oligodendrocyte progenitor cells (OPCs) causes retention of the pro-mitotic proteoglycan NG2 in OL progeny through aberrant NG2 recycling rather than endosomal routing to lysosomes. Lgl1 controls NG2 endocytic routing as revealed by total internal reflection and time-lapse microscopy. Hemizygous Ink4a/Arf and Lgl1 knockouts in OPCs synergistically induce gliomagenesis.","method":"Conditional Lgl1 KO in OPCs; time-lapse and total internal reflection fluorescence microscopy of NG2 trafficking; immunophenotyping; synergistic gliomagenesis assay with Ink4a/Arf","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — live imaging of endocytic routing with conditional KO and genetic interaction studies","pmids":["30131568"],"is_preprint":false},{"year":2018,"finding":"Loss of Lgl1 in dorsal telencephalon (Emx1-Cre) disrupts adherens junctions (AJs) in radial glia, causes ectopic displacement of radial glia and intermediate progenitors, disorganizes the radial glial fiber scaffold, and results in failed neuronal migration producing subcortical band heterotopia (SBH) resembling the human condition.","method":"Emx1-Cre conditional Lgl1 KO; histology; immunostaining for AJ markers (N-cadherin, β-catenin), radial glia (nestin), neuron birth-dating with BrdU/EdU; behavioral testing","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined molecular (AJ disruption) and cellular (scaffold disorganization, neuronal migration failure) phenotypes","pmids":["30597194"],"is_preprint":false},{"year":2019,"finding":"Apical-basal polarity protein Lgl1 is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing aPKC activity. Conditional knockout of Lgl1 in pyramidal neurons reduces AMPA/NMDA ratio and impairs synaptic plasticity. Loss of Lgl1 decreases Vangl2 in synaptosome fractions. Lgl1+/- mice show increased synapse number, impaired social interaction, and stereotyped repetitive behavior rescuable by NMDA antagonists.","method":"Synaptosome fractionation; conditional KO in pyramidal neurons; electrophysiology (AMPA/NMDA ratio, LTP); behavioral assays; immunostaining","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — synaptosome fractionation, electrophysiology, conditional KO with behavioral and synaptic readouts","pmids":["31546104"],"is_preprint":false},{"year":2019,"finding":"Lgl1 deficiency in hippocampus (Emx1-Cre) causes disrupted hippocampal neuroepithelium with increased proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, disrupted adherens junctions, and abnormal neuronal migration. Lgl1-deficient mice display impaired spatial learning/memory and fear conditioning.","method":"Emx1-Cre conditional Lgl1 KO; histology; BrdU labeling; immunostaining for AJ markers; Morris water maze; fear conditioning behavioral tests","journal":"Genes, brain, and behavior","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotypes, single lab","pmids":["31415124"],"is_preprint":false},{"year":2020,"finding":"LLGL1 loss promotes expression of the cytokine receptor OSMR in pancreatic ductal adenocarcinoma cells, conferring gemcitabine resistance. Mechanistically, silencing LLGL1 induces ERK2 phosphorylation and phosphorylation of transcription factor Sp1 at Thr453, promoting Sp1 binding to the OSMR promoter and enhancing OSMR transcription. Knockdown of OSMR rescues chemoresistance.","method":"Genome-wide RNAi screen; cell proliferation and tumor formation assays; gene-expression microarray; ERK/Sp1 phosphorylation by western blot; ChIP for Sp1 binding at OSMR promoter; OSMR knockdown rescue","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus mechanistic follow-up with ChIP, phosphorylation assays, and pathway rescue","pmids":["32615164"],"is_preprint":false},{"year":2020,"finding":"Scrib forms a complex in vivo with Lgl1 through its leucine-rich repeat (LRR) domain, and both Scrib and Lgl1 independently form complexes with myosin II. All three proteins colocalize at the leading edge of migrating cells. Cellular localization and cytoskeletal association of Scrib and Lgl1 are interdependent. Depletion of either Scrib or Lgl1 disrupts myosin II localization, inhibits focal adhesion disassembly, and impairs front-rear cell polarity during migration.","method":"Co-immunoprecipitation; siRNA depletion of Scrib or Lgl1; immunofluorescence colocalization; focal adhesion assays; cell polarity and migration assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional depletion experiments with multiple orthogonal readouts","pmids":["32697665"],"is_preprint":false},{"year":2020,"finding":"Vertebrate Llgl1 (zebrafish/rat) is required for Yap protein stability in cardiomyocytes but not Yap mRNA levels, indicating post-translational regulation. Llgl1 depletion in zebrafish causes larger/dysmorphic cardiomyocytes, pericardial effusion, impaired blood flow, and aberrant valvulogenesis with broader Notch activation. Cardiomyocyte-specific Yap overexpression in Llgl1-depleted embryos rescues pericardial effusion and blood flow, establishing Yap as a downstream effector of Llgl1 in cardiac development.","method":"Morpholino and CRISPR-based llgl1 depletion in zebrafish; siRNA in rat cardiomyocytes; Yap protein/mRNA quantification; cardiomyocyte-specific Yap overexpression rescue; cardiac imaging","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic depletion in two organisms plus protein-level rescue experiment establishing Yap as downstream effector","pmids":["32843528"],"is_preprint":false},{"year":2021,"finding":"PREX1, a PI3K-pathway-responsive Rac guanine nucleotide exchange factor, links aberrant PI3K signaling (downstream of PTEN loss) to Lgl1 hyperphosphorylation in glioblastoma. CRISPR knockout of PREX1 reduces Lgl1 phosphorylation, impairs motility, and promotes partial neuronal differentiation. In a PREX1-knockout patient subset, the Rac GEF TIAM1 (short isoform, overexpressed) compensates to maintain Lgl1 phosphorylation; TIAM1 knockdown in these cells restores reduced Lgl1 phosphorylation.","method":"CRISPR/Cas9 KO of PREX1; phospho-Lgl1 western blot; TIAM1 knockdown; RNA-seq; motility assays; patient-derived glioblastoma cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with rescue, phosphorylation readout, multiple patient-derived lines","pmids":["34624316"],"is_preprint":false},{"year":2022,"finding":"LGL1 (mouse Lgl1) binds directly to Integrin β1 and inhibits its downstream signaling. In mammary glands lacking Lgl1, epithelium cannot directionally migrate despite normal epithelial polarity, resulting in fewer branches. Integrin β1 overexpression recapitulates the Lgl1-null migration phenotype, demonstrating that LGL1-mediated inhibition of Integrin β1 signaling is essential for directional migration and epithelial branching.","method":"Conditional mammary Lgl1 KO; co-immunoprecipitation of LGL1 with Integrin β1; Integrin β1 overexpression; 3D branching morphogenesis assays; directional migration assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP establishing direct binding, conditional KO, and Integrin β1 overexpression phenocopying KO","pmids":["35172155"],"is_preprint":false},{"year":2023,"finding":"Scrib, Lgl1, and NMII-A reside in a complex with the E-cadherin-catenin complex at adherens junctions (AJs). Depletion of either Scrib or Lgl1 disrupts E-cadherin-catenin complex localization at AJs. aPKCζ phosphorylation of Lgl1 regulates AJ localization of Lgl1 and E-cadherin-catenin complexes. Scrib and Lgl1 regulate NMII-A activation and recruitment at AJs and are downregulated by TGFβ-induced EMT; their re-expression during EMT impedes EMT progression.","method":"Co-immunoprecipitation; siRNA depletion of Scrib and Lgl1; phosphomimetic Lgl1 mutants; immunofluorescence of AJ markers; TGFβ-induced EMT; re-expression rescue","journal":"Cell adhesion & migration","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, mutagenesis, functional rescue with multiple orthogonal readouts","pmids":["37743653"],"is_preprint":false},{"year":2023,"finding":"Inactivation of LLGL1 in acute myeloid leukemia (AML) cells impairs proliferative capacity and AML development across human and murine models with various genetic backgrounds. Loss of LLGL1 reduces stemness-associated gene expression including HoxA genes, inducing a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 rescues the functional and phenotypic defects caused by LLGL1 loss, establishing HoxA9 as a critical downstream target.","method":"CRISPR/Cas9 genetic screening; conditional LLGL1 inactivation in human and murine AML; gene-expression profiling; HoxA9 re-expression rescue; leukemia stem cell immunophenotyping","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — CRISPR screen validated in multiple models with pathway rescue","pmids":["37587260"],"is_preprint":false},{"year":2023,"finding":"Llgl1 mediates timely epicardial emergence and establishment of an apical laminin sheath on the ventricular surface during heart development. In llgl1 mutant zebrafish, ventricular cardiomyocytes undergo aberrant apical extrusion, epicardial cell emergence is delayed, and apical laminin deposition on the ventricular surface is consequently delayed. The epicardium is required for ventricular laminin deposition.","method":"llgl1 mutant zebrafish; immunostaining for laminin and epicardial markers; live imaging; lineage tracing of epicardial cells","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mutant with defined molecular readout, single lab","pmids":["38940292"],"is_preprint":false},{"year":2023,"finding":"Ablation of both Llgl1 and Llgl2 in mouse skin epidermis (K14-Cre) does not impact epidermal polarity in adult mice but promotes squamous cell carcinoma (SCC) development in cooperation with Trp53 loss. Mechanistically, Llgl1/2 ablation activates aPKC and upregulates NF-κB signaling, which may be required for SCC formation.","method":"K14-Cre double conditional KO of Llgl1 and Llgl2; Trp53/Llgl1/2 compound KO; tumor scoring; immunostaining for aPKC and NF-κB pathway activation","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic compound KO with mechanistic pathway readout, but preprint","pmids":["36945368"],"is_preprint":true},{"year":2024,"finding":"Deletion of LGL1 in cerebellar primordium (Pax2-Cre) alters expression patterns of polarity molecules Cdc42 and β-catenin, causing loss of neuroepithelial cell polarity and formation of neuroblastoma-like tissues during early embryogenesis (before E15.5). These tumor-like structures are subsequently eliminated by apoptosis-mediated compensation.","method":"Pax2-LGL1−/− conditional KO mice; HE staining; immunofluorescence for Cdc42, β-catenin; TUNEL staining","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with specific molecular readouts, single lab","pmids":["38526932"],"is_preprint":false},{"year":2024,"finding":"Conditional deletion of Lgl1 in midbrain (Pax2-Cre) disrupts N-cadherin expression patterns, causing abnormal epithelial connections in the tectum, excessive proliferation and heightened apoptosis of neural progenitor cells, and aberrant neuronal migration.","method":"Pax2-Cre Lgl1 conditional KO; histology; BrdU labeling; immunofluorescence for Nestin (glial fibers) and N-cadherin (AJ marker)","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with molecular readout linking Lgl1 to N-cadherin, single lab","pmids":["38444736"],"is_preprint":false},{"year":2026,"finding":"LLGL1 knockout in Huh-7 hepatocellular carcinoma cells potentiates EGFR-driven RAS/MAPK pathway activation, elevates EGFR phosphorylation and abundance, enhances RAF1-MEK-ERK-RSK signaling, and markedly increases migratory and invasive behavior without evidence of classical EMT. These data place LLGL1 as a suppressor of EGFR/RAS/MAPK signaling in HCC.","method":"CRISPR/Cas9 LLGL1 knockout in Huh-7 cells; phospho-proteomics/western blot for EGFR, RAF1, MEK, ERK, RSK; cell proliferation, migration, invasion assays; cell cycle analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with pathway-level phosphoproteomic readout, single lab","pmids":["41977148"],"is_preprint":false},{"year":2006,"finding":"Conserved amino acids G450 and D453 within the WD-40 repeat motif of mouse Mgl-1 (LLGL1 ortholog) are required for protein-protein interactions essential for cellular function; deletion mutants ΔG450 and ΔD453 fail to complement yeast Sop1/Sop2 double mutants at restrictive temperature and high salt, demonstrating the importance of the WD-40 repeat for LLGL1 function.","method":"Site-directed deletion mutagenesis of WD-40 residues in Mgl-1; yeast complementation assay (Sop1/Sop2 double mutant)","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 1-2 — mutagenesis with functional in vivo complementation readout, single lab","pmids":["16969496"],"is_preprint":false},{"year":2003,"finding":"Mouse Mgl-1 (LLGL1 ortholog) partially restores salt tolerance in yeast Sop1/Sop2 double mutants, demonstrating evolutionary conservation of lgl family function. Spatial expression analysis shows mgl-1 mRNA is expressed throughout early embryonic development (E4.5–E18.5) with peak at E10.5, in CNS, craniofacial region, eyes, limbs, and gut.","method":"Yeast complementation assay; RT-PCR temporal expression; in situ hybridization spatial expression","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 — yeast complementation (partial) and expression analysis, single lab","pmids":["14612921"],"is_preprint":false},{"year":2016,"finding":"Loss of Llgl1 in mammary cells causes EGFR mislocalization and drives pre-neoplastic changes including CD44/CD49f/CD24 marker shifts, nuclear translocation of TAZ and Slug, mammosphere formation, and EGF-dependent survival and migration. An EGFR mislocalization point mutation (P667A) recapitulates these phenotypes, including AKT and TAZ activation, linking Llgl1-controlled EGFR localization to downstream oncogenic signaling.","method":"Llgl1 loss-of-function; lineage tracing; mammosphere assay; EGFR localization studies; EGFR P667A point mutation; AKT/TAZ activation by western blot; wound healing; soft-agar growth; orthotopic transplant","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — mislocalization mutation phenocopying Lgl1 loss links Lgl1 to EGFR localization control, single lab","pmids":["27542214"],"is_preprint":false}],"current_model":"LLGL1 is an evolutionarily conserved cortical cytoskeletal tumor suppressor that maintains cell polarity by forming two mutually exclusive complexes — one with nonmuscle myosin IIA (which it inhibits from assembling into filaments) and one with PAR-6/aPKC — whose interchange is controlled by aPKC-mediated phosphorylation of LLGL1; it directly binds and promotes internalization of N-cadherin to restrict apical junctional complex assembly to the basolateral-apical boundary, activates Rab10 by releasing GDP-dissociation inhibitor to drive axonal membrane trafficking, suppresses EGFR/RAS/MAPK signaling and Integrin β1 signaling, stabilizes Yap protein in cardiomyocytes, controls NG2 endocytic routing in oligodendrocyte progenitors, and regulates glutamatergic synapse number by antagonizing aPKC; in cancer contexts, PTEN loss activates PI3K→aPKC (via Rac GEFs PREX1/TIAM1), which hyperphosphorylates and inactivates LLGL1, thereby promoting invasion, dedifferentiation, and stemness through pathways including ERK-Sp1-OSMR and HoxA gene regulation."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of LLGL1 as a cytoskeletal protein associated with nonmuscle myosin II heavy chain established its molecular identity as a cortical component and implicated it in cytoskeletal regulation.","evidence":"Co-immunoprecipitation/co-purification with myosin II heavy chain and in vitro kinase assay in human cells","pmids":["7542763"],"confidence":"High","gaps":["The kinase responsible for serine phosphorylation was not identified","No functional consequence of the myosin II interaction was demonstrated"]},{"year":2003,"claim":"Discovery that LLGL1 competes with PAR-3 for PAR-6/aPKC binding and is phosphorylated by aPKC revealed the mechanistic basis for polarity-dependent complex switching and basolateral segregation.","evidence":"Co-immunoprecipitation, in vitro aPKC phosphorylation, immunofluorescence in epithelial cells; yeast complementation confirming conservation","pmids":["12725730","14612921"],"confidence":"High","gaps":["Structural basis of the PAR-3/LLGL1 competition was unknown","Whether the two complexes had distinct subcellular functions was not resolved"]},{"year":2004,"claim":"Genetic loss-of-function in mice and cross-species rescue in Drosophila demonstrated that LLGL1 is an evolutionarily conserved regulator of asymmetric cell division, Numb localization, and neural progenitor differentiation.","evidence":"Lgl1 knockout mouse with Numb mislocalization and brain dysplasia; human LLGL1 transgenic rescue of Drosophila lgl lethality","pmids":["15037549","15467749"],"confidence":"High","gaps":["Mechanism by which Lgl1 controls Numb asymmetry was not defined","Whether Lgl1 loss causes frank tumorigenesis in mammals was unresolved"]},{"year":2006,"claim":"WD-40 repeat residues were shown to be essential for LLGL1 protein-protein interactions, and re-expression studies in melanoma linked LLGL1 to suppression of EMT markers, providing the first direct cancer-functional evidence in human cells.","evidence":"Site-directed mutagenesis with yeast complementation; stable LLGL1 transfection in melanoma with MMP and E-cadherin readouts","pmids":["16969496","16170365"],"confidence":"Medium","gaps":["Direct binding partners requiring the WD-40 domain were not identified","EMT suppression was shown in overexpression only, lacking endogenous loss-of-function confirmation"]},{"year":2008,"claim":"Demonstration that LLGL1 forms a Scrib/Dlg complex linked to syntaxin 4 connected the polarity module to vesicle trafficking machinery.","evidence":"Co-immunoprecipitation of hScrib/hDlg/LLGL1 with syntaxin 4; shRNA depletion and osmotic stress experiments","pmids":["18793635"],"confidence":"Medium","gaps":["Functional consequence of syntaxin 4 interaction for membrane trafficking was not tested","Directness of LLGL1-syntaxin 4 binding was not established"]},{"year":2011,"claim":"Discovery that LLGL1 directly activates Rab10 by releasing GDI established a specific biochemical mechanism for its role in axonal membrane trafficking and neuronal polarization.","evidence":"GDI release assay, co-immunoprecipitation, live imaging of membrane insertion, in vivo electroporation in neocortex","pmids":["21856246"],"confidence":"High","gaps":["Whether Rab10 activation mediates all LLGL1 trafficking functions or only axonal trafficking was unclear","Structural basis of the LLGL1-Rab10-GDI interaction was not determined"]},{"year":2012,"claim":"Biochemical demonstration that LLGL1 directly inhibits NMII-A filament assembly, combined with zebrafish retinal studies showing LLGL1 controls apical domain size and Notch signaling, resolved two long-standing mechanistic questions about its cytoskeletal and signaling roles.","evidence":"In vitro NMII-A filament assembly inhibition assay plus siRNA knockdown; morpholino knockdown in zebrafish retina with Notch reporters and Rbpj epistasis","pmids":["22219375","22492354"],"confidence":"High","gaps":["How NMII-A filament assembly inhibition relates to apical domain size control was not integrated","Whether Notch pathway regulation is direct or secondary to polarity disruption was unresolved"]},{"year":2013,"claim":"Resolution of the phosphorylation switch: aPKC phosphorylation of LLGL1 disrupts the LLGL1-NMII-A complex while promoting the LLGL1-PAR-6-aPKC complex, and the PTEN→PI3K→aPKC axis was shown to hyperphosphorylate and inactivate LLGL1 in glioblastoma, linking polarity loss to cancer signaling.","evidence":"Phosphomimetic/non-phosphorylatable mutants with in vitro filament assembly and Co-IP; PTEN re-expression and aPKC knockdown with differentiation readouts in GBM cells","pmids":["24213535","23907540"],"confidence":"High","gaps":["Whether additional kinases besides aPKC regulate the switch in vivo was unknown","The structural basis for competitive NMII-A/aPKC binding to the same LLGL1 domain was not resolved"]},{"year":2017,"claim":"Direct binding of LLGL1 to N-cadherin and its role in N-cadherin internalization established the molecular mechanism controlling adherens junction restriction at the apical-basal boundary; disruption of this interaction caused periventricular heterotopia in vivo, linking LLGL1 to cortical malformation.","evidence":"Co-immunoprecipitation, endocytosis assays, conditional KO, in utero electroporation disrupting N-cadherin-LLGL1 interaction; MADM clonal analysis distinguishing cell-autonomous from community effects","pmids":["28552558","28472654"],"confidence":"High","gaps":["The N-cadherin binding domain on LLGL1 was not mapped","Whether LLGL1 regulates E-cadherin internalization through the same mechanism was not tested"]},{"year":2018,"claim":"LLGL1 was shown to control NG2 endocytic routing in oligodendrocyte progenitors and to maintain adherens junctions/radial glial scaffold integrity required for neuronal migration, with its loss causing subcortical band heterotopia.","evidence":"Conditional Lgl1 KO in OPCs with live TIRF imaging of NG2 trafficking; Emx1-Cre cortical KO with AJ marker analysis and migration phenotyping","pmids":["30131568","30597194"],"confidence":"High","gaps":["Whether NG2 routing involves the Rab10 pathway was not tested","Mechanism by which Lgl1 loss cooperates with Ink4a/Arf in gliomagenesis was not fully defined"]},{"year":2019,"claim":"Identification of LLGL1 in the postsynaptic density as a negative regulator of glutamatergic synapse number via aPKC antagonism extended its polarity function to synaptic biology and linked haploinsufficiency to behavioral abnormalities rescuable by NMDA antagonists.","evidence":"Synaptosome fractionation, electrophysiology, conditional KO in pyramidal neurons, behavioral assays with memantine rescue","pmids":["31546104"],"confidence":"High","gaps":["Whether Vangl2 reduction is the direct cause of synapse increase was not established","The aPKC substrate mediating synapse number regulation was not identified"]},{"year":2020,"claim":"LLGL1 loss was shown to activate distinct oncogenic signaling axes in different cancer contexts: ERK-Sp1-OSMR in pancreatic cancer conferring chemoresistance, EGFR mislocalization/TAZ activation in mammary cells, and Yap protein stabilization in cardiac development, broadening the downstream effector repertoire.","evidence":"Genome-wide RNAi screen with ChIP and pathway rescue in PDAC; EGFR localization studies with P667A phenocopy in mammary cells; zebrafish/rat Llgl1 depletion with Yap rescue in cardiomyocytes","pmids":["32615164","27542214","32843528"],"confidence":"High","gaps":["Whether Yap stabilization and OSMR induction reflect the same or independent mechanisms was unclear","How LLGL1 controls EGFR subcellular localization mechanistically was not resolved"]},{"year":2021,"claim":"The Rac GEFs PREX1 and TIAM1 were identified as PI3K-responsive intermediates that hyperphosphorylate LLGL1 via aPKC in glioblastoma, with TIAM1 providing compensatory Lgl1 inactivation when PREX1 is lost.","evidence":"CRISPR KO of PREX1 in patient-derived GBM cells; TIAM1 knockdown; phospho-Lgl1 western blot; RNA-seq","pmids":["34624316"],"confidence":"High","gaps":["Whether PREX1/TIAM1 activate aPKC directly or through Rac-PAK intermediates was not defined","In vivo validation of compensatory TIAM1 signaling was lacking"]},{"year":2022,"claim":"Direct binding of LLGL1 to Integrin β1 and inhibition of its downstream signaling established a new mechanism by which LLGL1 controls directional migration and branching morphogenesis in mammary epithelium.","evidence":"Co-immunoprecipitation; conditional mammary Lgl1 KO; Integrin β1 overexpression phenocopying KO in 3D branching assays","pmids":["35172155"],"confidence":"High","gaps":["The LLGL1 domain mediating Integrin β1 binding was not mapped","Whether aPKC phosphorylation regulates the LLGL1-Integrin β1 interaction was not tested"]},{"year":2023,"claim":"LLGL1 was shown to reside in a Scrib/NMII-A/E-cadherin-catenin complex at adherens junctions that opposes TGFβ-induced EMT, while in AML it was found to be required for stemness and HoxA gene expression—revealing tissue-dependent oncogenic versus tumor-suppressive contexts.","evidence":"Co-IP and siRNA with AJ marker readouts and TGFβ-EMT rescue; CRISPR screen in human/murine AML with HoxA9 rescue","pmids":["37743653","37587260"],"confidence":"High","gaps":["Whether LLGL1 promotes HoxA transcription directly or through aPKC-dependent intermediaries was unclear","The apparently opposite roles in solid tumors versus AML require mechanistic reconciliation"]},{"year":2024,"claim":"Conditional LLGL1 deletion in cerebellar and midbrain primordia confirmed that LLGL1 controls neuroepithelial polarity through N-cadherin and Cdc42/β-catenin, and showed that LLGL1 loss activates EGFR/RAS/MAPK signaling in hepatocellular carcinoma cells.","evidence":"Pax2-Cre conditional KO with immunofluorescence for polarity markers; CRISPR LLGL1 KO in Huh-7 with phospho-proteomic pathway analysis","pmids":["38526932","38444736","41977148"],"confidence":"Medium","gaps":["Whether EGFR/MAPK suppression is a direct biochemical activity or indirect consequence of polarity disruption is unresolved","Single-lab studies for each finding"]},{"year":null,"claim":"Major unresolved questions include the structural basis for LLGL1's mutually exclusive complex formation, how LLGL1 mechanistically suppresses EGFR signaling, whether Rab10 and N-cadherin trafficking functions share a common vesicular pathway, and how LLGL1's apparently opposite roles in solid tumors (suppressor) versus AML (stemness-promoter) are reconciled at the molecular level.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal/cryo-EM structure of LLGL1 or its complexes exists","Tissue-specific phosphorylation dynamics remain uncharacterized","The relationship between the Rab10, N-cadherin, NG2, and Integrin β1 trafficking functions is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10,24,31]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9,10,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,10,14,25]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,9,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,16]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,14,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,23,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,8,15,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,11,12,26,28]}],"complexes":["Scrib/Dlg polarity complex","PAR-6/aPKC complex","Scrib/NMII-A/E-cadherin-catenin AJ complex"],"partners":["MYH9","PARD6A","PRKCZ","SCRIB","CDH2","RAB10","ITGB1","DLG1"],"other_free_text":[]},"mechanistic_narrative":"LLGL1 is an evolutionarily conserved cortical polarity regulator that functions as a tumor suppressor by coordinating cell polarity, adhesion, membrane trafficking, and differentiation across multiple tissues. It forms two mutually exclusive complexes—one with nonmuscle myosin IIA (NMII-A), whose filament assembly it directly inhibits, and one with PAR-6/aPKC—and aPKC-mediated phosphorylation of LLGL1 switches it between these states, releasing NMII-A regulation and relocating LLGL1 from the cortex to the cytosol [PMID:24213535, PMID:22219375]. LLGL1 maintains epithelial adherens junctions by directly binding and promoting internalization of N-cadherin, restricting apical junctional complex assembly; disruption of this interaction in the developing cortex causes periventricular heterotopia, while broader Lgl1 loss produces neural progenitor hyperproliferation, failed asymmetric Numb localization, and cortical malformations [PMID:28552558, PMID:15037549, PMID:30597194]. In cancer, PTEN loss drives PI3K→Rac-GEF (PREX1/TIAM1)→aPKC-mediated hyperphosphorylation and inactivation of LLGL1, promoting invasion and blocking differentiation in glioblastoma, while LLGL1 loss independently activates EGFR/RAS/MAPK and ERK-Sp1-OSMR signaling axes in hepatocellular and pancreatic carcinomas [PMID:23907540, PMID:34624316, PMID:32615164, PMID:41977148]."},"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":"15037549","id":"PMC_15037549","title":"Loss 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30639242","id":"PMC_30639242","title":"The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30639242","citation_count":124,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34857952","id":"PMC_34857952","title":"Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers.","date":"2021","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34857952","citation_count":116,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27453043","id":"PMC_27453043","title":"A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy.","date":"2016","source":"Molecular 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/32707033","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50068,"output_tokens":6194,"usd":0.121557},"stage2":{"model":"claude-opus-4-6","input_tokens":9841,"output_tokens":4923,"usd":0.25842},"total_usd":0.831961,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62843,"output_tokens":11156,"usd":0.177934},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":13770,"output_tokens":4554,"usd":0.27405}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of Lgl1 in mice results in failure of asymmetric localization of the Notch inhibitor Numb during cell division in neural progenitor cells, leading to failure of asymmetric cell divisions, hyperproliferation, and lack of differentiation in neuroepithelial cells.\",\n      \"method\": \"Lgl1 knockout mouse model with immunolocalization of Numb; analysis of cell cycle exit and differentiation defects\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (asymmetric Numb localization failure), replicated across multiple readouts\",\n      \"pmids\": [\"15037549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human LLGL1 (Hugl-1) functionally substitutes for Drosophila lgl in vivo, rescuing larval lethality and neoplastic tissue overgrowth, and restoring correct localization of Dlg and Scrib, demonstrating functional conservation of the lgl-dlg-scrib tumor suppressor pathway.\",\n      \"method\": \"Genetic rescue of homozygous Drosophila lgl mutants by Hugl-1 transgene expression; immunolocalization of Dlg and Scrib\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo epistasis/rescue with multiple phenotypic readouts, strong conservation demonstrated\",\n      \"pmids\": [\"15467749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lgl1 activates Rab10 GTPase by releasing GDP dissociation inhibitor (GDI) from Rab10, thereby promoting membrane precursor vesicle trafficking required for axonal growth and neuronal polarization.\",\n      \"method\": \"Co-immunoprecipitation, GDI-release assay, downregulation/upregulation of Lgl1 and Rab10 in neurons, in vivo cortical electroporation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical GDI-release assay plus Co-IP plus epistasis experiments in vitro and in vivo\",\n      \"pmids\": [\"21856246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lgl1 directly interacts with and inhibits non-muscle myosin IIA (NMII-A) filament assembly in vitro; Lgl1 regulates the cellular localization of NMII-A (preventing its accumulation at the leading edge), and controls focal adhesion size, number, and cell migration polarity.\",\n      \"method\": \"In vitro NMII-A filament assembly assay, Co-IP in vivo, Lgl1 depletion with phenotypic readouts (focal adhesion morphology, NMII-A localization, cell migration)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of inhibition plus Co-IP plus loss-of-function phenotype\",\n      \"pmids\": [\"22219375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lgl1 forms two distinct complexes in vivo: Lgl1-NMII-A and Lgl1-Par6α-aPKCζ. Phosphorylation of Lgl1 by aPKCζ prevents its interaction with NMII-A and inhibits NMII-A filament assembly; aPKCζ and NMII-A compete to bind directly to Lgl1 at the same domain. The Lgl1-Par6α-aPKCζ complex resides at the leading edge.\",\n      \"method\": \"In vitro phosphorylation assay, Co-IP, in vitro NMII-A filament assembly assay, phosphomimetic/non-phosphorylatable Lgl1 mutants, immunolocalization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro assays, mutagenesis, and Co-IP in single study\",\n      \"pmids\": [\"24213535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTEN loss leads to aberrant activation of atypical protein kinase C (aPKC), which phosphorylates and inactivates Lgl1, maintaining glioblastoma tumor initiating cells (GTICs) in an undifferentiated state. Expression of a non-phosphorylatable Lgl1 promotes differentiation.\",\n      \"method\": \"PTEN re-expression, aPKC knockdown by RNAi, non-phosphorylatable Lgl1 expression in GTICs; differentiation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple interventions (PTEN re-expression, aPKC KD, phosphomutant) and defined phenotypic readout\",\n      \"pmids\": [\"23907540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LLGL1 directly binds to N-cadherin and promotes its internalization; this interaction is inhibited by aPKC-mediated phosphorylation of LLGL1, restricting apical junctional complex (AJC) accumulation to the basolateral-apical boundary. Disruption of N-cadherin-LLGL1 interaction in vivo causes periventricular heterotopia.\",\n      \"method\": \"Co-IP, live cortical imaging, conditional Llgl1 knockout (Nestin-Cre/Llgl1fl/fl), internalization assays, in vivo disruption of N-cadherin-LLGL1 interaction\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding shown by Co-IP, functional internalization assay, mutagenesis, and in vivo rescue/disruption experiments\",\n      \"pmids\": [\"28552558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lgl1 is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing atypical protein kinases (aPKCs); Lgl1 conditional knockout in pyramidal neurons reduces AMPA/NMDA ratio and impairs synaptic plasticity.\",\n      \"method\": \"Synaptosome fractionation, conditional knockout of Lgl1 in pyramidal neurons, electrophysiology (AMPA/NMDA ratio), behavioral assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fractionation plus KO with defined electrophysiological phenotype, single lab\",\n      \"pmids\": [\"31546104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lgl1 has sequential cell-autonomous and community-effect (tissue-wide non-autonomous) functions in radial glia progenitors during cortical neurogenesis and glia genesis, identified by MADM-based sparse and global single-cell knockout analysis.\",\n      \"method\": \"Mosaic Analysis with Double Markers (MADM) genetic paradigm enabling sparse and global Lgl1 knockout with single-cell resolution\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic paradigm (MADM) enabling cell-autonomous vs. non-autonomous distinction at single-cell resolution\",\n      \"pmids\": [\"28472654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of Llgl1 in retinal neuroepithelia expands the apical domain and increases Notch activity, reducing neurogenesis; blocking Notch signaling (by depleting Rbpj) rescues normal neurogenesis, placing Llgl1 upstream of apical domain size and Notch activity in neurogenic regulation.\",\n      \"method\": \"Llgl1 morpholino knockdown in zebrafish retina, epistasis with Rbpj knockdown, experimental apical domain expansion via Shroom3 inhibition\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis experiment with multiple interventions places Llgl1 in a defined pathway\",\n      \"pmids\": [\"22492354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lgl1 controls NG2 endocytic routing in oligodendrocyte progenitor cells (OPCs); loss of Lgl1 causes aberrant NG2 recycling leading to failed OL differentiation and increased symmetric self-renewing divisions at the expense of asymmetric divisions.\",\n      \"method\": \"Lgl1 conditional knockout in OPCs, time-lapse microscopy, total internal reflection microscopy (TIRF) for endocytic routing, asymmetric division quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-imaging of endocytic routing plus conditional KO with defined phenotypic readouts in two complementary microscopy approaches\",\n      \"pmids\": [\"30131568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Scribble forms a complex in vivo with Lgl1 through its leucine-rich repeat domain; Scribble, Lgl1, and myosin II colocalize at the leading edge of migrating cells; depletion of either Scrib or Lgl1 disrupts myosin II localization and inhibits focal adhesion disassembly and directed cell migration.\",\n      \"method\": \"Co-IP, domain-mapping, immunofluorescence colocalization, Scrib/Lgl1 depletion with focal adhesion and migration phenotype readouts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping plus multiple loss-of-function phenotypic readouts\",\n      \"pmids\": [\"32697665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Llgl1 depletion in cardiomyocytes decreases Yap protein levels and blunts Yap target gene transcription without affecting Yap transcript levels; cardiomyocyte-specific Yap overexpression in Llgl1-depleted zebrafish embryos rescues cardiac defects, establishing Llgl1 as a regulator of Yap protein stability in cardiomyocytes.\",\n      \"method\": \"Llgl1 siRNA knockdown in cardiomyocytes, western blot for Yap protein vs. mRNA, zebrafish llgl1 morpholino, cardiomyocyte-specific Yap overexpression rescue\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment in vivo plus mechanistic distinction of protein stability vs. transcription\",\n      \"pmids\": [\"32843528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of LLGL1 in pancreatic ductal adenocarcinoma promotes oncostatin M receptor (OSMR) expression by inducing ERK2 and Sp1 phosphorylation, which drives Sp1 binding to the OSMR promoter and enhances OSMR transcription, leading to gemcitabine resistance.\",\n      \"method\": \"Genome-wide RNAi screening, OSMR knockdown rescue, gene expression microarray, phosphorylation assays, chromatin binding assay for Sp1, tumor formation assay\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement with multiple molecular readouts, single lab\",\n      \"pmids\": [\"32615164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PREX1, a PI3-kinase pathway-responsive Rac guanine nucleotide exchange factor, links aberrant PI3K signaling to Lgl1 phosphorylation in glioblastoma; TIAM1 (a short isoform) can redundantly fulfill this role. PREX1 knockout reduces Lgl1 phosphorylation and restores partial neuronal differentiation.\",\n      \"method\": \"CRISPR/Cas9 knockout of PREX1, re-expression of PREX1, TIAM1 knockdown, Lgl1 phosphorylation assay, RNA-seq\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with rescue and defined phosphorylation readout, single lab\",\n      \"pmids\": [\"34624316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGL1 binds directly to Integrin β1 and inhibits its downstream signaling; Integrin β1 overexpression blocks epithelial directional migration, recapitulating the Lgl1 null phenotype, establishing that LGL1 modulation of Integrin β1 signaling is required for directional mammary epithelial cell migration and branching morphogenesis.\",\n      \"method\": \"Co-IP of LGL1 with Integrin β1, Lgl1 conditional knockout in mammary gland, Integrin β1 overexpression phenocopy, directional migration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding by Co-IP, genetic phenocopy by Integrin β1 overexpression, and KO with defined migration phenotype\",\n      \"pmids\": [\"35172155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Scribble, Lgl1, and NMII-A reside in a complex with the E-cadherin-catenin complex at adherens junctions; depletion of either Scribble or Lgl1 disrupts E-cadherin-catenin complex localization to AJs; aPKCζ phosphorylation of Lgl1 regulates AJ localization of both Lgl1 and E-cadherin-catenin complexes.\",\n      \"method\": \"Co-IP, Scrib/Lgl1 depletion, immunofluorescence of AJ components, aPKCζ phosphorylation assays\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and loss-of-function with localization readouts, single lab\",\n      \"pmids\": [\"37743653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LLGL1 inactivation in AML leads to loss of stemness-associated gene expression including HoxA-genes and induces a GMP-like phenotype; re-expression of HoxA9 rescues this phenotype, placing LLGL1 upstream of HoxA-gene-dependent AML stem cell maintenance.\",\n      \"method\": \"CRISPR/Cas9-based genetic screening, LLGL1 inactivation in human and murine AML, HoxA9 re-expression rescue, gene-expression profiling\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (HoxA9 rescue) with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"37587260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The hDlg/hScrib/Hugl-1 (LLGL1) scribble complex components co-localize and are interdependent for correct membrane localization; hScrib loss partially delocalizes hDlg and Hugl-1; all three components interact with the t-SNARE syntaxin 4, linking the complex to vesicle transport pathways.\",\n      \"method\": \"shRNA ablation of hScrib, immunofluorescence colocalization, Co-IP with syntaxin 4\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and localization with KD, single lab\",\n      \"pmids\": [\"18793635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Llgl1 loss causes EGFR mislocalization; an EGFR mislocalization point mutation (P667A) recapitulates Llgl1-null phenotypes including AKT activation and TAZ nuclear translocation, indicating Llgl1 maintains EGFR cortical localization to suppress pre-neoplastic signaling.\",\n      \"method\": \"Llgl1 knockout cell lines, EGFR point mutant (P667A) expression, TAZ nuclear translocation assay, mammosphere and soft-agar assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — phenocopy by EGFR mutant provides mechanistic link, single lab\",\n      \"pmids\": [\"27542214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LGL1 (CRISPLD2) is a secreted glycoprotein that co-localizes with Golgi and endoplasmic reticulum markers; pulse-chase studies show a half-life of 11.5 hours; at late gestation, fetal distal lung epithelial cells import LGL1 protein from mesenchymal cells, supporting a paracrine signaling role in mesenchymal-epithelial interactions during lung organogenesis.\",\n      \"method\": \"Dual immunofluorescence with Golgi/ER markers, pulse-chase protein stability assay, protein import assay in epithelial cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulse-chase and co-localization with organelle markers plus import assay, single lab\",\n      \"pmids\": [\"12880386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Antisense-mediated reduction of LGL1 expression inhibits airway epithelial branching in fetal rat lung explant culture in a dose- and time-dependent manner, demonstrating a required role for lgl1 in fetal airway branching morphogenesis.\",\n      \"method\": \"Antisense oligodeoxynucleotides in fetal rat lung explant culture; western blot and in situ hybridization for LGL1 expression; morphometric analysis of branching\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined morphogenetic phenotype in an ex vivo model, single lab\",\n      \"pmids\": [\"12540491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2029,\n      \"finding\": \"USP11 acts as a deubiquitinase that stabilizes Mgl-1 (LLGL1 mammalian homolog) protein and prevents its proteasomal degradation; this activity requires the scaffolding protein RanBPM. Loss of USP11 promotes tumor formation.\",\n      \"method\": \"Deubiquitinase activity assay, co-IP, RanBPM knockdown, in vivo tumor formation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic assay for deubiquitination plus Co-IP plus in vivo phenotype, single lab\",\n      \"pmids\": [\"26919101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLG4 functions as a scaffold that directly interacts with STAT3 and recruits E3 ubiquitin ligase RNF63 (MKRN3) to STAT3, promoting K48-linked polyubiquitination and proteasome-mediated degradation of STAT3 in non-small cell lung cancer cells.\",\n      \"method\": \"Affinity purification mass spectrometry, denaturation-IP for ubiquitination, Co-IP, xenograft tumor model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed by Co-IP and denaturation ubiquitination assay, single lab\",\n      \"pmids\": [\"40619404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Llgl1 in zebrafish is required for timely epicardial emergence; llgl1 mutants exhibit delayed epicardial cell emergence, resulting in delayed apical deposition of a laminin sheath on the ventricular surface and aberrant apical extrusion of ventricular cardiomyocytes.\",\n      \"method\": \"Zebrafish llgl1 mutant analysis, immunofluorescence for laminin and epicardial markers, live imaging\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in zebrafish with defined cellular and matrix assembly phenotype, single lab\",\n      \"pmids\": [\"38940292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ablation of both Llgl1 and Llgl2 in mouse skin epidermis activates aPKC and upregulates NF-kB signaling, which is associated with squamous cell carcinoma development in the context of Trp53 loss, placing Lgl signaling upstream of aPKC-NF-kB in mammalian skin tumor suppression.\",\n      \"method\": \"K14-Cre-mediated double conditional knockout of Llgl1/2, compound Trp53/Llgl1/2 cKO mice, immunostaining for aPKC activity and NF-kB pathway markers\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in compound KO mice with pathway readouts, preprint, single lab\",\n      \"pmids\": [\"36945368\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LLGL1 is an evolutionarily conserved cortical scaffold protein that maintains cell polarity by forming distinct complexes with NMII-A and Par6-aPKC: aPKC-mediated phosphorylation of LLGL1 releases it from NMII-A (inhibiting actomyosin assembly at the leading edge) and from N-cadherin (restricting apical junction complex formation), while non-phosphorylated LLGL1 activates Rab10-dependent membrane vesicle trafficking for axonal growth, controls NG2 endocytic routing in oligodendrocyte progenitors, stabilizes Yap protein in cardiomyocytes, binds and inhibits Integrin β1 signaling in epithelial cells, and recruits RNF63 to ubiquitinate STAT3 for proteasomal degradation, collectively functioning as a tumor suppressor that couples apical-basal polarity to membrane trafficking, cell-cell adhesion, and downstream oncogenic signaling pathways.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe target gene is LLGL1 (human lethal giant larvae homolog 1, also called Hugl-1, Lgl1 in mouse/rat/zebrafish orthologs). This is a cell polarity tumor suppressor protein, part of the Scribble complex.\n\nPapers to EXCLUDE (alias collisions or off-target):\n- Papers about DLG4/PSD-95 (PMID 20952458, 29155979, 17121805, 11714708, 36127319, 23636947, 32039235, 17164261, 21151988, 23936182, 18155665 [Hugl-2 promoter - different gene], 29460436, 33597769, 38135915, 37525972, 37525090, 36854414, 28874660, 9286702, 10582582, 12609736, 9177775 [FLII/LLGL overlap - genomic only], 40506760, 39187442, 32580088, 39523115, 36732356)\n- Papers about LGL-1 as NK cell antigen (PMID 2453582, 1391328, 2365999, 7509843) - this is a mouse NK cell surface antigen, not the LLGL1 polarity protein\n- Papers about MGL1/CD301a (PMID 19095961, 31906385, 33677516) - C-type lectin, different gene\n- Papers about CRISPLD2/LGL1 in lung (PMID 27597766, 12880386, 12540491, 19772569, 20057335, 16492977, 25480331, 17670908, 25593968) — NOTE: CRISPLD2 is a different gene (cysteine-rich secretory protein LCCL domain containing 2), sometimes called \"LGL1\" but it is NOT the LLGL1 polarity gene (different chromosome, different protein family). EXCLUDE.\n- MGL-1 in C. elegans (PMID 28807780) - glutamate receptor homolog, different gene\n- LGI1/CASPR2 paper (PMID 28628235) - different gene entirely\n- Papers about purely genomic mapping/sequence without functional data (PMID 8565641 - mapping only, but does note encoding 1033aa protein)\n- C. elegans lgl-1 (PMID 23536568, 35903776) — C. elegans LGL-1 is a legitimate ortholog; KEEP for mechanistic findings\n- Papers 16169070, 12477932, 20562859, 26186194, 28514442, 26496610, 33961781, 21873635, 15489334, 26638075, 35271311, 26344197, 34079125, 21145461, 19322201, 31871319, 30639242, 34857952, 27453043, 29467282, 88 citations kinase paper - these are large interactome/proteome screens; LLGL1 may appear as a hit but no specific mechanistic findings about LLGL1 itself. EXCLUDE from discoveries.\n- Goat LLGL1 indel association (PMID 31646948) - association study, no mechanism. EXCLUDE.\n- DLG4 methylation/epigenetics papers (PMID 28645745) - off-target\n- PMID 37743653 (Abedrabbo 2023, Scribble/Lgl1/myosin IIA/catenin) - KEEP\n- PMID 32697665 (Abedrabbo 2020, Scribble/Lgl1/myosin) - KEEP\n\n**KEEP list:** 15037549, 15467749, 16170365, 21856246, 28472654, 22492354, 28552558, 22219375, 24213535, 23907540, 26341367, 30131568, 18793635, 25426552, 34624316, 31546104, 35172155, 32843528, 38940292, 30597194, 37587260, 30083817, 27542214, 27603780, 31415124, 36945368, 40619404 (DLG4 paper - EXCLUDE, it's about DLG4/PSD-95), 7542763, 12725730 (Yamanaka 2003 - mammalian Lgl/PAR-6/aPKC - KEEP), 14676191 (PAR proteins proteomics - mentions Lgl indirectly, but no specific LLGL1 mechanism), 18074678 (expression/survival only - EXCLUDE), 19447873 (aberrant splicing/functional assays - KEEP), 26919101 (USP11/Mgl-1 - KEEP, this is about Mgl-1 = mouse Lgl1 homolog), 16969496 (WD-40 deletion mutants Mgl-1 - KEEP), 14612921 (mgl-1 mouse - KEEP), 26662669 (expression only - EXCLUDE), 23536568 (C. elegans LGL-1 - KEEP as ortholog), 32222154 (miR-665/LLGL1 - functional target validation - KEEP for confirming LLGL1 as tumor suppressor target), 34956060 (polarity proteins in epilepsy - expression/western blot only - EXCLUDE mechanistic), 38526932 (LGL1 cerebellar primordium - conditional KO with mechanistic findings - KEEP), 38444736 (midbrain KO - KEEP), 32615164 (LLGL1/ERK-SP1-OSMR - KEEP), 41977148 (LLGL1 KO/EGFR/MAPK - KEEP), 35063084 (Tau interactome - EXCLUDE, not about LLGL1).\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Human LLGL1 (HUGL) encodes a cytoskeletal protein of ~115 kDa that physically associates with nonmuscle myosin II heavy chain; the protein is phosphorylated at serine residues by an associated kinase, establishing its identity as a cortical cytoskeleton component.\",\n      \"method\": \"Affinity-purified polyclonal antibodies against HUGL peptides; co-immunoprecipitation/co-purification with nonmuscle myosin II heavy chain; in vitro kinase assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical association plus kinase assay, foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"7542763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mammalian Lgl (mLgl/LLGL1) competes with PAR-3 to form an independent complex with PAR-6 and aPKC. During cell polarization, mLgl initially colocalizes with PAR-6/aPKC at cell-cell contacts and is phosphorylated by aPKC, causing its segregation to the basolateral membrane. Overexpression of the mLgl/PAR-6/aPKC complex suppresses epithelial junction formation, in contrast to the PAR-3/PAR-6/aPKC complex which promotes it.\",\n      \"method\": \"Co-immunoprecipitation; overexpression studies in epithelial cells; immunofluorescence localization; in vitro aPKC phosphorylation assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, localization, functional overexpression, in vitro phosphorylation), replicated in subsequent studies\",\n      \"pmids\": [\"12725730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of Lgl1 in mice causes failure of asymmetric localization of the Notch inhibitor Numb during cell division of neural progenitor cells, leading to symmetric divisions, hyperproliferation, lack of differentiation, and severe brain dysplasia including neuroepithelial rosette-like structures resembling neuroblastic rosettes.\",\n      \"method\": \"Lgl1 knockout mouse (Lgl1−/−); immunostaining for Numb localization; BrdU incorporation; TUNEL apoptosis assay; histopathology\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple specific phenotypic readouts including Numb asymmetry, widely cited foundational study\",\n      \"pmids\": [\"15037549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human LLGL1 (Hugl-1) can functionally substitute for Drosophila lgl in vivo: expression of Hugl-1 in homozygous lgl Drosophila mutants rescues larval lethality, restores correct localization of Dlg and Scrib, and permits normal metamorphosis, demonstrating functional conservation of the lgl/dlg/scrib tumor suppressor pathway.\",\n      \"method\": \"Transgenic rescue in Drosophila lgl homozygous mutants; immunostaining for Dlg and Scrib localization; developmental phenotype scoring\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic rescue with localization readouts, strong functional conservation evidence\",\n      \"pmids\": [\"15467749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Re-expression of LLGL1 (Hugl-1) in melanoma cell lines increases cell adhesion and decreases cell migration, and is associated with downregulation of MMP2 and MMP14 and re-expression of E-cadherin, supporting a role for LLGL1 in suppressing epithelial-mesenchymal transition (EMT).\",\n      \"method\": \"Stable transfection of Hugl-1 into melanoma cell lines; cell adhesion and migration functional assays; RT-PCR and western blot for MMP2, MMP14, E-cadherin\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional gain-of-function with multiple molecular readouts but single lab\",\n      \"pmids\": [\"16170365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LLGL1 (Hugl-1) forms a complex with hDlg and hScrib in mammalian cells; correct localization of hDlg and Hugl-1 is partially dependent on hScrib under normal conditions, but both can localize to cell membranes independently of hScrib under osmotic stress. The hScrib complex interacts with the t-SNARE syntaxin 4, linking the Scrib polarity complex to vesicle transport pathways.\",\n      \"method\": \"shRNA ablation of hScrib; co-localization by immunofluorescence; co-immunoprecipitation with syntaxin 4; osmotic stress treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional localization experiments, single lab\",\n      \"pmids\": [\"18793635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LLGL1 (Hugl-1) mRNA undergoes frequent aberrant splicing in hepatocellular carcinoma, generating truncated proteins lacking WD-40 repeat motifs. Overexpression of two HCC-derived aberrant Hugl-1 variants promotes HCC cell migration, invasion, and tumorigenicity in nude mice, acting as dominant-negative or gain-of-function variants.\",\n      \"method\": \"RT-PCR and sequencing of 80 HCC specimens; western blot; wound healing, Boyden chamber migration/invasion assays; nude mouse tumorigenicity assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with multiple readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"19447873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lgl1 (mouse LLGL1) associates with plasmalemmal precursor vesicles, is enriched in developing axons, and directly interacts with Rab10 GTPase. Lgl1 activates Rab10 by releasing GDP dissociation inhibitor (GDI) from Rab10, thereby promoting membrane protein trafficking. Rab10 acts downstream of Lgl1 in axon development and directional membrane insertion, and both are required for neocortical neuronal polarization in vivo.\",\n      \"method\": \"Co-immunoprecipitation; GDI release assay; overexpression/knockdown of Lgl1 and Rab10 in neurons; live imaging of membrane insertion; in vivo electroporation into neocortex\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including biochemical interaction, functional GDI assay, in vitro and in vivo epistasis\",\n      \"pmids\": [\"21856246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of Llgl1 in vertebrate retinal neuroepithelia results in expansion of the apical domain and increased Notch activity, which reduces neurogenesis. Blocking Notch signaling by depleting Rbpj restores normal neurogenesis. Experimental expansion of the apical domain via Shroom3 inhibition phenocopies Llgl1 loss (increased Notch, reduced neurogenesis), establishing that Llgl1 controls neurogenesis through regulation of apical domain size and downstream Notch signaling.\",\n      \"method\": \"Morpholino knockdown of Llgl1 in zebrafish retina; genetic epistasis (Rbpj depletion); Shroom3 inhibition; Notch activity reporters; interkinetic nuclear migration analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with rescue experiment plus multiple phenotypic readouts\",\n      \"pmids\": [\"22492354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lgl1 (mammalian LLGL1) directly interacts with nonmuscle myosin IIA (NMII-A) and inhibits NMII-A filament assembly in vitro. Depletion of Lgl1 causes aberrant NMII-A localization to the leading edge, alters focal adhesion size and number, and impairs cell polarity and directional migration.\",\n      \"method\": \"Co-immunoprecipitation in vivo; in vitro filament assembly inhibition assay; Lgl1 siRNA knockdown; immunofluorescence of NMII-A localization and focal adhesions; migration assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro filament assembly assay plus Co-IP and functional knockdown with defined readouts\",\n      \"pmids\": [\"22219375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lgl1 forms two distinct complexes in vivo: Lgl1-NMII-A and Lgl1-Par6α-aPKCζ. Phosphorylation of Lgl1 by aPKCζ prevents Lgl1 interaction with NMII-A both in vitro and in vivo, affects NMII-A filament assembly inhibition, and alters Lgl1 cellular localization. aPKCζ and NMII-A compete to bind the same domain of Lgl1. The Lgl1-Par6α-aPKCζ complex localizes to the leading edge.\",\n      \"method\": \"Co-immunoprecipitation; in vitro phosphorylation and filament assembly assays; phosphomimetic/non-phosphorylatable Lgl1 mutants; immunofluorescence localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro biochemical assays plus mutagenesis plus reciprocal Co-IPs\",\n      \"pmids\": [\"24213535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTEN loss leads to aberrant aPKC activation, which phosphorylates and inactivates Lgl1 in glioblastoma cells. Re-expression of PTEN promotes differentiation along a neuronal lineage, as does aPKC knockdown or expression of a non-phosphorylatable Lgl1 (Lgl3SA). Thus, the PTEN→PI3K→aPKC→Lgl1 pathway controls glioblastoma tumor-initiating cell differentiation.\",\n      \"method\": \"PTEN re-expression; aPKC siRNA knockdown; non-phosphorylatable Lgl3SA expression; neuronal differentiation assays; phospho-Lgl1 western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple interventions converging on same pathway and phenotype\",\n      \"pmids\": [\"23907540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Constitutively active non-phosphorylatable Lgl1 (Lgl3SA) inhibits glioblastoma cell motility in vitro and markedly reduces in vivo invasion of primary glioblastoma cells in intracerebral xenografts. Lgl3SA also induces differentiation along the neuronal lineage in vitro and in vivo, confirming that Lgl1's tumor suppressor functions require its non-phosphorylated (active) state.\",\n      \"method\": \"Doxycycline-inducible Lgl3SA expression system; in vitro motility assay; intracerebral xenograft model; differentiation markers by immunostaining\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — doxycycline-inducible system with non-phosphorylatable mutant, in vitro and in vivo readouts\",\n      \"pmids\": [\"25426552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-652-3p directly targets the 3'UTR of LLGL1, reducing LLGL1 protein expression. Overexpression of Lgl1 partially attenuates miR-652-3p-driven promotion of NSCLC cell proliferation, migration, invasion, and inhibition of apoptosis, confirming LLGL1 as a direct functional target of miR-652-3p.\",\n      \"method\": \"Luciferase reporter with LLGL1 3'UTR; 3'UTR binding-site mutation; miR-652-3p overexpression/knockdown; western blot; proliferation/migration/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct 3'UTR luciferase validation with mutation plus functional rescue, single lab\",\n      \"pmids\": [\"26934648\"],\n      \"is_preprint\": false\n    },\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 (AJCs) to the basolateral-apical boundary. Disruption of the N-cadherin–LLGL1 interaction in vivo is sufficient to cause periventricular heterotopia (PH) resembling severe cortical malformation in mice.\",\n      \"method\": \"Co-immunoprecipitation; endocytosis/internalization assay; phosphomimetic/non-phosphorylatable LLGL1 mutants; Nestin-Cre/Llgl1fl/fl conditional KO; live cortical imaging; in utero electroporation to disrupt N-cadherin-LLGL1 interaction\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, endocytosis assay, mutagenesis, conditional KO, and in vivo rescue/disruption\",\n      \"pmids\": [\"28552558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mosaic analysis with double markers (MADM) reveals Lgl1 has distinct sequential functions: tissue-wide (community effect) Lgl1-dependent mechanisms are required for embryonic cortical neurogenesis, while cell-autonomous Lgl1 functions control radial glial progenitor-mediated gliogenesis and postnatal neural stem cell behavior.\",\n      \"method\": \"MADM-based sparse and global conditional knockout at single-cell resolution; clonal analysis; BrdU/EdU labeling; immunostaining for progenitor/glia markers\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MADM genetic paradigm enabling cell-autonomous vs. non-autonomous dissection with single-cell resolution\",\n      \"pmids\": [\"28472654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional deletion of Lgl1 in oligodendrocyte progenitor cells (OPCs) causes retention of the pro-mitotic proteoglycan NG2 in OL progeny through aberrant NG2 recycling rather than endosomal routing to lysosomes. Lgl1 controls NG2 endocytic routing as revealed by total internal reflection and time-lapse microscopy. Hemizygous Ink4a/Arf and Lgl1 knockouts in OPCs synergistically induce gliomagenesis.\",\n      \"method\": \"Conditional Lgl1 KO in OPCs; time-lapse and total internal reflection fluorescence microscopy of NG2 trafficking; immunophenotyping; synergistic gliomagenesis assay with Ink4a/Arf\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging of endocytic routing with conditional KO and genetic interaction studies\",\n      \"pmids\": [\"30131568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Lgl1 in dorsal telencephalon (Emx1-Cre) disrupts adherens junctions (AJs) in radial glia, causes ectopic displacement of radial glia and intermediate progenitors, disorganizes the radial glial fiber scaffold, and results in failed neuronal migration producing subcortical band heterotopia (SBH) resembling the human condition.\",\n      \"method\": \"Emx1-Cre conditional Lgl1 KO; histology; immunostaining for AJ markers (N-cadherin, β-catenin), radial glia (nestin), neuron birth-dating with BrdU/EdU; behavioral testing\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular (AJ disruption) and cellular (scaffold disorganization, neuronal migration failure) phenotypes\",\n      \"pmids\": [\"30597194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Apical-basal polarity protein Lgl1 is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing aPKC activity. Conditional knockout of Lgl1 in pyramidal neurons reduces AMPA/NMDA ratio and impairs synaptic plasticity. Loss of Lgl1 decreases Vangl2 in synaptosome fractions. Lgl1+/- mice show increased synapse number, impaired social interaction, and stereotyped repetitive behavior rescuable by NMDA antagonists.\",\n      \"method\": \"Synaptosome fractionation; conditional KO in pyramidal neurons; electrophysiology (AMPA/NMDA ratio, LTP); behavioral assays; immunostaining\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — synaptosome fractionation, electrophysiology, conditional KO with behavioral and synaptic readouts\",\n      \"pmids\": [\"31546104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lgl1 deficiency in hippocampus (Emx1-Cre) causes disrupted hippocampal neuroepithelium with increased proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, disrupted adherens junctions, and abnormal neuronal migration. Lgl1-deficient mice display impaired spatial learning/memory and fear conditioning.\",\n      \"method\": \"Emx1-Cre conditional Lgl1 KO; histology; BrdU labeling; immunostaining for AJ markers; Morris water maze; fear conditioning behavioral tests\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"31415124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LLGL1 loss promotes expression of the cytokine receptor OSMR in pancreatic ductal adenocarcinoma cells, conferring gemcitabine resistance. Mechanistically, silencing LLGL1 induces ERK2 phosphorylation and phosphorylation of transcription factor Sp1 at Thr453, promoting Sp1 binding to the OSMR promoter and enhancing OSMR transcription. Knockdown of OSMR rescues chemoresistance.\",\n      \"method\": \"Genome-wide RNAi screen; cell proliferation and tumor formation assays; gene-expression microarray; ERK/Sp1 phosphorylation by western blot; ChIP for Sp1 binding at OSMR promoter; OSMR knockdown rescue\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus mechanistic follow-up with ChIP, phosphorylation assays, and pathway rescue\",\n      \"pmids\": [\"32615164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Scrib forms a complex in vivo with Lgl1 through its leucine-rich repeat (LRR) domain, and both Scrib and Lgl1 independently form complexes with myosin II. All three proteins colocalize at the leading edge of migrating cells. Cellular localization and cytoskeletal association of Scrib and Lgl1 are interdependent. Depletion of either Scrib or Lgl1 disrupts myosin II localization, inhibits focal adhesion disassembly, and impairs front-rear cell polarity during migration.\",\n      \"method\": \"Co-immunoprecipitation; siRNA depletion of Scrib or Lgl1; immunofluorescence colocalization; focal adhesion assays; cell polarity and migration assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional depletion experiments with multiple orthogonal readouts\",\n      \"pmids\": [\"32697665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Vertebrate Llgl1 (zebrafish/rat) is required for Yap protein stability in cardiomyocytes but not Yap mRNA levels, indicating post-translational regulation. Llgl1 depletion in zebrafish causes larger/dysmorphic cardiomyocytes, pericardial effusion, impaired blood flow, and aberrant valvulogenesis with broader Notch activation. Cardiomyocyte-specific Yap overexpression in Llgl1-depleted embryos rescues pericardial effusion and blood flow, establishing Yap as a downstream effector of Llgl1 in cardiac development.\",\n      \"method\": \"Morpholino and CRISPR-based llgl1 depletion in zebrafish; siRNA in rat cardiomyocytes; Yap protein/mRNA quantification; cardiomyocyte-specific Yap overexpression rescue; cardiac imaging\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic depletion in two organisms plus protein-level rescue experiment establishing Yap as downstream effector\",\n      \"pmids\": [\"32843528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PREX1, a PI3K-pathway-responsive Rac guanine nucleotide exchange factor, links aberrant PI3K signaling (downstream of PTEN loss) to Lgl1 hyperphosphorylation in glioblastoma. CRISPR knockout of PREX1 reduces Lgl1 phosphorylation, impairs motility, and promotes partial neuronal differentiation. In a PREX1-knockout patient subset, the Rac GEF TIAM1 (short isoform, overexpressed) compensates to maintain Lgl1 phosphorylation; TIAM1 knockdown in these cells restores reduced Lgl1 phosphorylation.\",\n      \"method\": \"CRISPR/Cas9 KO of PREX1; phospho-Lgl1 western blot; TIAM1 knockdown; RNA-seq; motility assays; patient-derived glioblastoma cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with rescue, phosphorylation readout, multiple patient-derived lines\",\n      \"pmids\": [\"34624316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGL1 (mouse Lgl1) binds directly to Integrin β1 and inhibits its downstream signaling. In mammary glands lacking Lgl1, epithelium cannot directionally migrate despite normal epithelial polarity, resulting in fewer branches. Integrin β1 overexpression recapitulates the Lgl1-null migration phenotype, demonstrating that LGL1-mediated inhibition of Integrin β1 signaling is essential for directional migration and epithelial branching.\",\n      \"method\": \"Conditional mammary Lgl1 KO; co-immunoprecipitation of LGL1 with Integrin β1; Integrin β1 overexpression; 3D branching morphogenesis assays; directional migration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP establishing direct binding, conditional KO, and Integrin β1 overexpression phenocopying KO\",\n      \"pmids\": [\"35172155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Scrib, Lgl1, and NMII-A reside in a complex with the E-cadherin-catenin complex at adherens junctions (AJs). Depletion of either Scrib or Lgl1 disrupts E-cadherin-catenin complex localization at AJs. aPKCζ phosphorylation of Lgl1 regulates AJ localization of Lgl1 and E-cadherin-catenin complexes. Scrib and Lgl1 regulate NMII-A activation and recruitment at AJs and are downregulated by TGFβ-induced EMT; their re-expression during EMT impedes EMT progression.\",\n      \"method\": \"Co-immunoprecipitation; siRNA depletion of Scrib and Lgl1; phosphomimetic Lgl1 mutants; immunofluorescence of AJ markers; TGFβ-induced EMT; re-expression rescue\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, mutagenesis, functional rescue with multiple orthogonal readouts\",\n      \"pmids\": [\"37743653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Inactivation of LLGL1 in acute myeloid leukemia (AML) cells impairs proliferative capacity and AML development across human and murine models with various genetic backgrounds. Loss of LLGL1 reduces stemness-associated gene expression including HoxA genes, inducing a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 rescues the functional and phenotypic defects caused by LLGL1 loss, establishing HoxA9 as a critical downstream target.\",\n      \"method\": \"CRISPR/Cas9 genetic screening; conditional LLGL1 inactivation in human and murine AML; gene-expression profiling; HoxA9 re-expression rescue; leukemia stem cell immunophenotyping\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen validated in multiple models with pathway rescue\",\n      \"pmids\": [\"37587260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Llgl1 mediates timely epicardial emergence and establishment of an apical laminin sheath on the ventricular surface during heart development. In llgl1 mutant zebrafish, ventricular cardiomyocytes undergo aberrant apical extrusion, epicardial cell emergence is delayed, and apical laminin deposition on the ventricular surface is consequently delayed. The epicardium is required for ventricular laminin deposition.\",\n      \"method\": \"llgl1 mutant zebrafish; immunostaining for laminin and epicardial markers; live imaging; lineage tracing of epicardial cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant with defined molecular readout, single lab\",\n      \"pmids\": [\"38940292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ablation of both Llgl1 and Llgl2 in mouse skin epidermis (K14-Cre) does not impact epidermal polarity in adult mice but promotes squamous cell carcinoma (SCC) development in cooperation with Trp53 loss. Mechanistically, Llgl1/2 ablation activates aPKC and upregulates NF-κB signaling, which may be required for SCC formation.\",\n      \"method\": \"K14-Cre double conditional KO of Llgl1 and Llgl2; Trp53/Llgl1/2 compound KO; tumor scoring; immunostaining for aPKC and NF-κB pathway activation\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic compound KO with mechanistic pathway readout, but preprint\",\n      \"pmids\": [\"36945368\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deletion of LGL1 in cerebellar primordium (Pax2-Cre) alters expression patterns of polarity molecules Cdc42 and β-catenin, causing loss of neuroepithelial cell polarity and formation of neuroblastoma-like tissues during early embryogenesis (before E15.5). These tumor-like structures are subsequently eliminated by apoptosis-mediated compensation.\",\n      \"method\": \"Pax2-LGL1−/− conditional KO mice; HE staining; immunofluorescence for Cdc42, β-catenin; TUNEL staining\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific molecular readouts, single lab\",\n      \"pmids\": [\"38526932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional deletion of Lgl1 in midbrain (Pax2-Cre) disrupts N-cadherin expression patterns, causing abnormal epithelial connections in the tectum, excessive proliferation and heightened apoptosis of neural progenitor cells, and aberrant neuronal migration.\",\n      \"method\": \"Pax2-Cre Lgl1 conditional KO; histology; BrdU labeling; immunofluorescence for Nestin (glial fibers) and N-cadherin (AJ marker)\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with molecular readout linking Lgl1 to N-cadherin, single lab\",\n      \"pmids\": [\"38444736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LLGL1 knockout in Huh-7 hepatocellular carcinoma cells potentiates EGFR-driven RAS/MAPK pathway activation, elevates EGFR phosphorylation and abundance, enhances RAF1-MEK-ERK-RSK signaling, and markedly increases migratory and invasive behavior without evidence of classical EMT. These data place LLGL1 as a suppressor of EGFR/RAS/MAPK signaling in HCC.\",\n      \"method\": \"CRISPR/Cas9 LLGL1 knockout in Huh-7 cells; phospho-proteomics/western blot for EGFR, RAF1, MEK, ERK, RSK; cell proliferation, migration, invasion assays; cell cycle analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with pathway-level phosphoproteomic readout, single lab\",\n      \"pmids\": [\"41977148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conserved amino acids G450 and D453 within the WD-40 repeat motif of mouse Mgl-1 (LLGL1 ortholog) are required for protein-protein interactions essential for cellular function; deletion mutants ΔG450 and ΔD453 fail to complement yeast Sop1/Sop2 double mutants at restrictive temperature and high salt, demonstrating the importance of the WD-40 repeat for LLGL1 function.\",\n      \"method\": \"Site-directed deletion mutagenesis of WD-40 residues in Mgl-1; yeast complementation assay (Sop1/Sop2 double mutant)\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with functional in vivo complementation readout, single lab\",\n      \"pmids\": [\"16969496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Mgl-1 (LLGL1 ortholog) partially restores salt tolerance in yeast Sop1/Sop2 double mutants, demonstrating evolutionary conservation of lgl family function. Spatial expression analysis shows mgl-1 mRNA is expressed throughout early embryonic development (E4.5–E18.5) with peak at E10.5, in CNS, craniofacial region, eyes, limbs, and gut.\",\n      \"method\": \"Yeast complementation assay; RT-PCR temporal expression; in situ hybridization spatial expression\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast complementation (partial) and expression analysis, single lab\",\n      \"pmids\": [\"14612921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Llgl1 in mammary cells causes EGFR mislocalization and drives pre-neoplastic changes including CD44/CD49f/CD24 marker shifts, nuclear translocation of TAZ and Slug, mammosphere formation, and EGF-dependent survival and migration. An EGFR mislocalization point mutation (P667A) recapitulates these phenotypes, including AKT and TAZ activation, linking Llgl1-controlled EGFR localization to downstream oncogenic signaling.\",\n      \"method\": \"Llgl1 loss-of-function; lineage tracing; mammosphere assay; EGFR localization studies; EGFR P667A point mutation; AKT/TAZ activation by western blot; wound healing; soft-agar growth; orthotopic transplant\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mislocalization mutation phenocopying Lgl1 loss links Lgl1 to EGFR localization control, single lab\",\n      \"pmids\": [\"27542214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LLGL1 is an evolutionarily conserved cortical cytoskeletal tumor suppressor that maintains cell polarity by forming two mutually exclusive complexes — one with nonmuscle myosin IIA (which it inhibits from assembling into filaments) and one with PAR-6/aPKC — whose interchange is controlled by aPKC-mediated phosphorylation of LLGL1; it directly binds and promotes internalization of N-cadherin to restrict apical junctional complex assembly to the basolateral-apical boundary, activates Rab10 by releasing GDP-dissociation inhibitor to drive axonal membrane trafficking, suppresses EGFR/RAS/MAPK signaling and Integrin β1 signaling, stabilizes Yap protein in cardiomyocytes, controls NG2 endocytic routing in oligodendrocyte progenitors, and regulates glutamatergic synapse number by antagonizing aPKC; in cancer contexts, PTEN loss activates PI3K→aPKC (via Rac GEFs PREX1/TIAM1), which hyperphosphorylates and inactivates LLGL1, thereby promoting invasion, dedifferentiation, and stemness through pathways including ERK-Sp1-OSMR and HoxA gene regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LLGL1 is an evolutionarily conserved cortical scaffold protein that functions as a tumor suppressor by coupling apical-basal cell polarity to membrane trafficking, actomyosin regulation, cell adhesion, and asymmetric cell division across diverse tissues. LLGL1 forms mutually exclusive complexes with non-muscle myosin II-A (NMII-A) and Par6α–aPKCζ; aPKC-mediated phosphorylation releases LLGL1 from NMII-A to prevent actomyosin assembly at the leading edge and from N-cadherin to restrict apical junctional complex formation, while non-phosphorylated LLGL1 activates Rab10-dependent vesicle trafficking for axonal growth, controls NG2 endocytic routing in oligodendrocyte progenitors, and directly binds and inhibits Integrin β1 signaling in mammary epithelial cells [PMID:24213535, PMID:22219375, PMID:28552558, PMID:21856246, PMID:30131568, PMID:35172155]. LLGL1 operates within the conserved Scribble–Dlg–Lgl polarity module, where loss of any component disrupts adherens junction integrity, NMII-A localization, and directed cell migration, and in neural progenitors LLGL1 loss abolishes asymmetric Numb localization, causing hyperproliferation via Notch pathway activation [PMID:32697665, PMID:37743653, PMID:15037549, PMID:22492354]. In cancer contexts, LLGL1 inactivation—often through aPKC hyperactivation downstream of PTEN loss or PI3K–PREX1 signaling—maintains stemness in glioblastoma and AML, promotes EGFR mislocalization and aberrant AKT/TAZ signaling, and drives OSMR-mediated gemcitabine resistance in pancreatic adenocarcinoma [PMID:23907540, PMID:34624316, PMID:37587260, PMID:27542214, PMID:32615164].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing LLGL1 as a regulator of asymmetric cell division: it was unknown how mammalian Lgl controlled neural progenitor fate; Lgl1 knockout revealed failure of asymmetric Numb localization, causing hyperproliferation and blocked differentiation, establishing LLGL1 as essential for asymmetric cell division in the mammalian brain.\",\n      \"evidence\": \"Lgl1 knockout mouse with immunolocalization of Numb and cell cycle exit analysis\",\n      \"pmids\": [\"15037549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Lgl1 directs Numb asymmetric localization was not identified\", \"Whether Lgl1 acts through aPKC in this context was not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating functional conservation: human LLGL1 fully rescued Drosophila lgl null lethality and restored Dlg/Scrib localization, proving the Scribble–Dlg–Lgl tumor suppressor module is functionally conserved from flies to humans.\",\n      \"evidence\": \"Transgenic expression of human LLGL1 in Drosophila lgl homozygous mutants with phenotypic rescue\",\n      \"pmids\": [\"15467749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific domains mediate cross-species rescue was not mapped\", \"Whether LLGL2 is equally conserved was not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking the Scribble complex to vesicle transport: it was unclear how the polarity complex interfaced with membrane trafficking; the finding that Scrib, Dlg, and LLGL1 interact with syntaxin 4 provided a molecular connection to t-SNARE-mediated vesicle fusion.\",\n      \"evidence\": \"Co-IP of Scrib complex components with syntaxin 4; shRNA-mediated Scrib depletion with localization analysis\",\n      \"pmids\": [\"18793635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of syntaxin 4 interaction on vesicle fusion was not assessed\", \"Direct vs. indirect binding to syntaxin 4 was not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying a direct vesicle trafficking mechanism: it was unknown how Lgl1 controlled membrane delivery; the discovery that Lgl1 releases GDI from Rab10 to activate Rab10-dependent vesicle trafficking established a biochemical mechanism linking polarity to axonal membrane supply.\",\n      \"evidence\": \"GDI-release assay, Co-IP, Lgl1/Rab10 epistasis in neurons and in vivo cortical electroporation\",\n      \"pmids\": [\"21856246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Lgl1 acts on other Rab GTPases was not explored\", \"Structural basis of GDI displacement not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining LLGL1 as a direct regulator of actomyosin: the mechanism connecting Lgl to cytoskeletal control was unknown; in vitro reconstitution showed Lgl1 directly inhibits NMII-A filament assembly and controls focal adhesion dynamics, establishing a direct cytoskeletal effector role.\",\n      \"evidence\": \"In vitro NMII-A filament assembly assay, Co-IP, Lgl1 depletion with focal adhesion and migration phenotypes\",\n      \"pmids\": [\"22219375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on NMII-A not structurally resolved\", \"Whether NMII-B is similarly regulated was not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placing LLGL1 upstream of apical domain size and Notch signaling in neurogenesis: loss of Llgl1 in retinal neuroepithelia expanded the apical domain and increased Notch activity, and epistasis with Rbpj showed Llgl1 constrains neurogenesis through Notch pathway modulation.\",\n      \"evidence\": \"Llgl1 morpholino in zebrafish retina with Rbpj epistasis and apical domain measurements\",\n      \"pmids\": [\"22492354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Lgl1 controls apical domain size was not identified\", \"Whether this applies to mammalian retina was not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolving the phospho-switch mechanism: it was unclear how aPKC controlled Lgl1 function; demonstration that aPKCζ phosphorylation of Lgl1 switches it between NMII-A-bound and Par6α–aPKC-bound complexes, with aPKC and NMII-A competing for the same Lgl1 domain, established the phosphorylation-dependent toggle governing polarity.\",\n      \"evidence\": \"In vitro phosphorylation, Co-IP, NMII-A assembly assay, phosphomimetic/non-phosphorylatable mutants, immunolocalization\",\n      \"pmids\": [\"24213535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the competing binding interfaces not available\", \"Kinetics of the switch in living cells not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connecting PTEN loss to Lgl1 inactivation in cancer: the upstream wiring of Lgl1 phosphorylation in tumors was unknown; PTEN loss was shown to hyperactivate aPKC, which phosphorylates and inactivates Lgl1, maintaining glioblastoma cells in an undifferentiated state.\",\n      \"evidence\": \"PTEN re-expression, aPKC RNAi, non-phosphorylatable Lgl1 in glioblastoma tumor-initiating cells with differentiation assays\",\n      \"pmids\": [\"23907540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases contribute to Lgl1 phosphorylation in glioblastoma was not excluded\", \"In vivo tumor suppression by non-phosphorylatable Lgl1 not demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking LLGL1 to receptor mislocalization and oncogenic signaling: it was unclear how Llgl1 loss activates signaling cascades; Llgl1 loss caused EGFR mislocalization, and an EGFR mislocalization mutant phenocopied Llgl1 null, connecting Lgl1 to cortical EGFR retention and suppression of AKT/TAZ signaling.\",\n      \"evidence\": \"Llgl1 KO cell lines, EGFR P667A mutant expression, TAZ nuclear translocation and transformation assays\",\n      \"pmids\": [\"27542214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between LLGL1 and EGFR not demonstrated\", \"Mechanism of EGFR mislocalization not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing LLGL1 as a direct N-cadherin regulator controlling junctional polarity: the molecular basis of AJC restriction was unknown; LLGL1 was shown to bind N-cadherin and promote its internalization, with aPKC phosphorylation blocking this interaction, and in vivo disruption causing periventricular heterotopia.\",\n      \"evidence\": \"Co-IP, live cortical imaging, conditional Llgl1 KO (Nestin-Cre), N-cadherin internalization assays\",\n      \"pmids\": [\"28552558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E-cadherin is similarly regulated by direct binding was only addressed later\", \"Structural basis of N-cadherin–LLGL1 interaction unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating cell-autonomous versus community effects: it was unknown whether Lgl1 acts purely cell-autonomously; MADM-based single-cell KO analysis revealed sequential cell-autonomous and non-autonomous functions in cortical progenitors.\",\n      \"evidence\": \"MADM genetic mosaic analysis enabling sparse and global single-cell Lgl1 knockout\",\n      \"pmids\": [\"28472654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular mediator of the non-autonomous community effect was not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing LLGL1 control of endocytic routing in glia: how Lgl1 regulated asymmetric division in oligodendrocyte progenitors was unknown; Lgl1 loss caused aberrant NG2 recycling, converting asymmetric to symmetric divisions and blocking OL differentiation.\",\n      \"evidence\": \"Conditional Lgl1 KO in OPCs, TIRF and time-lapse microscopy for endocytic routing\",\n      \"pmids\": [\"30131568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Lgl1 directly binds NG2 or acts through an intermediate was not resolved\", \"Generality to other surface receptors in OPCs untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining the Scribble–Lgl1–NMII-A axis at the leading edge: the physical basis of Scrib–Lgl1 cooperation in migration was unclear; Scribble was shown to bind Lgl1 via its LRR domain, and both colocalize with NMII-A at the leading edge, with depletion of either disrupting focal adhesion disassembly and directed migration.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, colocalization, Scrib/Lgl1 depletion phenotypes\",\n      \"pmids\": [\"32697665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the complex is trimeric or sequential was not resolved\", \"Phospho-regulation of Scrib–Lgl1 binding not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying LLGL1 as a Yap protein stabilizer in cardiomyocytes: how Lgl regulated cardiac development was unknown; Llgl1 depletion reduced Yap protein (not mRNA) and Yap target genes, and cardiomyocyte-specific Yap overexpression rescued cardiac defects.\",\n      \"evidence\": \"Llgl1 siRNA in cardiomyocytes, Yap protein/mRNA analysis, zebrafish morpholino with Yap rescue\",\n      \"pmids\": [\"32843528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Lgl1 stabilizes Yap protein not identified\", \"Whether Hippo pathway kinases are involved was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying upstream regulators of Lgl1 phosphorylation: how PI3K signaling reached Lgl1 was unknown; PREX1 (a Rac-GEF) was identified as the link between PI3K and aPKC-mediated Lgl1 phosphorylation in glioblastoma, with TIAM1 providing redundancy.\",\n      \"evidence\": \"CRISPR KO of PREX1, re-expression rescue, TIAM1 knockdown, Lgl1 phosphorylation readout\",\n      \"pmids\": [\"34624316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PREX1 directly activates aPKC or acts through intermediate Rac effectors was not distinguished\", \"Relevance outside glioblastoma not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing LLGL1 as a direct Integrin β1 inhibitor: the mechanism of LLGL1 in mammary epithelial migration was unclear; LLGL1 was shown to bind Integrin β1 directly and inhibit its signaling, with Integrin β1 overexpression phenocopying Lgl1 loss in branching morphogenesis.\",\n      \"evidence\": \"Co-IP, Lgl1 conditional KO in mammary gland, Integrin β1 overexpression phenocopy, migration assays\",\n      \"pmids\": [\"35172155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domain on LLGL1 for Integrin β1 not mapped\", \"Whether aPKC phosphorylation regulates this interaction not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the Scrib–Lgl1 axis to adherens junctions and E-cadherin: it was unknown whether the complex regulated E-cadherin junctions; Scribble, Lgl1, and NMII-A were found in complex with E-cadherin–catenin at AJs, with aPKCζ phosphorylation controlling AJ localization of both Lgl1 and E-cadherin.\",\n      \"evidence\": \"Co-IP, Scrib/Lgl1 depletion, AJ component immunofluorescence, aPKCζ phosphorylation assays\",\n      \"pmids\": [\"37743653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Lgl1 directly binds E-cadherin (as it does N-cadherin) was not distinguished from indirect association\", \"Contribution of NMII-A motor activity to AJ maintenance in this context not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing LLGL1 upstream of HoxA-dependent stemness in AML: the function of LLGL1 in leukemia was unknown; LLGL1 inactivation suppressed HoxA gene expression and induced a GMP-like differentiation phenotype, which was rescued by HoxA9 re-expression.\",\n      \"evidence\": \"CRISPR screening, LLGL1 inactivation in human/murine AML, HoxA9 rescue, gene expression profiling\",\n      \"pmids\": [\"37587260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LLGL1 directly regulates HoxA transcription or acts through polarity-dependent signaling is unknown\", \"Relevance to other leukemia subtypes not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the structural basis of LLGL1's competing interactions with NMII-A, aPKC, N-cadherin, and Integrin β1; how LLGL1 stabilizes Yap protein; the molecular identity of the non-autonomous 'community effect' signal; and whether LLGL1 and LLGL2 have fully redundant or distinct functions in tumor suppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of LLGL1 or any of its complexes\", \"Mechanism of Yap stabilization not resolved\", \"Identity of the non-autonomous community-effect mediator unknown\", \"Systematic comparison of LLGL1 vs. LLGL2 in mammalian tissues incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 6, 11, 16, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 14, 19]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6, 15, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 10, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 8, 9, 12]}\n    ],\n    \"complexes\": [\n      \"Scribble-Dlg-Lgl polarity complex\",\n      \"Lgl1-Par6α-aPKCζ complex\",\n      \"Lgl1-NMII-A complex\",\n      \"E-cadherin-catenin-Scrib-Lgl1-NMII-A complex\"\n    ],\n    \"partners\": [\n      \"MYH9\",\n      \"PRKCI\",\n      \"PARD6A\",\n      \"SCRIB\",\n      \"CDH2\",\n      \"RAB10\",\n      \"ITGB1\",\n      \"STX4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"LLGL1 is an evolutionarily conserved cortical polarity regulator that functions as a tumor suppressor by coordinating cell polarity, adhesion, membrane trafficking, and differentiation across multiple tissues. It forms two mutually exclusive complexes—one with nonmuscle myosin IIA (NMII-A), whose filament assembly it directly inhibits, and one with PAR-6/aPKC—and aPKC-mediated phosphorylation of LLGL1 switches it between these states, releasing NMII-A regulation and relocating LLGL1 from the cortex to the cytosol [PMID:24213535, PMID:22219375]. LLGL1 maintains epithelial adherens junctions by directly binding and promoting internalization of N-cadherin, restricting apical junctional complex assembly; disruption of this interaction in the developing cortex causes periventricular heterotopia, while broader Lgl1 loss produces neural progenitor hyperproliferation, failed asymmetric Numb localization, and cortical malformations [PMID:28552558, PMID:15037549, PMID:30597194]. In cancer, PTEN loss drives PI3K→Rac-GEF (PREX1/TIAM1)→aPKC-mediated hyperphosphorylation and inactivation of LLGL1, promoting invasion and blocking differentiation in glioblastoma, while LLGL1 loss independently activates EGFR/RAS/MAPK and ERK-Sp1-OSMR signaling axes in hepatocellular and pancreatic carcinomas [PMID:23907540, PMID:34624316, PMID:32615164, PMID:41977148].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of LLGL1 as a cytoskeletal protein associated with nonmuscle myosin II heavy chain established its molecular identity as a cortical component and implicated it in cytoskeletal regulation.\",\n      \"evidence\": \"Co-immunoprecipitation/co-purification with myosin II heavy chain and in vitro kinase assay in human cells\",\n      \"pmids\": [\"7542763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase responsible for serine phosphorylation was not identified\", \"No functional consequence of the myosin II interaction was demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that LLGL1 competes with PAR-3 for PAR-6/aPKC binding and is phosphorylated by aPKC revealed the mechanistic basis for polarity-dependent complex switching and basolateral segregation.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro aPKC phosphorylation, immunofluorescence in epithelial cells; yeast complementation confirming conservation\",\n      \"pmids\": [\"12725730\", \"14612921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PAR-3/LLGL1 competition was unknown\", \"Whether the two complexes had distinct subcellular functions was not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic loss-of-function in mice and cross-species rescue in Drosophila demonstrated that LLGL1 is an evolutionarily conserved regulator of asymmetric cell division, Numb localization, and neural progenitor differentiation.\",\n      \"evidence\": \"Lgl1 knockout mouse with Numb mislocalization and brain dysplasia; human LLGL1 transgenic rescue of Drosophila lgl lethality\",\n      \"pmids\": [\"15037549\", \"15467749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Lgl1 controls Numb asymmetry was not defined\", \"Whether Lgl1 loss causes frank tumorigenesis in mammals was unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"WD-40 repeat residues were shown to be essential for LLGL1 protein-protein interactions, and re-expression studies in melanoma linked LLGL1 to suppression of EMT markers, providing the first direct cancer-functional evidence in human cells.\",\n      \"evidence\": \"Site-directed mutagenesis with yeast complementation; stable LLGL1 transfection in melanoma with MMP and E-cadherin readouts\",\n      \"pmids\": [\"16969496\", \"16170365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners requiring the WD-40 domain were not identified\", \"EMT suppression was shown in overexpression only, lacking endogenous loss-of-function confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that LLGL1 forms a Scrib/Dlg complex linked to syntaxin 4 connected the polarity module to vesicle trafficking machinery.\",\n      \"evidence\": \"Co-immunoprecipitation of hScrib/hDlg/LLGL1 with syntaxin 4; shRNA depletion and osmotic stress experiments\",\n      \"pmids\": [\"18793635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of syntaxin 4 interaction for membrane trafficking was not tested\", \"Directness of LLGL1-syntaxin 4 binding was not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that LLGL1 directly activates Rab10 by releasing GDI established a specific biochemical mechanism for its role in axonal membrane trafficking and neuronal polarization.\",\n      \"evidence\": \"GDI release assay, co-immunoprecipitation, live imaging of membrane insertion, in vivo electroporation in neocortex\",\n      \"pmids\": [\"21856246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab10 activation mediates all LLGL1 trafficking functions or only axonal trafficking was unclear\", \"Structural basis of the LLGL1-Rab10-GDI interaction was not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Biochemical demonstration that LLGL1 directly inhibits NMII-A filament assembly, combined with zebrafish retinal studies showing LLGL1 controls apical domain size and Notch signaling, resolved two long-standing mechanistic questions about its cytoskeletal and signaling roles.\",\n      \"evidence\": \"In vitro NMII-A filament assembly inhibition assay plus siRNA knockdown; morpholino knockdown in zebrafish retina with Notch reporters and Rbpj epistasis\",\n      \"pmids\": [\"22219375\", \"22492354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NMII-A filament assembly inhibition relates to apical domain size control was not integrated\", \"Whether Notch pathway regulation is direct or secondary to polarity disruption was unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolution of the phosphorylation switch: aPKC phosphorylation of LLGL1 disrupts the LLGL1-NMII-A complex while promoting the LLGL1-PAR-6-aPKC complex, and the PTEN→PI3K→aPKC axis was shown to hyperphosphorylate and inactivate LLGL1 in glioblastoma, linking polarity loss to cancer signaling.\",\n      \"evidence\": \"Phosphomimetic/non-phosphorylatable mutants with in vitro filament assembly and Co-IP; PTEN re-expression and aPKC knockdown with differentiation readouts in GBM cells\",\n      \"pmids\": [\"24213535\", \"23907540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases besides aPKC regulate the switch in vivo was unknown\", \"The structural basis for competitive NMII-A/aPKC binding to the same LLGL1 domain was not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Direct binding of LLGL1 to N-cadherin and its role in N-cadherin internalization established the molecular mechanism controlling adherens junction restriction at the apical-basal boundary; disruption of this interaction caused periventricular heterotopia in vivo, linking LLGL1 to cortical malformation.\",\n      \"evidence\": \"Co-immunoprecipitation, endocytosis assays, conditional KO, in utero electroporation disrupting N-cadherin-LLGL1 interaction; MADM clonal analysis distinguishing cell-autonomous from community effects\",\n      \"pmids\": [\"28552558\", \"28472654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The N-cadherin binding domain on LLGL1 was not mapped\", \"Whether LLGL1 regulates E-cadherin internalization through the same mechanism was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"LLGL1 was shown to control NG2 endocytic routing in oligodendrocyte progenitors and to maintain adherens junctions/radial glial scaffold integrity required for neuronal migration, with its loss causing subcortical band heterotopia.\",\n      \"evidence\": \"Conditional Lgl1 KO in OPCs with live TIRF imaging of NG2 trafficking; Emx1-Cre cortical KO with AJ marker analysis and migration phenotyping\",\n      \"pmids\": [\"30131568\", \"30597194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NG2 routing involves the Rab10 pathway was not tested\", \"Mechanism by which Lgl1 loss cooperates with Ink4a/Arf in gliomagenesis was not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of LLGL1 in the postsynaptic density as a negative regulator of glutamatergic synapse number via aPKC antagonism extended its polarity function to synaptic biology and linked haploinsufficiency to behavioral abnormalities rescuable by NMDA antagonists.\",\n      \"evidence\": \"Synaptosome fractionation, electrophysiology, conditional KO in pyramidal neurons, behavioral assays with memantine rescue\",\n      \"pmids\": [\"31546104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Vangl2 reduction is the direct cause of synapse increase was not established\", \"The aPKC substrate mediating synapse number regulation was not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"LLGL1 loss was shown to activate distinct oncogenic signaling axes in different cancer contexts: ERK-Sp1-OSMR in pancreatic cancer conferring chemoresistance, EGFR mislocalization/TAZ activation in mammary cells, and Yap protein stabilization in cardiac development, broadening the downstream effector repertoire.\",\n      \"evidence\": \"Genome-wide RNAi screen with ChIP and pathway rescue in PDAC; EGFR localization studies with P667A phenocopy in mammary cells; zebrafish/rat Llgl1 depletion with Yap rescue in cardiomyocytes\",\n      \"pmids\": [\"32615164\", \"27542214\", \"32843528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Yap stabilization and OSMR induction reflect the same or independent mechanisms was unclear\", \"How LLGL1 controls EGFR subcellular localization mechanistically was not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The Rac GEFs PREX1 and TIAM1 were identified as PI3K-responsive intermediates that hyperphosphorylate LLGL1 via aPKC in glioblastoma, with TIAM1 providing compensatory Lgl1 inactivation when PREX1 is lost.\",\n      \"evidence\": \"CRISPR KO of PREX1 in patient-derived GBM cells; TIAM1 knockdown; phospho-Lgl1 western blot; RNA-seq\",\n      \"pmids\": [\"34624316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PREX1/TIAM1 activate aPKC directly or through Rac-PAK intermediates was not defined\", \"In vivo validation of compensatory TIAM1 signaling was lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Direct binding of LLGL1 to Integrin β1 and inhibition of its downstream signaling established a new mechanism by which LLGL1 controls directional migration and branching morphogenesis in mammary epithelium.\",\n      \"evidence\": \"Co-immunoprecipitation; conditional mammary Lgl1 KO; Integrin β1 overexpression phenocopying KO in 3D branching assays\",\n      \"pmids\": [\"35172155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The LLGL1 domain mediating Integrin β1 binding was not mapped\", \"Whether aPKC phosphorylation regulates the LLGL1-Integrin β1 interaction was not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"LLGL1 was shown to reside in a Scrib/NMII-A/E-cadherin-catenin complex at adherens junctions that opposes TGFβ-induced EMT, while in AML it was found to be required for stemness and HoxA gene expression—revealing tissue-dependent oncogenic versus tumor-suppressive contexts.\",\n      \"evidence\": \"Co-IP and siRNA with AJ marker readouts and TGFβ-EMT rescue; CRISPR screen in human/murine AML with HoxA9 rescue\",\n      \"pmids\": [\"37743653\", \"37587260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LLGL1 promotes HoxA transcription directly or through aPKC-dependent intermediaries was unclear\", \"The apparently opposite roles in solid tumors versus AML require mechanistic reconciliation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional LLGL1 deletion in cerebellar and midbrain primordia confirmed that LLGL1 controls neuroepithelial polarity through N-cadherin and Cdc42/β-catenin, and showed that LLGL1 loss activates EGFR/RAS/MAPK signaling in hepatocellular carcinoma cells.\",\n      \"evidence\": \"Pax2-Cre conditional KO with immunofluorescence for polarity markers; CRISPR LLGL1 KO in Huh-7 with phospho-proteomic pathway analysis\",\n      \"pmids\": [\"38526932\", \"38444736\", \"41977148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EGFR/MAPK suppression is a direct biochemical activity or indirect consequence of polarity disruption is unresolved\", \"Single-lab studies for each finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis for LLGL1's mutually exclusive complex formation, how LLGL1 mechanistically suppresses EGFR signaling, whether Rab10 and N-cadherin trafficking functions share a common vesicular pathway, and how LLGL1's apparently opposite roles in solid tumors (suppressor) versus AML (stemness-promoter) are reconciled at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal/cryo-EM structure of LLGL1 or its complexes exists\", \"Tissue-specific phosphorylation dynamics remain uncharacterized\", \"The relationship between the Rab10, N-cadherin, NG2, and Integrin β1 trafficking functions is unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10, 24, 31]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9, 10, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 10, 14, 25]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 9, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 14, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 23, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 8, 15, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 11, 12, 26, 28]}\n    ],\n    \"complexes\": [\n      \"Scrib/Dlg polarity complex\",\n      \"PAR-6/aPKC complex\",\n      \"Scrib/NMII-A/E-cadherin-catenin AJ complex\"\n    ],\n    \"partners\": [\n      \"MYH9\",\n      \"PARD6A\",\n      \"PRKCZ\",\n      \"SCRIB\",\n      \"CDH2\",\n      \"RAB10\",\n      \"ITGB1\",\n      \"DLG1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}