Affinage

LLGL1

Lethal(2) giant larvae protein homolog 1 · UniProt Q15334

Round 2 corrected
Length
1064 aa
Mass
115.4 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    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

    PMID:7542763

    Open questions at the time
    • The kinase responsible for serine phosphorylation was not identified
    • No functional consequence of the myosin II interaction was demonstrated
  2. 2003 High

    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

    PMID:12725730 PMID:14612921

    Open questions at the time
    • Structural basis of the PAR-3/LLGL1 competition was unknown
    • Whether the two complexes had distinct subcellular functions was not resolved
  3. 2004 High

    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

    PMID:15037549 PMID:15467749

    Open questions at the time
    • Mechanism by which Lgl1 controls Numb asymmetry was not defined
    • Whether Lgl1 loss causes frank tumorigenesis in mammals was unresolved
  4. 2006 Medium

    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

    PMID:16170365 PMID:16969496

    Open questions at the time
    • Direct binding partners requiring the WD-40 domain were not identified
    • EMT suppression was shown in overexpression only, lacking endogenous loss-of-function confirmation
  5. 2008 Medium

    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

    PMID:18793635

    Open questions at the time
    • Functional consequence of syntaxin 4 interaction for membrane trafficking was not tested
    • Directness of LLGL1-syntaxin 4 binding was not established
  6. 2011 High

    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

    PMID:21856246

    Open questions at the time
    • 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
  7. 2012 High

    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

    PMID:22219375 PMID:22492354

    Open questions at the time
    • 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
  8. 2013 High

    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

    PMID:23907540 PMID:24213535

    Open questions at the time
    • 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
  9. 2017 High

    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

    PMID:28472654 PMID:28552558

    Open questions at the time
    • The N-cadherin binding domain on LLGL1 was not mapped
    • Whether LLGL1 regulates E-cadherin internalization through the same mechanism was not tested
  10. 2018 High

    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

    PMID:30131568 PMID:30597194

    Open questions at the time
    • 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
  11. 2019 High

    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

    PMID:31546104

    Open questions at the time
    • Whether Vangl2 reduction is the direct cause of synapse increase was not established
    • The aPKC substrate mediating synapse number regulation was not identified
  12. 2020 High

    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

    PMID:27542214 PMID:32615164 PMID:32843528

    Open questions at the time
    • Whether Yap stabilization and OSMR induction reflect the same or independent mechanisms was unclear
    • How LLGL1 controls EGFR subcellular localization mechanistically was not resolved
  13. 2021 High

    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

    PMID:34624316

    Open questions at the time
    • Whether PREX1/TIAM1 activate aPKC directly or through Rac-PAK intermediates was not defined
    • In vivo validation of compensatory TIAM1 signaling was lacking
  14. 2022 High

    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

    PMID:35172155

    Open questions at the time
    • The LLGL1 domain mediating Integrin β1 binding was not mapped
    • Whether aPKC phosphorylation regulates the LLGL1-Integrin β1 interaction was not tested
  15. 2023 High

    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

    PMID:37587260 PMID:37743653

    Open questions at the time
    • 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
  16. 2024 Medium

    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

    PMID:38444736 PMID:38526932 PMID:41977148

    Open questions at the time
    • Whether EGFR/MAPK suppression is a direct biochemical activity or indirect consequence of polarity disruption is unresolved
    • Single-lab studies for each finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CDH2DLG1ITGB1MYH9PARD6APRKCZRAB10SCRIB
Complex memberships
PAR-6/aPKC complexScrib/Dlg polarity complexScrib/NMII-A/E-cadherin-catenin AJ complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 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. Affinity-purified polyclonal antibodies against HUGL peptides; co-immunoprecipitation/co-purification with nonmuscle myosin II heavy chain; in vitro kinase assay Oncogene High 7542763
2003 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. Co-immunoprecipitation; overexpression studies in epithelial cells; immunofluorescence localization; in vitro aPKC phosphorylation assay Current biology : CB High 12725730
2004 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. Lgl1 knockout mouse (Lgl1−/−); immunostaining for Numb localization; BrdU incorporation; TUNEL apoptosis assay; histopathology Genes & development High 15037549
2004 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. Transgenic rescue in Drosophila lgl homozygous mutants; immunostaining for Dlg and Scrib localization; developmental phenotype scoring Oncogene High 15467749
2006 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). 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 Oncogene Medium 16170365
2008 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. shRNA ablation of hScrib; co-localization by immunofluorescence; co-immunoprecipitation with syntaxin 4; osmotic stress treatment Experimental cell research Medium 18793635
2009 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. RT-PCR and sequencing of 80 HCC specimens; western blot; wound healing, Boyden chamber migration/invasion assays; nude mouse tumorigenicity assay Clinical cancer research Medium 19447873
2011 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. Co-immunoprecipitation; GDI release assay; overexpression/knockdown of Lgl1 and Rab10 in neurons; live imaging of membrane insertion; in vivo electroporation into neocortex Developmental cell High 21856246
2012 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. Morpholino knockdown of Llgl1 in zebrafish retina; genetic epistasis (Rbpj depletion); Shroom3 inhibition; Notch activity reporters; interkinetic nuclear migration analysis Development (Cambridge, England) High 22492354
2012 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. Co-immunoprecipitation in vivo; in vitro filament assembly inhibition assay; Lgl1 siRNA knockdown; immunofluorescence of NMII-A localization and focal adhesions; migration assays Molecular biology of the cell High 22219375
2013 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. Co-immunoprecipitation; in vitro phosphorylation and filament assembly assays; phosphomimetic/non-phosphorylatable Lgl1 mutants; immunofluorescence localization Journal of cell science High 24213535
2013 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. PTEN re-expression; aPKC siRNA knockdown; non-phosphorylatable Lgl3SA expression; neuronal differentiation assays; phospho-Lgl1 western blot Oncotarget High 23907540
2014 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. Doxycycline-inducible Lgl3SA expression system; in vitro motility assay; intracerebral xenograft model; differentiation markers by immunostaining Oncotarget High 25426552
2016 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. Luciferase reporter with LLGL1 3'UTR; 3'UTR binding-site mutation; miR-652-3p overexpression/knockdown; western blot; proliferation/migration/invasion assays Oncotarget Medium 26934648
2017 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. 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 Developmental cell High 28552558
2017 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. MADM-based sparse and global conditional knockout at single-cell resolution; clonal analysis; BrdU/EdU labeling; immunostaining for progenitor/glia markers Neuron High 28472654
2018 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. Conditional Lgl1 KO in OPCs; time-lapse and total internal reflection fluorescence microscopy of NG2 trafficking; immunophenotyping; synergistic gliomagenesis assay with Ink4a/Arf Nature communications High 30131568
2018 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. 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 Neuroscience High 30597194
2019 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. Synaptosome fractionation; conditional KO in pyramidal neurons; electrophysiology (AMPA/NMDA ratio, LTP); behavioral assays; immunostaining iScience High 31546104
2019 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. Emx1-Cre conditional Lgl1 KO; histology; BrdU labeling; immunostaining for AJ markers; Morris water maze; fear conditioning behavioral tests Genes, brain, and behavior Medium 31415124
2020 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. 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 Cellular and molecular gastroenterology and hepatology High 32615164
2020 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. Co-immunoprecipitation; siRNA depletion of Scrib or Lgl1; immunofluorescence colocalization; focal adhesion assays; cell polarity and migration assays Molecular biology of the cell High 32697665
2020 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. Morpholino and CRISPR-based llgl1 depletion in zebrafish; siRNA in rat cardiomyocytes; Yap protein/mRNA quantification; cardiomyocyte-specific Yap overexpression rescue; cardiac imaging Development (Cambridge, England) High 32843528
2021 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. CRISPR/Cas9 KO of PREX1; phospho-Lgl1 western blot; TIAM1 knockdown; RNA-seq; motility assays; patient-derived glioblastoma cells The Journal of biological chemistry High 34624316
2022 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. Conditional mammary Lgl1 KO; co-immunoprecipitation of LGL1 with Integrin β1; Integrin β1 overexpression; 3D branching morphogenesis assays; directional migration assays Cell reports High 35172155
2023 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. Co-immunoprecipitation; siRNA depletion of Scrib and Lgl1; phosphomimetic Lgl1 mutants; immunofluorescence of AJ markers; TGFβ-induced EMT; re-expression rescue Cell adhesion & migration High 37743653
2023 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. CRISPR/Cas9 genetic screening; conditional LLGL1 inactivation in human and murine AML; gene-expression profiling; HoxA9 re-expression rescue; leukemia stem cell immunophenotyping Leukemia High 37587260
2023 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. llgl1 mutant zebrafish; immunostaining for laminin and epicardial markers; live imaging; lineage tracing of epicardial cells Development (Cambridge, England) Medium 38940292
2023 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. K14-Cre double conditional KO of Llgl1 and Llgl2; Trp53/Llgl1/2 compound KO; tumor scoring; immunostaining for aPKC and NF-κB pathway activation bioRxiv : the preprint server for biologypreprint Medium 36945368
2024 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. Pax2-LGL1−/− conditional KO mice; HE staining; immunofluorescence for Cdc42, β-catenin; TUNEL staining Neuroreport Medium 38526932
2024 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. Pax2-Cre Lgl1 conditional KO; histology; BrdU labeling; immunofluorescence for Nestin (glial fibers) and N-cadherin (AJ marker) Biochemistry and biophysics reports Medium 38444736
2026 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. 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 International journal of molecular sciences Medium 41977148
2006 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. Site-directed deletion mutagenesis of WD-40 residues in Mgl-1; yeast complementation assay (Sop1/Sop2 double mutant) Oncology reports Medium 16969496
2003 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. Yeast complementation assay; RT-PCR temporal expression; in situ hybridization spatial expression International journal of oncology Low 14612921
2016 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. 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 Oncotarget Medium 27542214

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
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