{"gene":"LMO7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"LMO7 binds directly to emerin with ~125 nM affinity; the C-terminal half of human LMO7 is sufficient for this interaction in vitro. LMO7 is a nucleocytoplasmic shuttling protein that positively regulates emerin gene transcription (emerin mRNA decreased 93% on LMO7 knockdown), and emerin binding to LMO7 inhibits LMO7 transcriptional activity in a feedback loop.","method":"In vitro binding assay (affinity measurement), luciferase reporter assay, siRNA knockdown, microarray, real-time PCR","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding with quantified affinity, reporter assay, and knockdown with defined transcriptional phenotype in a single rigorous study","pmids":["17067998"],"is_preprint":false},{"year":2004,"finding":"LMO7 is an afadin- and alpha-actinin-binding protein at adherens junctions. It connects the nectin-afadin cell-cell adhesion system to the E-cadherin-catenin system through alpha-actinin, and localizes at cell-cell adherens junctions and apical membranes in epithelial cells.","method":"Immunoprecipitation, immunofluorescence, immunoelectron microscopy, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus immunoelectron microscopy localization, replicated with multiple binding partners","pmids":["15140894"],"is_preprint":false},{"year":2011,"finding":"LMO7 binds the Pax3, MyoD, and Myf5 promoters in C2C12 myoblasts and in vitro, and is required for myoblast differentiation. Emerin competes with these promoters for LMO7 binding, inhibiting LMO7-driven transcriptional activation of MyoD and Pax3 promoters.","method":"ChIP, in vitro promoter-binding assay, siRNA knockdown, overexpression, Co-IP competition assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP plus in vitro promoter binding plus competition assay with emerin mutant controls","pmids":["21525034"],"is_preprint":false},{"year":2011,"finding":"LMO7 activates myocardin-related transcription factors (MRTFs) by relieving actin-mediated inhibition in a manner synergistic with Rho GTPase. LMO7 colocalizes with F-actin and reduces the G-actin/F-actin ratio via a Rho-independent mechanism, promoting MRTF-SRF signaling and breast cancer cell migration.","method":"Reporter assay, siRNA knockdown, G/F-actin fractionation, cell migration assay, colocalization imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter, actin fractionation, migration assay) in a single lab","pmids":["21670154"],"is_preprint":false},{"year":2013,"finding":"Endogenous LMO7 associates with focal adhesions, co-localizing and co-immunoprecipitating with p130Cas. LMO7 nuclear localization and transcriptional activity increased in p130Cas-null MEFs, indicating that p130Cas-dependent focal adhesion association negatively regulates LMO7 nuclear activity.","method":"Co-immunoprecipitation, immunofluorescence, genetic knockout (p130Cas-null MEFs), transcriptional reporter assay","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and genetic null cell line, single lab","pmids":["24010014"],"is_preprint":false},{"year":2014,"finding":"Lmo7-null mice display growth retardation, decreased muscle fiber size, and impaired skeletal and cardiac function with lower levels of phosphorylated Rb, ERK, and JNK, consistent with altered Rb and MAPK signaling pathways.","method":"Lmo7-null mouse generation, histological analysis, echocardiography, neuromuscular tests, Western blotting","journal":"Muscle & nerve","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined cellular and signaling phenotype, single lab","pmids":["24825363"],"is_preprint":false},{"year":2019,"finding":"LMO7 is induced by TGF-β in vascular smooth muscle cells and acts as a negative feedback regulator of TGF-β signaling. Mechanistically, the LMO7 LIM domain interacts with AP-1 subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting AP-1-dependent TGF-β autoinduction. LMO7 deletion amplifies TGF-β signaling, ECM deposition, and neointimal formation.","method":"SMC-specific and global LMO7 knockout mice, carotid ligation/femoral artery denudation models, knockdown, overexpression, mutagenesis, Co-IP, Western blotting for ubiquitination","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, in vivo knockout models, and ubiquitination assays across mouse and human SMC","pmids":["30586711"],"is_preprint":false},{"year":2019,"finding":"LMO7 is specifically localized in the cuticular plate and cell junctions of inner ear hair cells. Lmo7 KO mice develop cuticular plate deficiencies (reduced F-actin density, abnormal stereociliar rootlets) and late-onset progressive hearing loss, demonstrating LMO7 is required for cuticular plate integrity and cochlear mechanotransduction.","method":"Lmo7 KO mouse, immunofluorescence/localization, auditory brainstem response, cochlear mechanics, electron microscopy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple structural and functional phenotypic readouts and direct localization evidence","pmids":["30850599"],"is_preprint":false},{"year":2021,"finding":"The Cryptosporidium rhoptry effector protein ROP1 directly interacts with LMO7 in the host cell terminal web. LMO7 acts as an organizer of epithelial cell polarity and cell-cell adhesion, and genetic ablation of LMO7 in mice impacts parasite burden in vivo.","method":"Parasite effector screen, direct interaction assay, genetic ablation (LMO7 KO mice), in vivo infection model","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction identified with genetic validation in vivo, single study","pmids":["34348092"],"is_preprint":false},{"year":2022,"finding":"LMO7 binds non-muscle myosin II (NMII) heavy chain and recruits it to apical junctions and the apical cortex in Xenopus ectoderm. This NMII recruitment is essential for LMO7-mediated apical constriction and promotion of circumferential actomyosin belt formation. LMO7 knockdown decreases NMIIA localization at apical junctions and delays neural tube closure.","method":"Co-immunoprecipitation, immunofluorescence, morpholino knockdown, overexpression in Xenopus embryos","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of direct interaction, knockdown with defined structural and developmental phenotype, Xenopus ortholog with consistent domain architecture","pmids":["35451459"],"is_preprint":false},{"year":2023,"finding":"LMO7 directly degrades PFKFB3 (a glycolysis regulator) through K48-linked polyubiquitination in macrophages. LMO7-mediated PFKFB3 degradation inhibits glycolysis and macrophage activation; PFKFB3 also regulates histone demethylase JMJD3 expression, thereby modulating H3K27me3 levels. This LMO7/PFKFB3/JMJD3 axis modulates macrophage function and inflammatory bowel disease.","method":"Ubiquitination assay (K48-linkage), Co-IP, siRNA knockdown, Western blotting, murine colitis model","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K48-linked ubiquitination assay and Co-IP with in vivo colitis model, single lab","pmids":["38045056"],"is_preprint":false},{"year":2025,"finding":"LMO7 acts as an E3 ubiquitin ligase that binds SMAD7, mediating its polyubiquitination at lysine 70 and proteasomal degradation, thereby increasing the stability of TGF-β receptor 1 (TGFβR1) and promoting profibrotic fibroblast polarization and pulmonary fibrosis.","method":"Co-IP, ubiquitination assay (site-specific K70 mutation), Western blotting, KO fibroblasts, BLM-induced fibrosis mouse model, AAV-mediated shRNA","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ubiquitination assay with site-specific mutagenesis (K70), Co-IP, and in vivo therapeutic validation","pmids":["40000880"],"is_preprint":false},{"year":2025,"finding":"LMO7 inhibits tumor-associated macrophage (TAM) phagocytosis by promoting K48-linked polyubiquitination at lysine 45 of the β chain of LRP1, leading to its proteasomal degradation. LMO7 deficiency enhances TAM phagocytic activity and antitumor immune responses.","method":"Ubiquitination assay (K48-linkage, K45 mutation), Co-IP, single-cell RNA-seq, LMO7 KO mouse tumor models, Western blotting","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific ubiquitination mutagenesis, Co-IP, and in vivo KO model with defined phagocytic phenotype","pmids":["41208232"],"is_preprint":false},{"year":2026,"finding":"LMO7 acts as an E3 ubiquitin ligase that is recruited to POLR2A (the largest subunit of RNA polymerase II), promoting its ubiquitination and proteasomal degradation. LMO7-mediated POLR2A degradation drives cellular senescence through the MDM4/p53/p21 axis. Depletion of LMO7 abolished POLR2A ubiquitination and reduction in H2O2-induced senescent cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blotting, CRISPRa","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with rescue experiment, single lab","pmids":["41896199"],"is_preprint":false},{"year":2026,"finding":"LMO7 directly binds MGMT via its F-box domain and promotes K48-linked polyubiquitination and proteasomal degradation of MGMT, increasing temozolomide sensitivity in NSCLC cells. TMZ treatment further strengthens the LMO7-MGMT interaction, creating a positive feedback loop accelerating MGMT degradation.","method":"Co-IP, ubiquitination assay (K48-linkage), F-box domain mutagenesis, MGMT-C145A catalytic mutant, cell viability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP with domain mutagenesis (F-box), K48-ubiquitination assay, and catalytic mutant controls","pmids":["41763308"],"is_preprint":false},{"year":2018,"finding":"A recurrent LMO7-BRAF fusion protein was identified in papillary thyroid carcinoma; enforced expression of LMO7-BRAF stimulated endogenous ERK1/2 phosphorylation and promoted anchorage-independent cell growth, demonstrating oncogenic activity of the fusion.","method":"RT-PCR, FISH, Sanger sequencing, enforced expression, ERK1/2 phosphorylation assay, anchorage-independent growth assay","journal":"Thyroid","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with enforced expression, single lab, validated at protein and genomic level","pmids":["29768105"],"is_preprint":false},{"year":2017,"finding":"LMO7 interacts with the spindle assembly checkpoint (SAC) protein MAD1. Overexpression but not depletion of LMO7 caused a SAC defect; the LIM domain of LMO7 interfered with kinetochore localization of MAD2 and BUBR1 but not MAD1. Overexpression of the LIM peptide prolonged mitotic timing and interfered with chromosome congression.","method":"Co-immunoprecipitation, immunofluorescence, overexpression and knockdown experiments, live-cell imaging of mitosis","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and functional overexpression/depletion with defined mitotic phenotype, single lab","pmids":["29158164"],"is_preprint":false},{"year":2016,"finding":"LMO7 knockdown in chick primary skeletal muscle cells reduces myotube number and width and reduces MyoD-positive myoblasts. Activation of Wnt/beta-catenin pathway (Wnt3a or Bio treatment) rescues the LMO7 knockdown phenotype, indicating crosstalk between Wnt/beta-catenin and LMO7-mediated signaling in myogenesis.","method":"siRNA knockdown, immunofluorescence, pharmacological rescue (Wnt3a, Bio)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA KD with defined phenotype and pharmacological rescue, single lab","pmids":["26786059"],"is_preprint":false},{"year":2022,"finding":"LMO7 is a positive regulator of fibroblast polarization and intrinsic directed migration (IDM). LMO7 is predominantly incorporated into the cytoskeletons of normal fibroblasts, and its depletion inhibits directed migration on fibronectin-rich surfaces and impairs morphological polarity establishment.","method":"Cytoskeletal fractionation proteomics, siRNA knockdown, live-cell migration assay, fibronectin-coated surfaces","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — cytoskeletal fractionation proteomics plus functional knockdown with migration phenotype, single lab","pmids":["36442233"],"is_preprint":false},{"year":2022,"finding":"LMO7 coordinates with FAK signaling to maintain epithelial junctional integrity under osmotic stress in renal epithelial cells. LMO7 depletion causes junctional integrity loss; FAK inhibition prevents robust cortical F-actin assembly and LMO7 association with cortical F-actin. LMO7-depleted cells show excessive FAK activation, suggesting LMO7 regulates FAK activation.","method":"siRNA depletion, FAK inhibitor (PF-573228), immunofluorescence, TEER/junctional integrity assay, hypertonic stress model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with inhibitor and defined functional outcome, single lab","pmids":["36497072"],"is_preprint":false},{"year":2025,"finding":"VILL (villin-like protein) directly interacts with LMO7 (E3 ubiquitin ligase) in the cytoplasm of nasopharyngeal carcinoma cells, as determined by Co-IP and GST pull-down. Overexpression of LMO7 partially counteracted the inhibitory effect of VILL on NPC cell proliferation.","method":"Co-immunoprecipitation, mass spectrometry, GST pull-down, Western blotting, immunofluorescence, overexpression rescue","journal":"Nan fang yi ke da xue xue bao","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus GST pull-down confirming direct interaction, with functional rescue experiment, single lab","pmids":["40415426"],"is_preprint":false},{"year":2026,"finding":"LMO7 ubiquitinates SIRT3, leading to its degradation and subsequent osteoarthritis progression. Molecular experiments confirmed the ability of LMO7 to ubiquitinate SIRT3 in vitro and in vivo.","method":"Ubiquitination assay, Co-IP, in vitro and in vivo experiments, molecular docking","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay with in vivo validation, but abstract lacks detail on controls; single lab","pmids":["41992271"],"is_preprint":false},{"year":2026,"finding":"Force-dependent dephosphorylation of Ser355 in the LMO7 myosin-binding domain enhances LMO7 binding to non-muscle myosin II (NMII) and increases NMII abundance at the apical cortex during neural tube closure in Xenopus. LMO7 is required to stabilize actomyosin at the apical cortex at the onset of neural tube folding, suggesting a positive feedback between mechanical forces and LMO7 activity.","method":"Morpholino knockdown, gain-of-function injection, phospho-specific mutants (Ser355), Co-IP, live imaging in Xenopus embryos","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific phosphorylation mutagenesis and Co-IP with in vivo developmental phenotype, preprint not yet peer reviewed","pmids":["41659634"],"is_preprint":true},{"year":2005,"finding":"TGF-β1 upregulates LMO7 and a splice variant LMO7S (PDZ domain only) in rat ascites hepatoma cells; LMO7 expression is elevated in highly metastatic clones, and TGF-β1-induced LMO7 upregulation is associated with enhanced invasive capacity.","method":"Differential hybridization, RT-PCR, invasion assay","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression correlation with invasion, single lab, no direct mechanistic experiment on LMO7 function","pmids":["15737692"],"is_preprint":false}],"current_model":"LMO7 is a multidomain scaffold/E3 ubiquitin ligase that operates at the intersection of cell adhesion, cytoskeletal organization, and transcriptional regulation: it binds emerin at the nuclear envelope to reciprocally regulate muscle-gene transcription (including its own); recruits non-muscle myosin II to apical junctions to drive actomyosin contractility and apical constriction in a force-sensitive, Ser355-phosphorylation-dependent manner; connects the nectin-afadin and E-cadherin-catenin adhesion systems via alpha-actinin; activates MRTF-SRF signaling by reducing G/F-actin ratio in concert with Rho; is negatively regulated by focal-adhesion-associated p130Cas; and functions as an E3 ubiquitin ligase that targets multiple substrates (PFKFB3, SMAD7, LRP1, MGMT, POLR2A, SIRT3) via K48-linked polyubiquitination, thereby acting as a context-dependent negative feedback regulator of TGF-β/SMAD signaling in fibrosis while also controlling macrophage phagocytosis, cellular senescence, and drug sensitivity."},"narrative":{"mechanistic_narrative":"LMO7 is a multidomain scaffold and E3 ubiquitin ligase that couples cell adhesion and cytoskeletal organization to transcriptional control and protein turnover [PMID:15140894, PMID:30586711]. At epithelial adherens junctions LMO7 binds afadin and alpha-actinin, bridging the nectin-afadin and E-cadherin-catenin adhesion systems [PMID:15140894], and it recruits non-muscle myosin II to apical junctions to drive actomyosin-belt formation and apical constriction during morphogenesis [PMID:35451459]. This contractile function is mechanically gated: force-dependent dephosphorylation of Ser355 in the myosin-binding domain strengthens the LMO7-NMII interaction, establishing positive feedback between mechanical force and LMO7 activity [PMID:41659634]. LMO7 also acts as a nucleocytoplasmic shuttling transcriptional regulator that binds emerin at the nuclear envelope and occupies myogenic promoters (Pax3, MyoD, Myf5), with emerin competing for LMO7 to form a reciprocal feedback loop governing muscle-gene expression [PMID:17067998, PMID:21525034]; its cytoplasmic sequestration by p130Cas-associated focal adhesions restrains this nuclear activity [PMID:24010014]. In parallel, LMO7 lowers the G/F-actin ratio to activate MRTF-SRF signaling and promote migration [PMID:21670154]. As an E3 ligase, LMO7 directs K48-linked polyubiquitination and proteasomal degradation of a diverse substrate set—SMAD7, the c-FOS/c-JUN AP-1 subunits, PFKFB3, the LRP1 beta chain, MGMT, POLR2A, and SIRT3—thereby tuning TGF-beta/SMAD signaling, glycolytic macrophage activation, tumor-associated macrophage phagocytosis, drug sensitivity, and cellular senescence [PMID:30586711, PMID:38045056, PMID:40000880, PMID:41208232, PMID:41763308]. Loss-of-function mouse models establish requirements in skeletal and cardiac muscle and in inner-ear cuticular-plate integrity and hearing [PMID:24825363, PMID:30850599].","teleology":[{"year":2004,"claim":"Established LMO7 as a junctional scaffold, answering where it acts in epithelia and what adhesion systems it links.","evidence":"Reciprocal Co-IP and immunoelectron microscopy identifying afadin and alpha-actinin binding at adherens junctions","pmids":["15140894"],"confidence":"High","gaps":["Did not define the binding domains on LMO7","No functional consequence of disrupting the bridge tested"]},{"year":2006,"claim":"Revealed a nuclear-envelope axis: LMO7 binds emerin and regulates emerin transcription in a feedback loop, framing LMO7 as a shuttling transcriptional regulator.","evidence":"Quantified in vitro binding (~125 nM), luciferase reporters, and siRNA knockdown with microarray in human cells","pmids":["17067998"],"confidence":"High","gaps":["Direct DNA-binding targets of LMO7 not yet defined","Mechanism of nucleocytoplasmic shuttling unresolved"]},{"year":2011,"claim":"Connected LMO7's nuclear and cytoskeletal roles to muscle differentiation and actin-dependent transcription, explaining how adhesion/cytoskeletal state feeds gene programs.","evidence":"ChIP and in vitro promoter binding at Pax3/MyoD/Myf5 with emerin competition; separately reporter assays and G/F-actin fractionation linking LMO7 to MRTF-SRF","pmids":["21525034","21670154"],"confidence":"High","gaps":["Whether actin-ratio modulation and promoter binding are mechanistically coupled is unclear","The Rho-independent mechanism reducing G-actin is undefined"]},{"year":2013,"claim":"Identified an upstream brake on LMO7 nuclear activity, showing focal-adhesion sequestration spatially regulates its transcriptional output.","evidence":"Co-IP with p130Cas and increased LMO7 nuclear activity in p130Cas-null MEFs","pmids":["24010014"],"confidence":"Medium","gaps":["Direct vs indirect p130Cas binding not resolved","Signal that releases LMO7 to the nucleus unknown"]},{"year":2014,"claim":"Demonstrated physiological requirement in muscle, linking LMO7 loss to Rb and MAPK signaling defects in vivo.","evidence":"Lmo7-null mouse with histology, echocardiography, neuromuscular tests, and phospho-Western blotting","pmids":["24825363"],"confidence":"Medium","gaps":["Direct molecular targets driving the muscle phenotype not identified","Causal link between signaling changes and tissue defects not established"]},{"year":2019,"claim":"Defined LMO7 as a negative-feedback E3 ligase in TGF-beta signaling and as a structural requirement in the inner ear, broadening its mechanistic repertoire to ubiquitination.","evidence":"SMC-specific/global knockout mice with vascular injury models plus Co-IP and ubiquitination assays for c-FOS/c-JUN; separate Lmo7 KO mouse with cochlear structural/functional assays","pmids":["30586711","30850599"],"confidence":"High","gaps":["Which LMO7 domain confers ligase activity not yet pinned for AP-1 substrates","How cuticular-plate localization relates to ligase vs scaffold function unclear"]},{"year":2022,"claim":"Mechanistically resolved LMO7's contractility role by showing it recruits non-muscle myosin II to drive apical constriction in morphogenesis.","evidence":"Co-IP of NMII heavy chain, morpholino knockdown, and overexpression in Xenopus ectoderm with neural-tube phenotype","pmids":["35451459"],"confidence":"High","gaps":["Regulation of the NMII interaction in mammalian tissue not tested","Relationship to junctional adhesion partners not integrated"]},{"year":2023,"claim":"Extended the E3-ligase function to metabolism and immunity, showing LMO7 degrades PFKFB3 to restrain glycolytic macrophage activation.","evidence":"K48-linkage ubiquitination assay, Co-IP, knockdown, and murine colitis model","pmids":["38045056"],"confidence":"Medium","gaps":["Recognition determinants on PFKFB3 not mapped","How LMO7 selects this substrate over others unknown"]},{"year":2025,"claim":"Identified site-specific substrate ubiquitination as a recurring mechanism, with SMAD7 (K70) degradation stabilizing TGFbetaR1 to promote fibrosis.","evidence":"Co-IP, site-specific K70 ubiquitination mutagenesis, KO fibroblasts, and bleomycin fibrosis model with AAV-shRNA","pmids":["40000880"],"confidence":"High","gaps":["Reconciliation with LMO7's opposite (negative-feedback) role in vascular TGF-beta signaling not addressed","Context determinants of pro- vs anti-fibrotic output unresolved"]},{"year":2026,"claim":"Consolidated LMO7 as a multi-substrate E3 ligase via site-specific K48 ubiquitination, linking it to phagocytosis, senescence, drug sensitivity, and osteoarthritis.","evidence":"Site-specific ubiquitination mutagenesis and Co-IP for LRP1 (K45), POLR2A, MGMT (F-box-dependent), and SIRT3 across KO/knockdown models and disease systems","pmids":["41208232","41896199","41763308","41992271"],"confidence":"Medium","gaps":["A unifying substrate-recognition logic across these targets is undefined","Whether the F-box domain mediates all substrates or only MGMT is unclear"]},{"year":null,"claim":"How a single scaffold reconciles its opposing context-dependent roles (e.g. negative vs positive regulation of TGF-beta; scaffold vs ligase activity) through domain usage, post-translational control, and substrate selection remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model relating LIM/PDZ/F-box domains to substrate choice","Switch between adhesion-scaffold and E3-ligase modes uncharacterized","Determinants of tissue-specific substrate repertoire unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[6,10,11,12,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,10,11,12,14,13,21]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,3,9,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,11,12,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,7,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,12]}],"complexes":[],"partners":["EMD","AFDN","ACTN","P130CAS","MYH9","SMAD7","MGMT","POLR2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WWI1","full_name":"LIM domain only protein 7","aliases":["F-box only protein 20","LOMP"],"length_aa":1683,"mass_kda":192.7,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8WWI1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMO7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTN4","stoichiometry":0.2},{"gene":"ARL8B","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LMO7","total_profiled":1310},"omim":[{"mim_id":"606220","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SHORT STATURE, FACIAL ANOMALIES, AND SPEECH DEFECTS; IDDSFAS","url":"https://www.omim.org/entry/606220"},{"mim_id":"605653","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 3; FBXL3","url":"https://www.omim.org/entry/605653"},{"mim_id":"604362","title":"LIM DOMAIN ONLY 7; LMO7","url":"https://www.omim.org/entry/604362"},{"mim_id":"603090","title":"UBIQUITIN CARBOXYL-TERMINAL ESTERASE L3; UCHL3","url":"https://www.omim.org/entry/603090"},{"mim_id":"601930","title":"BASONUCLIN 1; BNC1","url":"https://www.omim.org/entry/601930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":233.5}],"url":"https://www.proteinatlas.org/search/LMO7"},"hgnc":{"alias_symbol":["FBX20","KIAA0858"],"prev_symbol":["FBXO20"]},"alphafold":{"accession":"Q8WWI1","domains":[{"cath_id":"1.10.418.10","chopping":"30-201","consensus_level":"medium","plddt":73.8434,"start":30,"end":201},{"cath_id":"2.30.42.10","chopping":"1040-1125","consensus_level":"high","plddt":87.1037,"start":1040,"end":1125},{"cath_id":"2.10.110.10","chopping":"1627-1678","consensus_level":"high","plddt":82.1363,"start":1627,"end":1678}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWI1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWI1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWI1-F1-predicted_aligned_error_v6.png","plddt_mean":50.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMO7","jax_strain_url":"https://www.jax.org/strain/search?query=LMO7"},"sequence":{"accession":"Q8WWI1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWI1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWI1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWI1"}},"corpus_meta":[{"pmid":"28026121","id":"PMC_28026121","title":"Circulating exosomal microRNA-96 promotes cell proliferation, migration and drug resistance by targeting LMO7.","date":"2016","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28026121","citation_count":140,"is_preprint":false},{"pmid":"17067998","id":"PMC_17067998","title":"Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17067998","citation_count":140,"is_preprint":false},{"pmid":"15140894","id":"PMC_15140894","title":"Involvement of LMO7 in the association of two cell-cell adhesion molecules, nectin and E-cadherin, through afadin and alpha-actinin in epithelial cells.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15140894","citation_count":127,"is_preprint":false},{"pmid":"30586711","id":"PMC_30586711","title":"LMO7 Is a Negative Feedback 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LMO7 is a nucleocytoplasmic shuttling protein that positively regulates emerin gene transcription (emerin mRNA decreased 93% on LMO7 knockdown), and emerin binding to LMO7 inhibits LMO7 transcriptional activity in a feedback loop.\",\n      \"method\": \"In vitro binding assay (affinity measurement), luciferase reporter assay, siRNA knockdown, microarray, real-time PCR\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding with quantified affinity, reporter assay, and knockdown with defined transcriptional phenotype in a single rigorous study\",\n      \"pmids\": [\"17067998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LMO7 is an afadin- and alpha-actinin-binding protein at adherens junctions. It connects the nectin-afadin cell-cell adhesion system to the E-cadherin-catenin system through alpha-actinin, and localizes at cell-cell adherens junctions and apical membranes in epithelial cells.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, immunoelectron microscopy, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus immunoelectron microscopy localization, replicated with multiple binding partners\",\n      \"pmids\": [\"15140894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LMO7 binds the Pax3, MyoD, and Myf5 promoters in C2C12 myoblasts and in vitro, and is required for myoblast differentiation. Emerin competes with these promoters for LMO7 binding, inhibiting LMO7-driven transcriptional activation of MyoD and Pax3 promoters.\",\n      \"method\": \"ChIP, in vitro promoter-binding assay, siRNA knockdown, overexpression, Co-IP competition assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP plus in vitro promoter binding plus competition assay with emerin mutant controls\",\n      \"pmids\": [\"21525034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LMO7 activates myocardin-related transcription factors (MRTFs) by relieving actin-mediated inhibition in a manner synergistic with Rho GTPase. LMO7 colocalizes with F-actin and reduces the G-actin/F-actin ratio via a Rho-independent mechanism, promoting MRTF-SRF signaling and breast cancer cell migration.\",\n      \"method\": \"Reporter assay, siRNA knockdown, G/F-actin fractionation, cell migration assay, colocalization imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter, actin fractionation, migration assay) in a single lab\",\n      \"pmids\": [\"21670154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Endogenous LMO7 associates with focal adhesions, co-localizing and co-immunoprecipitating with p130Cas. LMO7 nuclear localization and transcriptional activity increased in p130Cas-null MEFs, indicating that p130Cas-dependent focal adhesion association negatively regulates LMO7 nuclear activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, genetic knockout (p130Cas-null MEFs), transcriptional reporter assay\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and genetic null cell line, single lab\",\n      \"pmids\": [\"24010014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lmo7-null mice display growth retardation, decreased muscle fiber size, and impaired skeletal and cardiac function with lower levels of phosphorylated Rb, ERK, and JNK, consistent with altered Rb and MAPK signaling pathways.\",\n      \"method\": \"Lmo7-null mouse generation, histological analysis, echocardiography, neuromuscular tests, Western blotting\",\n      \"journal\": \"Muscle & nerve\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined cellular and signaling phenotype, single lab\",\n      \"pmids\": [\"24825363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LMO7 is induced by TGF-β in vascular smooth muscle cells and acts as a negative feedback regulator of TGF-β signaling. Mechanistically, the LMO7 LIM domain interacts with AP-1 subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting AP-1-dependent TGF-β autoinduction. LMO7 deletion amplifies TGF-β signaling, ECM deposition, and neointimal formation.\",\n      \"method\": \"SMC-specific and global LMO7 knockout mice, carotid ligation/femoral artery denudation models, knockdown, overexpression, mutagenesis, Co-IP, Western blotting for ubiquitination\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, in vivo knockout models, and ubiquitination assays across mouse and human SMC\",\n      \"pmids\": [\"30586711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LMO7 is specifically localized in the cuticular plate and cell junctions of inner ear hair cells. Lmo7 KO mice develop cuticular plate deficiencies (reduced F-actin density, abnormal stereociliar rootlets) and late-onset progressive hearing loss, demonstrating LMO7 is required for cuticular plate integrity and cochlear mechanotransduction.\",\n      \"method\": \"Lmo7 KO mouse, immunofluorescence/localization, auditory brainstem response, cochlear mechanics, electron microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple structural and functional phenotypic readouts and direct localization evidence\",\n      \"pmids\": [\"30850599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Cryptosporidium rhoptry effector protein ROP1 directly interacts with LMO7 in the host cell terminal web. LMO7 acts as an organizer of epithelial cell polarity and cell-cell adhesion, and genetic ablation of LMO7 in mice impacts parasite burden in vivo.\",\n      \"method\": \"Parasite effector screen, direct interaction assay, genetic ablation (LMO7 KO mice), in vivo infection model\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction identified with genetic validation in vivo, single study\",\n      \"pmids\": [\"34348092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LMO7 binds non-muscle myosin II (NMII) heavy chain and recruits it to apical junctions and the apical cortex in Xenopus ectoderm. This NMII recruitment is essential for LMO7-mediated apical constriction and promotion of circumferential actomyosin belt formation. LMO7 knockdown decreases NMIIA localization at apical junctions and delays neural tube closure.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, morpholino knockdown, overexpression in Xenopus embryos\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of direct interaction, knockdown with defined structural and developmental phenotype, Xenopus ortholog with consistent domain architecture\",\n      \"pmids\": [\"35451459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMO7 directly degrades PFKFB3 (a glycolysis regulator) through K48-linked polyubiquitination in macrophages. LMO7-mediated PFKFB3 degradation inhibits glycolysis and macrophage activation; PFKFB3 also regulates histone demethylase JMJD3 expression, thereby modulating H3K27me3 levels. This LMO7/PFKFB3/JMJD3 axis modulates macrophage function and inflammatory bowel disease.\",\n      \"method\": \"Ubiquitination assay (K48-linkage), Co-IP, siRNA knockdown, Western blotting, murine colitis model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K48-linked ubiquitination assay and Co-IP with in vivo colitis model, single lab\",\n      \"pmids\": [\"38045056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LMO7 acts as an E3 ubiquitin ligase that binds SMAD7, mediating its polyubiquitination at lysine 70 and proteasomal degradation, thereby increasing the stability of TGF-β receptor 1 (TGFβR1) and promoting profibrotic fibroblast polarization and pulmonary fibrosis.\",\n      \"method\": \"Co-IP, ubiquitination assay (site-specific K70 mutation), Western blotting, KO fibroblasts, BLM-induced fibrosis mouse model, AAV-mediated shRNA\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ubiquitination assay with site-specific mutagenesis (K70), Co-IP, and in vivo therapeutic validation\",\n      \"pmids\": [\"40000880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LMO7 inhibits tumor-associated macrophage (TAM) phagocytosis by promoting K48-linked polyubiquitination at lysine 45 of the β chain of LRP1, leading to its proteasomal degradation. LMO7 deficiency enhances TAM phagocytic activity and antitumor immune responses.\",\n      \"method\": \"Ubiquitination assay (K48-linkage, K45 mutation), Co-IP, single-cell RNA-seq, LMO7 KO mouse tumor models, Western blotting\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific ubiquitination mutagenesis, Co-IP, and in vivo KO model with defined phagocytic phenotype\",\n      \"pmids\": [\"41208232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LMO7 acts as an E3 ubiquitin ligase that is recruited to POLR2A (the largest subunit of RNA polymerase II), promoting its ubiquitination and proteasomal degradation. LMO7-mediated POLR2A degradation drives cellular senescence through the MDM4/p53/p21 axis. Depletion of LMO7 abolished POLR2A ubiquitination and reduction in H2O2-induced senescent cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blotting, CRISPRa\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with rescue experiment, single lab\",\n      \"pmids\": [\"41896199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LMO7 directly binds MGMT via its F-box domain and promotes K48-linked polyubiquitination and proteasomal degradation of MGMT, increasing temozolomide sensitivity in NSCLC cells. TMZ treatment further strengthens the LMO7-MGMT interaction, creating a positive feedback loop accelerating MGMT degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay (K48-linkage), F-box domain mutagenesis, MGMT-C145A catalytic mutant, cell viability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP with domain mutagenesis (F-box), K48-ubiquitination assay, and catalytic mutant controls\",\n      \"pmids\": [\"41763308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A recurrent LMO7-BRAF fusion protein was identified in papillary thyroid carcinoma; enforced expression of LMO7-BRAF stimulated endogenous ERK1/2 phosphorylation and promoted anchorage-independent cell growth, demonstrating oncogenic activity of the fusion.\",\n      \"method\": \"RT-PCR, FISH, Sanger sequencing, enforced expression, ERK1/2 phosphorylation assay, anchorage-independent growth assay\",\n      \"journal\": \"Thyroid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with enforced expression, single lab, validated at protein and genomic level\",\n      \"pmids\": [\"29768105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LMO7 interacts with the spindle assembly checkpoint (SAC) protein MAD1. Overexpression but not depletion of LMO7 caused a SAC defect; the LIM domain of LMO7 interfered with kinetochore localization of MAD2 and BUBR1 but not MAD1. Overexpression of the LIM peptide prolonged mitotic timing and interfered with chromosome congression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, overexpression and knockdown experiments, live-cell imaging of mitosis\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and functional overexpression/depletion with defined mitotic phenotype, single lab\",\n      \"pmids\": [\"29158164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LMO7 knockdown in chick primary skeletal muscle cells reduces myotube number and width and reduces MyoD-positive myoblasts. Activation of Wnt/beta-catenin pathway (Wnt3a or Bio treatment) rescues the LMO7 knockdown phenotype, indicating crosstalk between Wnt/beta-catenin and LMO7-mediated signaling in myogenesis.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, pharmacological rescue (Wnt3a, Bio)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA KD with defined phenotype and pharmacological rescue, single lab\",\n      \"pmids\": [\"26786059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LMO7 is a positive regulator of fibroblast polarization and intrinsic directed migration (IDM). LMO7 is predominantly incorporated into the cytoskeletons of normal fibroblasts, and its depletion inhibits directed migration on fibronectin-rich surfaces and impairs morphological polarity establishment.\",\n      \"method\": \"Cytoskeletal fractionation proteomics, siRNA knockdown, live-cell migration assay, fibronectin-coated surfaces\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — cytoskeletal fractionation proteomics plus functional knockdown with migration phenotype, single lab\",\n      \"pmids\": [\"36442233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LMO7 coordinates with FAK signaling to maintain epithelial junctional integrity under osmotic stress in renal epithelial cells. LMO7 depletion causes junctional integrity loss; FAK inhibition prevents robust cortical F-actin assembly and LMO7 association with cortical F-actin. LMO7-depleted cells show excessive FAK activation, suggesting LMO7 regulates FAK activation.\",\n      \"method\": \"siRNA depletion, FAK inhibitor (PF-573228), immunofluorescence, TEER/junctional integrity assay, hypertonic stress model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with inhibitor and defined functional outcome, single lab\",\n      \"pmids\": [\"36497072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VILL (villin-like protein) directly interacts with LMO7 (E3 ubiquitin ligase) in the cytoplasm of nasopharyngeal carcinoma cells, as determined by Co-IP and GST pull-down. Overexpression of LMO7 partially counteracted the inhibitory effect of VILL on NPC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GST pull-down, Western blotting, immunofluorescence, overexpression rescue\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus GST pull-down confirming direct interaction, with functional rescue experiment, single lab\",\n      \"pmids\": [\"40415426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LMO7 ubiquitinates SIRT3, leading to its degradation and subsequent osteoarthritis progression. Molecular experiments confirmed the ability of LMO7 to ubiquitinate SIRT3 in vitro and in vivo.\",\n      \"method\": \"Ubiquitination assay, Co-IP, in vitro and in vivo experiments, molecular docking\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay with in vivo validation, but abstract lacks detail on controls; single lab\",\n      \"pmids\": [\"41992271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Force-dependent dephosphorylation of Ser355 in the LMO7 myosin-binding domain enhances LMO7 binding to non-muscle myosin II (NMII) and increases NMII abundance at the apical cortex during neural tube closure in Xenopus. LMO7 is required to stabilize actomyosin at the apical cortex at the onset of neural tube folding, suggesting a positive feedback between mechanical forces and LMO7 activity.\",\n      \"method\": \"Morpholino knockdown, gain-of-function injection, phospho-specific mutants (Ser355), Co-IP, live imaging in Xenopus embryos\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific phosphorylation mutagenesis and Co-IP with in vivo developmental phenotype, preprint not yet peer reviewed\",\n      \"pmids\": [\"41659634\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TGF-β1 upregulates LMO7 and a splice variant LMO7S (PDZ domain only) in rat ascites hepatoma cells; LMO7 expression is elevated in highly metastatic clones, and TGF-β1-induced LMO7 upregulation is associated with enhanced invasive capacity.\",\n      \"method\": \"Differential hybridization, RT-PCR, invasion assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression correlation with invasion, single lab, no direct mechanistic experiment on LMO7 function\",\n      \"pmids\": [\"15737692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LMO7 is a multidomain scaffold/E3 ubiquitin ligase that operates at the intersection of cell adhesion, cytoskeletal organization, and transcriptional regulation: it binds emerin at the nuclear envelope to reciprocally regulate muscle-gene transcription (including its own); recruits non-muscle myosin II to apical junctions to drive actomyosin contractility and apical constriction in a force-sensitive, Ser355-phosphorylation-dependent manner; connects the nectin-afadin and E-cadherin-catenin adhesion systems via alpha-actinin; activates MRTF-SRF signaling by reducing G/F-actin ratio in concert with Rho; is negatively regulated by focal-adhesion-associated p130Cas; and functions as an E3 ubiquitin ligase that targets multiple substrates (PFKFB3, SMAD7, LRP1, MGMT, POLR2A, SIRT3) via K48-linked polyubiquitination, thereby acting as a context-dependent negative feedback regulator of TGF-β/SMAD signaling in fibrosis while also controlling macrophage phagocytosis, cellular senescence, and drug sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMO7 is a multidomain scaffold and E3 ubiquitin ligase that couples cell adhesion and cytoskeletal organization to transcriptional control and protein turnover [#1, #6]. At epithelial adherens junctions LMO7 binds afadin and alpha-actinin, bridging the nectin-afadin and E-cadherin-catenin adhesion systems [#1], and it recruits non-muscle myosin II to apical junctions to drive actomyosin-belt formation and apical constriction during morphogenesis [#9]. This contractile function is mechanically gated: force-dependent dephosphorylation of Ser355 in the myosin-binding domain strengthens the LMO7-NMII interaction, establishing positive feedback between mechanical force and LMO7 activity [#22]. LMO7 also acts as a nucleocytoplasmic shuttling transcriptional regulator that binds emerin at the nuclear envelope and occupies myogenic promoters (Pax3, MyoD, Myf5), with emerin competing for LMO7 to form a reciprocal feedback loop governing muscle-gene expression [#0, #2]; its cytoplasmic sequestration by p130Cas-associated focal adhesions restrains this nuclear activity [#4]. In parallel, LMO7 lowers the G/F-actin ratio to activate MRTF-SRF signaling and promote migration [#3]. As an E3 ligase, LMO7 directs K48-linked polyubiquitination and proteasomal degradation of a diverse substrate set—SMAD7, the c-FOS/c-JUN AP-1 subunits, PFKFB3, the LRP1 beta chain, MGMT, POLR2A, and SIRT3—thereby tuning TGF-beta/SMAD signaling, glycolytic macrophage activation, tumor-associated macrophage phagocytosis, drug sensitivity, and cellular senescence [#6, #10, #11, #12, #14]. Loss-of-function mouse models establish requirements in skeletal and cardiac muscle and in inner-ear cuticular-plate integrity and hearing [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established LMO7 as a junctional scaffold, answering where it acts in epithelia and what adhesion systems it links.\",\n      \"evidence\": \"Reciprocal Co-IP and immunoelectron microscopy identifying afadin and alpha-actinin binding at adherens junctions\",\n      \"pmids\": [\"15140894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the binding domains on LMO7\", \"No functional consequence of disrupting the bridge tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a nuclear-envelope axis: LMO7 binds emerin and regulates emerin transcription in a feedback loop, framing LMO7 as a shuttling transcriptional regulator.\",\n      \"evidence\": \"Quantified in vitro binding (~125 nM), luciferase reporters, and siRNA knockdown with microarray in human cells\",\n      \"pmids\": [\"17067998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding targets of LMO7 not yet defined\", \"Mechanism of nucleocytoplasmic shuttling unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected LMO7's nuclear and cytoskeletal roles to muscle differentiation and actin-dependent transcription, explaining how adhesion/cytoskeletal state feeds gene programs.\",\n      \"evidence\": \"ChIP and in vitro promoter binding at Pax3/MyoD/Myf5 with emerin competition; separately reporter assays and G/F-actin fractionation linking LMO7 to MRTF-SRF\",\n      \"pmids\": [\"21525034\", \"21670154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether actin-ratio modulation and promoter binding are mechanistically coupled is unclear\", \"The Rho-independent mechanism reducing G-actin is undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an upstream brake on LMO7 nuclear activity, showing focal-adhesion sequestration spatially regulates its transcriptional output.\",\n      \"evidence\": \"Co-IP with p130Cas and increased LMO7 nuclear activity in p130Cas-null MEFs\",\n      \"pmids\": [\"24010014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect p130Cas binding not resolved\", \"Signal that releases LMO7 to the nucleus unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated physiological requirement in muscle, linking LMO7 loss to Rb and MAPK signaling defects in vivo.\",\n      \"evidence\": \"Lmo7-null mouse with histology, echocardiography, neuromuscular tests, and phospho-Western blotting\",\n      \"pmids\": [\"24825363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets driving the muscle phenotype not identified\", \"Causal link between signaling changes and tissue defects not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined LMO7 as a negative-feedback E3 ligase in TGF-beta signaling and as a structural requirement in the inner ear, broadening its mechanistic repertoire to ubiquitination.\",\n      \"evidence\": \"SMC-specific/global knockout mice with vascular injury models plus Co-IP and ubiquitination assays for c-FOS/c-JUN; separate Lmo7 KO mouse with cochlear structural/functional assays\",\n      \"pmids\": [\"30586711\", \"30850599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which LMO7 domain confers ligase activity not yet pinned for AP-1 substrates\", \"How cuticular-plate localization relates to ligase vs scaffold function unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically resolved LMO7's contractility role by showing it recruits non-muscle myosin II to drive apical constriction in morphogenesis.\",\n      \"evidence\": \"Co-IP of NMII heavy chain, morpholino knockdown, and overexpression in Xenopus ectoderm with neural-tube phenotype\",\n      \"pmids\": [\"35451459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of the NMII interaction in mammalian tissue not tested\", \"Relationship to junctional adhesion partners not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the E3-ligase function to metabolism and immunity, showing LMO7 degrades PFKFB3 to restrain glycolytic macrophage activation.\",\n      \"evidence\": \"K48-linkage ubiquitination assay, Co-IP, knockdown, and murine colitis model\",\n      \"pmids\": [\"38045056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recognition determinants on PFKFB3 not mapped\", \"How LMO7 selects this substrate over others unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified site-specific substrate ubiquitination as a recurring mechanism, with SMAD7 (K70) degradation stabilizing TGFbetaR1 to promote fibrosis.\",\n      \"evidence\": \"Co-IP, site-specific K70 ubiquitination mutagenesis, KO fibroblasts, and bleomycin fibrosis model with AAV-shRNA\",\n      \"pmids\": [\"40000880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with LMO7's opposite (negative-feedback) role in vascular TGF-beta signaling not addressed\", \"Context determinants of pro- vs anti-fibrotic output unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Consolidated LMO7 as a multi-substrate E3 ligase via site-specific K48 ubiquitination, linking it to phagocytosis, senescence, drug sensitivity, and osteoarthritis.\",\n      \"evidence\": \"Site-specific ubiquitination mutagenesis and Co-IP for LRP1 (K45), POLR2A, MGMT (F-box-dependent), and SIRT3 across KO/knockdown models and disease systems\",\n      \"pmids\": [\"41208232\", \"41896199\", \"41763308\", \"41992271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A unifying substrate-recognition logic across these targets is undefined\", \"Whether the F-box domain mediates all substrates or only MGMT is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold reconciles its opposing context-dependent roles (e.g. negative vs positive regulation of TGF-beta; scaffold vs ligase activity) through domain usage, post-translational control, and substrate selection remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model relating LIM/PDZ/F-box domains to substrate choice\", \"Switch between adhesion-scaffold and E3-ligase modes uncharacterized\", \"Determinants of tissue-specific substrate repertoire unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [6, 10, 11, 12, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 10, 11, 12, 14, 13, 21]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 3, 9, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 7, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EMD\", \"AFDN\", \"ACTN\", \"p130Cas\", \"MYH9\", \"SMAD7\", \"MGMT\", \"POLR2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}