Affinage

MAGI1

Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 · UniProt Q96QZ7

Round 2 corrected
Length
1491 aa
Mass
164.6 kDa
Annotated
2026-04-28
130 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAGI1 is a multi-domain MAGUK scaffolding protein that organizes signaling complexes at epithelial tight junctions, adherens junctions, and endothelial cell contacts, thereby regulating cell-cell adhesion, barrier integrity, and signal transduction. Its five PDZ domains mediate binding to β-catenin (PDZ5), cadherin-23 (PDZ4), and viral oncoproteins such as HPV E6 and adenovirus E4-ORF1 (PDZ1), while its WW domains engage PY-motif-containing partners; through these interactions MAGI1 stabilizes Dll1 at adherens junctions to promote Notch signaling, recruits JAM4 to strengthen tight junctions, negatively regulates GLT-1 surface expression in astrocytes, and suppresses tumor cell migration and invasion by stabilizing a PTEN/β-catenin complex and inhibiting MAPK/ERK and PI3K/AKT pathways (PMID:10772923, PMID:15908431, PMID:12773569, PMID:21426345, PMID:28373751, PMID:31352641). In endothelial cells, MAGI1 transduces fluid shear stress into eNOS activation via PKA and AMPK, and its phosphorylation by p90RSK and deSUMOylation drive nuclear translocation linked to endothelial activation and atherogenesis (PMID:31035633, PMID:30944250). SRC-mediated phosphorylation of MAGI1 inhibits a latent MAGI1–PP2A tumor-suppressive complex; upon SRC inhibition, this complex dephosphorylates S6K independently of mTOR, suppressing protein synthesis and promoting cell death in cholangiocarcinoma (PMID:38748774).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Identification of MAGI1 as a novel MAGUK with inverted domain architecture (GK-WW-PDZ) established it as a distinct scaffolding protein with isoform-dependent nuclear versus membrane localization.

    Evidence cDNA cloning, subcellular fractionation, and immunolocalization in MDCK cells; parallel WW domain ligand screens

    PMID:9169421 PMID:9395497

    Open questions at the time
    • Functional significance of nuclear isoform unclear
    • WW domain ligand specificity not mapped in vivo
    • No loss-of-function data
  2. 2000 High

    Discovery that PDZ5 anchors MAGI1 to junctional membranes via β-catenin binding, and that viral oncoproteins (HPV E6, adenovirus E4-ORF1) hijack PDZ1, established MAGI1 as a junctional scaffold targeted in oncogenesis.

    Evidence PDZ domain deletion mapping, co-IP of β-catenin/E-cadherin complexes in MDCK cells; co-IP and mutational analysis of viral oncoprotein interactions

    PMID:10772923 PMID:11077444

    Open questions at the time
    • Mechanism by which E6-mediated MAGI1 degradation drives transformation not established
    • Relative contributions of individual PDZ domains to junctional assembly unknown
  3. 2002 High

    Mapping MAGI1 to tight junctions across epithelial tissues in vivo and demonstrating colocalization with ZO-1/ZO-2 in pre-assembled complexes showed that MAGI1 is a general tight junction component rather than a cell-type-specific adaptor.

    Evidence Immunofluorescence in multiple epithelial cell types and tissues, isoform-specific domain deletions

    PMID:11969287

    Open questions at the time
    • Causal role in tight junction assembly vs. maintenance not distinguished
    • Redundancy with MAGI-2/MAGI-3 at tight junctions not tested
  4. 2003 High

    Identification of JAM4 as a MAGI1 partner that strengthens cell-cell adhesion and barrier sealing when scaffolded by MAGI1 provided the first functional evidence that MAGI1 actively reinforces tight junction integrity.

    Evidence GST pulldown, co-IP, functional adhesion and permeability assays in L and CHO cells

    PMID:12773569

    Open questions at the time
    • In vivo barrier function of MAGI1–JAM4 interaction not tested
    • Stoichiometry and competition among PDZ ligands at the junction unknown
  5. 2005 High

    Demonstration that MAGI1 recruits Dll1 to adherens junctions and stabilizes it on the cell surface linked MAGI1 scaffolding to Notch ligand presentation during neural development.

    Evidence Y2H, co-IP, in situ hybridization in developing neural tube, cell-surface biotinylation in fibroblasts

    PMID:15908431

    Open questions at the time
    • Downstream effect on Notch signaling output not directly measured
    • Whether MAGI1 is required for Dll1 function in vivo not shown by loss-of-function
  6. 2008 High

    Identification of cadherin-23 as a PDZ4 ligand in stereocilia and TRIP6 as a PDZ5 ligand that promotes invasiveness expanded the repertoire of MAGI1 PDZ interactions and revealed context-dependent roles in sensory cells and cancer.

    Evidence Cochlear library screen and immunolocalization for Cdh23; Y2H, invasion and aggregation assays with domain-specific mutants for TRIP6

    PMID:18971469 PMID:19017743

    Open questions at the time
    • MAGI1–Cdh23 functional significance for hearing not tested by genetic loss-of-function
    • How TRIP6–MAGI1 interaction is regulated remains unknown
  7. 2009 High

    C. elegans genetic studies showed MAGI-1 controls glutamate receptor (GLR-1) clustering in specific neurons during associative learning in a β-catenin-dependent manner, establishing a conserved neuronal scaffolding function.

    Evidence magi-1 mutant behavioral analysis, neuron-specific rescue, GLR-1::GFP imaging, epistasis with hmp-2/β-catenin

    PMID:19551147

    Open questions at the time
    • Mammalian counterpart of this learning/memory circuit function not established
    • Direct physical interaction between MAGI-1 and GLR-1 not shown
  8. 2010 High

    Quantitative biophysical characterization of PDZ1–HPV E6 binding and demonstration that HPV E6-driven MAGI1 degradation causally disrupts tight junctions defined the structural basis and functional consequence of viral targeting.

    Evidence SPR binding measurements with mutagenesis; siRNA of E6 in HPV+ cervical cancer cells with MAGI1 rescue of ZO-1 localization

    PMID:20842623 PMID:21123374

    Open questions at the time
    • Crystal structure of full PDZ1–E6 complex not available at this point
    • Whether MAGI1 degradation is sufficient for HPV-driven malignancy not determined
  9. 2011 High

    Discovery that MAGI1 binds GLT-1 and negatively regulates its surface expression in astrocytes extended MAGI1's scaffolding function to control of glutamate transporter trafficking in glial cells, complementing its neuronal role.

    Evidence GST pulldown, co-IP, cell-surface biotinylation, siRNA knockdown with glutamate uptake assay in differentiated astrocytes

    PMID:21426345

    Open questions at the time
    • Which PDZ domain mediates GLT-1 binding not mapped
    • In vivo relevance for glutamate homeostasis not tested
  10. 2011 High

    NMR structure of MAGI1 PDZ1 alone and in complex with E6 peptide revealed a global conformational response to ligand binding including quenching of backbone dynamics in the C-terminal extension, providing the first atomic-resolution model of MAGI1 ligand recognition.

    Evidence NMR spectroscopy, backbone dynamics analysis, mutagenesis with binding affinity measurements

    PMID:21238461

    Open questions at the time
    • Structures of other PDZ domains not solved
    • How conformational changes propagate to multi-domain function unknown
  11. 2017 Medium

    Loss-of-function studies in gastric and hepatocellular carcinoma cells demonstrated that MAGI1 suppresses migration and invasion through inhibition of MAPK/ERK signaling and stabilization of PTEN, solidifying its role as a broadly acting tumor suppressor.

    Evidence shRNA knockdown in gastric cancer cells with MAPK/ERK and EMT marker readouts; MAGI1 overexpression in HepG2 with PTEN correlation in HCC tissues

    PMID:21685691 PMID:28373751

    Open questions at the time
    • Direct mechanism linking MAGI1 scaffolding to PTEN stabilization not defined
    • No epistasis experiments placing MAGI1 upstream of MAPK directly
  12. 2019 High

    Two studies revealed MAGI1 as a mechanosensitive endothelial signaling hub: shear stress induces MAGI1 expression to activate eNOS via PKA/AMPK, while disturbed flow triggers p90RSK-mediated MAGI1 phosphorylation and SENP2-mediated deSUMOylation that drive nuclear translocation and pro-atherogenic endothelial activation.

    Evidence siRNA/overexpression with pharmacological kinase inhibition and flow chambers; transgenic MAGI1 mice with ex vivo NO measurement; phosphorylation/SUMOylation site mutagenesis and Magi1+/- atherogenesis model

    PMID:30944250 PMID:31035633

    Open questions at the time
    • How MAGI1 senses or transduces mechanical force is unknown
    • Relative contribution of phosphorylation vs. SUMOylation to atherogenesis not separated in vivo
  13. 2020 High

    MAGI1 was established as a tumor suppressor in ER+ breast cancer where it sustains ER expression, and its loss accelerates primary tumor growth and metastasis; MAGI1 is itself regulated by estrogen/ER and suppressed by COX-2/PGE2, forming a feed-forward regulatory loop.

    Evidence shRNA knockdown in MCF7 and 67NR cells, in vivo xenograft and lung metastasis models, pharmacological stimulation/inhibition of ER and COX-2 pathways

    PMID:31963297

    Open questions at the time
    • Mechanism by which MAGI1 maintains ER expression is unknown
    • Whether NSAID-mediated MAGI1 upregulation is clinically actionable not tested
  14. 2024 High

    Phosphoproteomic identification of MAGI1 as a SRC substrate revealed a latent MAGI1–PP2A tumor-suppressive complex: SRC phosphorylation inhibits this complex, while SRC inhibition enables MAGI1–PP2A to dephosphorylate S6K independently of mTOR, defining a druggable axis in IDH-mutant cholangiocarcinoma.

    Evidence Unbiased phosphoproteomics, co-IP of MAGI1–PP2A, PP2A activity assays, patient tissue validation, patient-derived organoids and xenograft models

    PMID:38748774

    Open questions at the time
    • Structural basis of SRC phosphorylation-dependent PP2A dissociation unknown
    • Whether MAGI1–PP2A complex operates in other SRC-driven cancers not tested
    • Which MAGI1 phosphosite(s) regulate PP2A binding not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MAGI1's multiple PDZ and WW domain interactions are coordinated in space and time to balance its junctional scaffolding, tumor-suppressive, and endothelial signaling functions remains unresolved, as does the in vivo phenotype of complete MAGI1 loss in mammals.
  • No full mammalian knockout phenotype published
  • No structural model of multi-domain MAGI1 or full-length complex assembly
  • Interplay among PTMs (phosphorylation, SUMOylation) in different tissue contexts not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1500931 Cell-Cell communication 5 R-HSA-1643685 Disease 4
Partners
AMICA1CDH23CTNNB1DLL1PPP2CAPTENSLC1A2TRIP6
Complex memberships
MAGI1-PP2A complexMAGI1-beta-catenin-E-cadherin junctional complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MAGI-1 was identified as a novel MAGUK scaffolding protein with an inverted domain structure: guanylate kinase (GK) domain at the N-terminus, two WW domains replacing the SH3 domain, and five PDZ domains at the C-terminus. Subcellular fractionation and immunolocalization in MDCK cells showed that the longest splice variant (MAGI-1c), which contains bipartite nuclear localization signals in its unique C-terminal sequence, localizes predominantly to the nucleus, while shorter forms lacking these signals are found in membrane and cytoplasmic fractions. cDNA cloning, subcellular fractionation, immunolocalization in MDCK cells The Journal of biological chemistry High 9395497
1997 MAGI-1 WW domains were identified as binding partners for PY-motif (PPxY)-containing proteins; cloning of ligand targets (COLT) screen identified MAGI-1 among novel WW domain proteins capable of binding PY-motif ligands from signaling and regulatory proteins. COLT screen (cDNA expression library screening with peptide ligands), in vitro WW domain binding assays The Journal of biological chemistry Medium 9169421
1998 MAGI-1 (as AIP1/AIP3) was identified as an atrophin-1 interacting protein through its WW domains; yeast two-hybrid and in vitro binding assays confirmed that atrophin-1 binds to MAGI-1 in the vicinity of its polyglutamine tract. Yeast two-hybrid screen, in vitro binding assays (GST pulldown) Molecular and cellular neurosciences Medium 9647693
2000 MAGI-1 was identified as a binding partner of adenovirus type 9 E4-ORF1 and high-risk HPV E6 oncoproteins via PDZ domain interaction. E4-ORF1 aberrantly sequesters MAGI-1 in the cytoplasm, while high-risk HPV E6 targets MAGI-1 for degradation. Transformation-defective viral mutants are deficient for these activities, implicating MAGI-1 interaction in viral oncogenesis. Co-immunoprecipitation, immunofluorescence localization, mutational analysis of viral oncoproteins Oncogene High 11077444
2000 MAGI-1b fifth PDZ domain (PDZ5) is essential for membrane localization of MAGI-1b, and this PDZ domain binds beta-catenin. MAGI-1b forms complexes with beta-catenin and E-cadherin during formation of cell-cell junctions in MDCK cells; GFP-MAGI-1b localizes to the basolateral membrane of polarized MDCK cells. PDZ domain deletion analysis, co-immunoprecipitation, GFP-fusion localization in MDCK cells Biochemical and biophysical research communications High 10772923
2002 MAGI-1 and MAGI-3 are components of tight junctions in cultured epithelial cells and in all epithelial cell types examined in vivo. Human MAGI-1 is alternatively spliced at three sites producing isoforms with different C-termini; two brain-specific forms lack nuclear targeting signals. MAGI-1 colocalizes with ZO-1 and ZO-2 in non-polarized epithelial cells, suggesting a pre-assembled complex incorporated into tight junctions upon polarization. All alternatively spliced forms show tight junction localization independently of the GK and WW domains or extended C-terminus. Immunofluorescence colocalization, isoform-specific domain deletion analysis in cultured epithelial cells, in vivo tissue expression analysis Experimental cell research High 11969287
2003 JAM4 (junctional adhesion molecule 4) was identified as a novel MAGI-1 binding protein at tight junctions. JAM4 binds MAGI-1 (but not ZO-1) in vitro, co-clusters with MAGI-1 in COS-7 cells, and MAGI-1 strengthens JAM4-mediated cell-cell adhesion and epithelial barrier sealing effects. MAGI-1 also recruits ZO-1, occludin, and other tight junction proteins to JAM4-based cell contacts. In vitro GST pulldown, co-immunoprecipitation, colocalization in COS-7 cells, functional adhesion and permeability assays in L cells and CHO cells Molecular and cellular biology High 12773569
2005 MAGI-1 recruits Delta-like 1 (Dll1) to cadherin-based adherens junctions (AJs) and stabilizes Dll1 on the cell surface. In developing neural tube, MAGI-1 accumulates at AJs at apical termini of radial processes. MAGI-1 binds both Dll1 and N-cadherin-beta-catenin complexes. In cultured fibroblasts, MAGI-1 localizes to AJs and recruits Dll1 to these sites through direct binding, stabilizing Dll1 on the cell surface. Yeast two-hybrid, co-immunoprecipitation, in situ hybridization, immunofluorescence colocalization in vivo and in cultured fibroblasts, cell surface biotinylation The Journal of biological chemistry High 15908431
2005 A novel MAGI-1-associated protein (MASCOT) was identified that binds to the first WW domain of MAGI-1 via a variant LPxY motif (not the canonical PPxY). MASCOT colocalizes with MAGI-1 at tight junctions in MDCK cells and its coiled-coil domain is necessary for this junctional localization. Glomerular cDNA library screen, GST pulldown assays, co-immunoprecipitation with endogenous MAGI-1, immunofluorescence in MDCK cells, domain deletion analysis Biochimica et biophysica acta Medium 16019084
2008 MAGI-1 was identified as a candidate stereociliary scaffolding protein that binds the hair-cell-specific Cdh23(+68) splice variant of cadherin 23 via its PDZ4 domain interacting with the C-terminal PDZ-binding site of Cdh23. MAGI-1 immunoreactivity is present throughout neonatal stereocilia in a distribution similar to Cdh23, becoming punctate in adult, and is proposed to replace harmonin's PDZ2 binding at the Cdh23 C-terminus in the tip-link complex. Cochlear cDNA library screen using Cdh23 intracellular domain as bait, PDZ domain binding assays, immunofluorescence in cochlear hair cells The Journal of neuroscience Medium 18971469
2008 TRIP6, a zyxin-family protein, was identified as a direct MAGI-1b interactor binding to its fifth PDZ domain (PDZ5). Ectopic TRIP6 expression induced invasiveness in MDCK cells in a PI3-kinase- and NF-κB-dependent manner and impaired cell-cell aggregation by uncoupling adherens junctional complexes from the cytoskeleton. A TRIP6 mutant lacking the PDZ-binding motif could not promote invasiveness or interfere with cell-cell aggregation, despite retaining NF-κB and Akt activation, demonstrating that PDZ scaffold interactions are required for these functions. Yeast two-hybrid screening, direct binding assays, ectopic expression in MDCK/MDCKts-src cells, invasion assays, cell aggregation assays, intracellular peptide delivery competition FASEB journal High 19017743
2009 C. elegans MAGI-1 (ortholog of mammalian MAGI/S-SCAM) is required in specific neurons for different aspects of associative learning and memory. MAGI-1 in RIA interneurons controls, in a cell non-autonomous manner, the dynamic remodeling of AVA/AVD/AVE synapses containing ionotropic glutamate receptor (iGluR) GLR-1 during learning. During memory consolidation, MAGI-1 controls GLR-1 clustering in AVA and AVD interneurons cell-autonomously, dependent on interaction with beta-catenin HMP-2. Genetic analysis of magi-1 mutants, neuron-specific rescue experiments, fluorescence imaging of GLR-1::GFP synaptic clusters, epistasis analysis with hmp-2 (beta-catenin) PloS one High 19551147
2010 MAGI-1 is a major degradation target of both HPV-16 and HPV-18 E6 oncoproteins in cervical cancer cells. E6 preferentially targets MAGI-1 within the nucleus and at membrane sites. MAGI-1 degradation directly causes loss of tight junction integrity (mislocalization of ZO-1), and restoration of tight junctions after E6 ablation is dependent on the presence of MAGI-1. siRNA knockdown of E6 in CaSKi (HPV-16+) and HeLa (HPV-18+) cells, Western blot quantification of PDZ substrates, immunofluorescence of ZO-1, MAGI-1 rescue experiments Journal of virology High 21123374
2010 Surface plasmon resonance (SPR) quantification established that high-risk HPV E6 C-terminal peptides bind the PDZ1 domain of MAGI-1 with dissociation constants in the micromolar range, comparable to cellular PDZ1 ligands (LPP, Tax). MAGI-1 PDZ1 shows preference for C-termini with valine at position 0 and a negative charge at position -3. Mutagenesis identified K499 of MAGI-1 PDZ1 as a novel determinant of binding specificity; charged residues upstream of the PDZ-binding motif strongly contribute to binding selectivity. Surface plasmon resonance (SPR) with GST-fusion peptides, site-directed mutagenesis of HPV16 E6 C-terminal peptide and MAGI-1 PDZ1 Journal of molecular recognition High 20842623
2011 MAGI-1 binds glutamate transporter GLT-1 (EAAT2) as shown by GST pulldown and co-immunoprecipitation; the two proteins co-distribute in astrocytes. Co-expression of MAGI-1 with GLT-1 in C6 glioma cells significantly reduces GLT-1 surface expression as measured by cell-surface biotinylation. Conversely, partial knockdown of endogenous MAGI-1 in differentiated astrocytes increases glutamate uptake and surface expression of GLT-1, demonstrating that MAGI-1 negatively regulates GLT-1 surface expression and GLT-1-mediated glutamate uptake. GST pulldown, co-immunoprecipitation, immunofluorescence, cell-surface biotinylation, siRNA knockdown, glutamate uptake assay Journal of neurochemistry High 21426345
2011 NMR solution structure of MAGI-1 PDZ1 domain (with noncanonical extended boundaries) was solved alone and in complex with HPV16 E6 C-terminal peptide. E6 peptide binding induces quenching of high-frequency backbone motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical binding motif. Mutations in the C-terminal flanking region of PDZ1 significantly decrease binding affinity for E6 peptides, revealing a global conformational response to binding with effects propagated to distal sites. NMR spectroscopy (3D structure determination), backbone dynamics analysis, site-directed mutagenesis with binding affinity measurements Journal of molecular biology High 21238461
2012 Biochemical fractionation of rat brain tissue revealed that MAGI-1 is enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from MAGI-2 and MAGI-3, which are enriched in the postsynaptic density fraction). Immunohistochemistry showed MAGI-1 expression in Purkinje cells, hippocampal CA1 neurons, the glomerulus region of the olfactory bulb, and the dorsal root entry zone in embryonic spinal cord, with diffuse distribution in cell bodies and processes of primary cultured hippocampal neurons (unlike the synaptic enrichment of MAGI-2/3). Subcellular fractionation with Western blotting, immunofluorescence in primary neurons, immunohistochemistry in rat brain sections Journal of neuroscience research Medium 22605569
2017 MAGI1 knockdown in gastric cancer cells significantly promotes cell migration and invasion. Mechanistically, MAGI1 inhibits migration and invasion by altering expression of matrix metalloproteinases (MMPs) and EMT-related molecules through inhibition of the MAPK/ERK signaling pathway. shRNA knockdown in GC cell lines, MTT/colony formation assays, scratch wound and transwell migration/invasion assays, Western blotting for MAPK/ERK pathway components and EMT markers Chinese journal of cancer research Medium 28373751
2019 MAGI1 mediates fluid shear stress-induced eNOS activation and NO production in endothelial cells. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbs KLF4 expression, endothelial cell alignment, eNOS phosphorylation, and NO production, while MAGI1 overexpression induces PKA, AMPK, and CaMKII phosphorylation. Pharmacological inhibition of PKA and AMPK prevents MAGI1-mediated eNOS phosphorylation. Endothelial-specific transgenic MAGI1 mice show increased PKA and eNOS phosphorylation in vivo and increased NO production ex vivo. siRNA silencing, MAGI1 overexpression, pharmacological kinase inhibition, flow chamber experiments, transgenic mouse model with ex vivo NO measurement, Western blotting for phospho-kinases Cells High 31035633
2019 In endothelial cells exposed to disturbed flow (d-flow), p90RSK binds MAGI1 and phosphorylates MAGI1 at S741, activating Rap1 to upregulate EC activation. Separately, MAGI1-K931 deSUMOylation (mediated by SENP2-T368 phosphorylation) drives nuclear translocation of p90RSK-MAGI1 and ATF6-MAGI1 complexes, accelerating EC activation and apoptosis respectively. MAGI1 associates with ATF-6, linking it to the ER stress response. Magi1+/- heterozygous mice show inhibited d-flow-induced atherogenesis. Co-immunoprecipitation, phosphorylation/SUMOylation site mutagenesis, microarray screening, immunofluorescence, in vivo atherogenesis in Magi1+/- mice, nuclear fractionation JCI insight High 30944250
2019 MAGI1 suppresses tumor metastasis in renal cell carcinoma (RCC) by stabilizing the PTEN/MAGI1/β-catenin complex, thereby inhibiting β-catenin signaling. MAGI1 is transcriptionally suppressed by miR-520h, which is itself activated by c-Myb, defining a c-Myb/miR-520h/MAGI1 regulatory axis in RCC metastasis. Overexpression and knockdown in RCC cell lines, invasion/migration assays, co-immunoprecipitation of MAGI1/PTEN/β-catenin complex, luciferase reporter assay for miR-520h/MAGI1 3'UTR interaction Apoptosis Medium 31352641
2020 miR-486-5p directly targets the 3'UTR of MAGI1 and RASSF5, as confirmed by dual-luciferase reporter assay and FREMSA. MAGI1 knockdown in K562 cells reverses HQ-induced inhibition of erythroid differentiation via downregulation of RAPGEF2 and RAP1A, placing MAGI1 upstream of the Rap1 signaling pathway. MAGI1 and downstream Rap1 pathway genes are dose-dependently upregulated by hydroquinone. Dual-luciferase reporter assay, fluorescence-based RNA EMSA (FREMSA), miR-486-5p overexpression/knockdown, MAGI1 siRNA knockdown, Western blotting for Rap1 pathway Toxicology in vitro Medium 32198055
2020 MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+)/HER2- breast cancer. MAGI1 downregulation in MCF7 cells impairs ER expression and signaling, promotes cell proliferation, reduces apoptosis, and reduces epithelial differentiation. In murine 67NR ER+ BC cells, MAGI1 downregulation accelerates primary tumor growth and enhances experimental lung metastasis formation. MAGI1 expression is upregulated by estrogen/ER signaling and downregulated by the prostaglandin E2/COX-2 axis. siRNA/shRNA knockdown, cell proliferation and apoptosis assays, in vivo tumor xenograft and lung metastasis models in mice, Western blotting for ER signaling, pharmacological stimulation/inhibition Cancers High 31963297
2021 MAGI1 is a comprehensive scaffold/tumor suppressor protein: it stabilizes cadherin-mediated cell-cell adhesion in epithelial and endothelial cells, localizes at mature focal adhesions, and regulates integrin-mediated adhesion and signaling in endothelial cells. MAGI1 modulates PI3K/AKT and Wnt/β-catenin oncogenic pathways. NSAIDs upregulate MAGI1 expression in breast and colorectal cancers, suggesting MAGI1 mediates part of NSAID tumor suppressive activity. Review compiling experimental evidence from multiple studies; original data includes localization at focal adhesions Cells Low 34198584
2022 HPV-16 E6 intragenic variants (E-G350, E-C188/G350, E-A176/G350, AAa, AAc) show increased binding affinity to MAGI-1 PDZ1 domain compared to the E6 reference sequence, as modeled by molecular dynamics simulation and protein-protein docking with two MAGI-1 PDZ1 structural models. Molecular dynamics simulation, protein-protein docking (in silico) Scientific reports Low 35115618
2019 MAGI1 silencing in glioma cell lines and glioma stem cells (GSCs) enhances proliferation and inhibits apoptosis. MAGI1 knockdown increases N-cadherin, vimentin, β-catenin, cyclin D1, and phospho-Akt, and reduces E-cadherin and PTEN, indicating MAGI1 suppresses glioma progression via the Wnt/β-catenin and PTEN/AKT signaling pathways. shRNA knockdown, CCK8 and colony-formation assays, flow cytometry apoptosis, Western blotting for EMT/pathway markers OncoTargets and therapy Medium 32009799
2011 MAGI1 inhibits migration and invasion of hepatocellular carcinoma (HepG2) cells; stable overexpression of MAGI1 significantly slows wound healing and reduces Matrigel invasion. MAGI1 overexpression substantially elevates PTEN protein levels, and MAGI1 and PTEN expression levels are positively correlated in HCC tissues (r=0.913), suggesting MAGI1 suppresses HCC cell motility by upregulating PTEN. Stable transfection of MAGI1 plasmid in HepG2, wound healing assay, Matrigel invasion assay, Western blot for PTEN Journal of Central South University. Medical sciences Medium 21685691
2024 SRC kinase phosphorylates MAGI1 in IDH-mutant intrahepatic cholangiocarcinoma (IDHm ICC), inhibiting a latent tumor-suppressing MAGI1-PP2A complex. SRC inhibition by dasatinib enables MAGI1 to recruit and activate PP2A, which dephosphorylates S6K, reducing ribosomal S6 phosphorylation and protein synthesis, leading to cell death. This MAGI1-PP2A-S6K axis operates independently of mTOR. Unbiased phosphoproteomic screen identifying MAGI1 as SRC substrate, biochemical co-IP of MAGI1-PP2A complex, functional PP2A phosphatase activity assays, patient tissue validation, patient-derived organoids, xenograft mouse models Science translational medicine High 38748774
2012 Copy number variations (CNVs) >100 kb in MAGI1 are enriched in patients with bipolar affective disorder (BPAD) and schizophrenia compared to controls (pooled analysis: 7 large CNVs in cases vs. 2 in controls, p=0.023). A ~200 kb deletion in the first intron of MAGI1 segregated with BPAD in a pedigree (6/6 affected individuals carried it), suggesting MAGI1 has a role in psychiatric disease etiology. Genome-wide CNV assessment in 48 BPAD families, follow-up in 4084 psychiatric samples, pooled analysis of 10,925 cases and 16,747 controls Biological psychiatry Low 22381734

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nature cell biology 830 30202049
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 330 28614305
2013 Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America 305 24347639
2015 Loss of BAP1 function leads to EZH2-dependent transformation. Nature medicine 297 26437366
2013 Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers. PLoS genetics 292 23382691
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2000 Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 244 11077444
2012 BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. Journal of translational medicine 239 22935333
2020 Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer. Cancer discovery 231 32690542
2013 Tumours associated with BAP1 mutations. Pathology 222 23277170
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2018 Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. Journal of the National Cancer Institute 203 30517737
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2008 Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of general psychiatry 194 18519826
2015 Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. JAMA psychiatry 190 25993607
2015 BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5. Nature communications 179 26419610
1997 MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of protein-protein interaction domains. The Journal of biological chemistry 171 9395497
2016 BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nature communications 165 26739236
2010 A human MAP kinase interactome. Nature methods 165 20936779
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2005 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer. Molecular & cellular proteomics : MCP 153 15778465
2017 Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-oncology 152 28170043
1997 Identification of novel human WW domain-containing proteins by cloning of ligand targets. The Journal of biological chemistry 148 9169421
1998 Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Molecular and cellular neurosciences 147 9647693
2000 MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures. Biochemical and biophysical research communications 146 10772923
2017 Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade. Cancer discovery 144 28473526
2003 JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Molecular and cellular biology 142 12773569
2020 BAP1: Not just a BRCA1-associated protein. Cancer treatment reviews 139 32877777
2021 Roles and mechanisms of BAP1 deubiquitinase in tumor suppression. Cell death and differentiation 134 33462414
2018 Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nature communications 109 30013160
2015 Loss of expression of BAP1 predicts longer survival in mesothelioma. Pathology 103 25938359
2011 An emerging model for BAP1's role in regulating cell cycle progression. Cell biochemistry and biophysics 102 21484256
2013 PBRM1 and BAP1 as novel targets for renal cell carcinoma. Cancer journal (Sudbury, Mass.) 98 23867514
2017 SF3B1 and BAP1 mutations in blue nevus-like melanoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 85 28409567
2014 Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clinical genetics 83 25080371
2017 BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response. Proceedings of the National Academy of Sciences of the United States of America 82 28275095
2002 MAGI-1: a widely expressed, alternatively spliced tight junction protein. Experimental cell research 82 11969287
2018 Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. Journal of current ophthalmology 81 29988936
2016 Gene of the month: BAP1. Journal of clinical pathology 76 27235536
2014 BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes. The Journal of biological chemistry 74 25451922
2010 A systematic analysis of human papillomavirus (HPV) E6 PDZ substrates identifies MAGI-1 as a major target of HPV type 16 (HPV-16) and HPV-18 whose loss accompanies disruption of tight junctions. Journal of virology 74 21123374
2012 The ASXL-BAP1 axis: new factors in myelopoiesis, cancer and epigenetics. Leukemia 72 23147254
2021 Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia. Nature cancer 68 35122023
2017 Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma. Histopathology 67 27859460
2016 CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. Cancer letters 61 27181379
2005 MAGI1 recruits Dll1 to cadherin-based adherens junctions and stabilizes it on the cell surface. The Journal of biological chemistry 58 15908431
2008 TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 19017743
2017 BAP1, a tumor suppressor gene driving malignant mesothelioma. Translational lung cancer research 56 28713672
2009 Neuron-specific regulation of associative learning and memory by MAGI-1 in C. elegans. PloS one 55 19551147
2019 BRCA1-associated protein (BAP1)-inactivated melanocytic tumors. Journal of cutaneous pathology 53 31233225
2020 ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. Genome medicine 51 32669118
2019 BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas. Clinical cancer research : an official journal of the American Association for Cancer Research 49 31285370
2019 MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress. Cells 47 31035633
2021 BAP1-Mutated Clear Cell Renal Cell Carcinoma. American journal of clinical pathology 46 33210135
2021 Roles of the BAP1 Tumor Suppressor in Cell Metabolism. Cancer research 45 33446574
2021 Estimation of the timing of BAP1 mutation in uveal melanoma progression. Scientific reports 45 33903674
2008 MAGI-1, a candidate stereociliary scaffolding protein, associates with the tip-link component cadherin 23. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 18971469
2011 The structural and dynamic response of MAGI-1 PDZ1 with noncanonical domain boundaries to the binding of human papillomavirus E6. Journal of molecular biology 44 21238461
2019 MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. JCI insight 43 30944250
2020 BAP1: role in carcinogenesis and clinical implications. Translational lung cancer research 40 32206571
2012 MAGI1 copy number variation in bipolar affective disorder and schizophrenia. Biological psychiatry 40 22381734
2021 BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion. eLife 39 34170818
2015 Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma. Cancer letters 39 26300492
2005 Identification and characterization of a novel tight junction-associated family of proteins that interacts with a WW domain of MAGI-1. Biochimica et biophysica acta 38 16019084
2020 Identifying BAP1 Mutations in Clear-Cell Renal Cell Carcinoma by CT Radiomics: Preliminary Findings. Frontiers in oncology 36 32185138
2016 BAP1 suppresses lung cancer progression and is inhibited by miR-31. Oncotarget 36 26885612
2020 BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN. Molecular oncology 35 33155366
2010 Surface plasmon resonance analysis of the binding of high-risk mucosal HPV E6 oncoproteins to the PDZ1 domain of the tight junction protein MAGI-1. Journal of molecular recognition : JMR 34 20842623
2017 MAGI1 inhibits migration and invasion via blocking MAPK/ERK signaling pathway in gastric cancer. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 33 28373751
2016 Loss of expression of BAP1 is very rare in non-small cell lung carcinoma. Pathology 33 27114369
2015 Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients. Ophthalmic genetics 32 25687217
2014 Regulation and involvement in cancer and pathological conditions of MAGI1, a tight junction protein. Anticancer research 32 24982328
2018 BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression. Genes & development 31 30463901
2022 The expanding role of BAP1 in clear cell renal cell carcinoma. Human pathology 29 35932824
2020 Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network. Protein & cell 29 32683582
2021 BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos. Proceedings of the National Academy of Sciences of the United States of America 28 34815344
2019 BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress. The Biochemical journal 28 31657441
2021 MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions. Cells 25 34198584
2019 Long noncoding RNA MAGI1-IT1 promoted invasion and metastasis of epithelial ovarian cancer via the miR-200a/ZEB axis. Cell cycle (Georgetown, Tex.) 25 31122127
2023 BAP1 promotes osteoclast function by metabolic reprogramming. Nature communications 24 37740028
2021 BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression. Experimental cell research 24 33516665
2015 A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer. Cancer genetics 23 26774355
2021 Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence. Molecular oncology 22 34706158
2020 Uveal Melanoma in BAP1 Tumor Predisposition Syndrome: Estimation of Risk. American journal of ophthalmology 21 33316260
2019 Population-based analysis of BAP1 germline variations in patients with uveal melanoma. Human molecular genetics 21 31058963
2022 Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma. Molecular cancer research : MCR 20 35426938
2021 Novel insights into the BAP1-inactivated melanocytic tumor. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 34857909
2011 Regulation of glutamate transporter GLT-1 by MAGI-1. Journal of neurochemistry 20 21426345
2019 BAP1 in solid tumors. Future oncology (London, England) 19 31159579
2012 Biochemical and morphological characterization of MAGI-1 in neuronal tissue. Journal of neuroscience research 19 22605569
2024 Tumor suppressor BAP1 suppresses disulfidptosis through the regulation of SLC7A11 and NADPH levels. Oncogenesis 17 39266549
2023 Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma. Cell reports. Medicine 17 36657447
2018 G-quadruplexes in the BAP1 promoter positively regulate its expression. Experimental cell research 17 29787736
2022 Molecular insights into the interaction of HPV-16 E6 variants against MAGI-1 PDZ1 domain. Scientific reports 16 35115618
2022 Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma. Genes 16 36292588
2022 BAP1 in cancer: epigenetic stability and genome integrity. Discover oncology 16 36318367
2020 MiR-486-5p-directed MAGI1/Rap1/RASSF5 signaling pathway contributes to hydroquinone-induced inhibition of erythroid differentiation in K562 cells. Toxicology in vitro : an international journal published in association with BIBRA 16 32198055
2021 Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression. Cancers 15 33800007
2021 The AMP-dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma. Pigment cell & melanoma research 15 34347929
2020 MAGI1, a New Potential Tumor Suppressor Gene in Estrogen Receptor Positive Breast Cancer. Cancers 15 31963297
2020 BAP1 maintains chromosome stability by stabilizing DIDO1 in renal cell carcinoma. American journal of cancer research 15 32509391
2022 Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma. Oncogene 14 35046531
2022 Impacts of Cancer-associated Mutations on the Structure-Activity Relationship of BAP1. Journal of molecular biology 14 35317997
2021 BAP1 promotes viability and migration of ECA109 cells through KLF5/CyclinD1/FGF-BP1. FEBS open bio 14 33529461
2021 The spectrum of tumors harboring BAP1 gene alterations. Cancer genetics 14 33866194
2020 MAGI1-IT1 stimulates proliferation in non-small cell lung cancer by upregulating AKT1 as a ceRNA. European review for medical and pharmacological sciences 14 32016970
2011 MAGI1 inhibits cancer cell migration and invasion of hepatocellular carcinoma via regulating PTEN. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 14 21685691
2024 SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma. Science translational medicine 13 38748774
2022 Tumor suppressor BAP1 nuclear import is governed by transportin-1. The Journal of cell biology 13 35446349
2021 Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1. Frontiers in immunology 13 33912157
2019 MAGI1 mediates tumor metastasis through c-Myb/miR-520h/MAGI1 signaling pathway in renal cell carcinoma. Apoptosis : an international journal on programmed cell death 13 31352641
2019 Silencing Of MAGI1 Promotes The Proliferation And Inhibits Apoptosis Of Glioma Cells Via The Wnt/β-Catenin And PTEN/AKT Signaling Pathways. OncoTargets and therapy 13 32009799
2024 ATF2/BAP1 Axis Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage via P53 Pathway. Stroke 12 38965653
2024 BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer. European journal of cancer (Oxford, England : 1990) 12 39151323
2021 BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma. The Journal of biological chemistry 12 34597666