Affinage

LNX1

E3 ubiquitin-protein ligase LNX · UniProt Q8TBB1

Round 2 corrected
Length
728 aa
Mass
80.6 kDa
Annotated
2026-04-28
96 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LNX1 is a RING-type E3 ubiquitin-protein ligase that couples a Zn-RING-Zn catalytic domain—functioning as a homodimer that recruits Ubc13/Ube2V2—with four PDZ domains that select substrates and scaffold multiprotein complexes (PMID:29496391, PMID:11782429). Through ubiquitin-dependent degradation of Numb, LNX1 activates Notch signaling to regulate neural stem cell proliferation, glioma stem cell expansion, and macrophage polarization (PMID:11782429, PMID:30833887, PMID:33255632, PMID:36093061); additional substrates targeted for proteasomal degradation include PBK, BCR, NEK6, connexin36, and liprin-α1, while non-degradative ubiquitination of RhoC modulates Rho-GTPase activity (PMID:22889411, PMID:30295974, PMID:29121065, PMID:36192543). In the hippocampus, LNX1 acts as a postsynaptic scaffold that stabilizes EphB receptors and an NMDAR–EphB2 complex at the membrane, and loss of Lnx1 causes defective mossy fiber targeting, impaired synaptogenesis, and social memory deficits, while the neuronal LNX1p70 isoform—lacking the RING domain—serves as a non-catalytic scaffold recruiting other TRIM-family E3 ligases to ubiquitinate shared partners (PMID:30185604, PMID:31772302, PMID:35531068, PMID:29121065).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    The initial question was what proteins interact with the Numb PTB domain; yeast two-hybrid screening identified LNX as a novel RING-finger and PDZ-domain protein that binds Numb via an NPXY-like motif, establishing the founding interaction of the LNX field.

    Evidence Yeast two-hybrid with Numb PTB domain bait, mutational and peptide competition analyses in vitro

    PMID:9535908

    Open questions at the time
    • No functional consequence of the Numb–LNX interaction was tested
    • Enzymatic activity of the RING domain was not assessed
    • In vivo relevance of the interaction was unknown
  2. 2002 High

    The critical question of whether the RING domain confers E3 ligase activity was answered: LNX ubiquitinates Numb in a RING-dependent manner, targets it for proteasomal degradation, and thereby activates Notch signaling, establishing LNX as a functional E3 ligase in the Numb/Notch pathway.

    Evidence In vitro reconstituted ubiquitin ligase assay, RING cysteine mutagenesis, proteasome inhibitor treatment, Notch reporter assay in mammalian cells

    PMID:11782429

    Open questions at the time
    • The E2 partner(s) were not identified
    • In vivo physiological requirement for LNX-mediated Numb degradation was untested
    • Other substrates beyond Numb were unknown
  3. 2002 Medium

    The scope of LNX PDZ-domain interactions was broadened when LNX1 was shown to bind the Coxsackievirus and adenovirus receptor (CAR) via PDZ2, establishing the PDZ domains as versatile substrate-recruitment modules.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and colocalization in mammalian cells

    PMID:12468544

    Open questions at the time
    • Whether CAR is a ubiquitination substrate of LNX1 was not tested
    • Functional consequence for viral entry or cell adhesion was not determined
  4. 2005 Medium

    Cell-type-specific expression studies at the neuromuscular junction revealed LNX1 in perisynaptic Schwann cells and its interaction with ErbB2, suggesting a role in regulating neuregulin signaling at synapses and extending LNX1 biology beyond the Numb/Notch axis.

    Evidence Immunostaining of NMJ, direct protein interaction assay, denervation model correlation

    PMID:16122940

    Open questions at the time
    • Direct ubiquitination of ErbB2 by LNX1 was not demonstrated
    • Functional rescue experiments were not performed
    • Mechanism of ErbB2 downregulation remained correlative
  5. 2009 High

    Zebrafish studies demonstrated an in vivo developmental requirement: LNX orthologs ubiquitinate the homeodomain protein Bozozok via K48-linked chains for proteasomal degradation, restricting dorsal organizer expansion and controlling dorsoventral axis formation.

    Evidence Morpholino knockdown, K48-polyubiquitination assay, genetic epistasis in zebrafish embryos

    PMID:19668196

    Open questions at the time
    • Whether mammalian LNX1 has analogous developmental patterning roles was unknown
    • The identity of the E2 was not determined in vivo
  6. 2012 High

    A systematic substrate-discovery approach identified PBK and BCR as endogenous LNX1 substrates and showed that LNX1-mediated PBK degradation inhibits cell proliferation and sensitizes cells to apoptosis, expanding the substrate repertoire and linking LNX1 to cell cycle control.

    Evidence Random peptide library screen, in vitro ubiquitination, in vivo ubiquitination assay, proliferation and apoptosis assays

    PMID:22889411

    Open questions at the time
    • Whether PBK/BCR are physiological substrates in normal tissues was not established
    • The PDZ domain specificity for each substrate was not fully mapped
  7. 2016 High

    The long-standing assumption that LNX1 is a major Numb regulator in vivo was overturned: LNX1/LNX2 double-knockout mice showed normal Numb levels and no neuroanatomical defects attributable to Numb dysfunction, but exhibited decreased anxiety behavior, redirecting attention toward synaptic scaffold functions.

    Evidence LNX1/LNX2 double-knockout mice, behavioral testing, proteomics identifying presynaptic active zone interactors (ERC1/2, liprin-αs, FCHSD2, SRGAP2)

    PMID:27889896

    Open questions at the time
    • Compensatory mechanisms that maintain Numb levels were not identified
    • Tissue-specific Numb regulation (e.g., in specific developmental windows) was not ruled out
  8. 2017 High

    AP-MS interactomics and in vitro assays revealed liprin-α1, KLHL11, KIF7, and ERC2 as ubiquitination substrates and, critically, demonstrated that the RING-less LNX1p70 neuronal isoform acts as a non-catalytic scaffold that recruits TRIM-family E3 ligases (MID2/TRIM1, TRIM27) to ubiquitinate shared substrates.

    Evidence Affinity purification–mass spectrometry, in vitro ubiquitination with domain mapping, Co-IP for TRIM E3 recruitment

    PMID:29121065

    Open questions at the time
    • Whether TRIM E3 recruitment by LNX1p70 occurs at synapses in vivo was not shown
    • Structural basis for the LNX1p70–TRIM interaction was not determined
  9. 2018 High

    Structural determination of the Zn-RING-Zn domain in complex with Ubc13~Ub resolved how LNX1 catalyzes ubiquitin transfer: the homodimeric architecture creates a unique trans-monomer ubiquitin-sharing surface essential for catalysis, identifying Ubc13/Ube2V2 as the functional E2.

    Evidence Crystal structure of LNX1 Zn-RING-Zn:Ubc13~Ub complex, mutagenesis, in vitro ubiquitination

    PMID:29496391

    Open questions at the time
    • How dimerization is regulated in cells was not addressed
    • Chain-type specificity (K48 vs. K63) conferred by E2 choice was not fully resolved for all substrates
  10. 2018 High

    Two concurrent studies established LNX1 as a postsynaptic scaffold essential for hippocampal circuit wiring: LNX1 stabilizes EphB1/B2 receptors on the CA3 membrane, prevents their internalization, and organizes an NMDAR–EphB2 complex required for mossy fiber targeting and connexin36-based electrical synapses.

    Evidence Lnx1 knockout mice with mossy fiber tracing, Co-IP of EphB/NMDAR complexes, receptor internalization assays, connexin36 gap junction loss with ligase-active vs. inactive LNX

    PMID:30185604 PMID:30295974

    Open questions at the time
    • Whether the scaffold and E3 functions operate simultaneously on the same complex was unclear
    • The triggering signals for LNX1-mediated Cx36 ubiquitination were not identified
  11. 2019 High

    The scaffold function was linked to behavior: Lnx1 deficiency disrupts the LNX1–NMDAR–EphB2 complex in hippocampal CA3, causing NMDAR hypofunction, impaired neuronal activity, and social memory deficits that are rescued by region-specific Lnx1 or EphB2 restoration.

    Evidence Lnx1 KO mice, PSD fractionation, stereotaxic viral rescue of CA3, electrophysiology, social recognition assay

    PMID:31772302

    Open questions at the time
    • Whether human LNX1 variants associate with social cognition phenotypes was not tested
    • Contribution of LNX1p70 vs. LNX1p80 to the synaptic complex was not dissected
  12. 2019 High

    LNX1's substrate range was extended to tumor suppressor pathways: LNX1 interacts with p53 and MDM2, enhances MDM2-dependent p53 ubiquitination, and LNX1 knockout stabilizes p53, suppressing xenograft tumor growth.

    Evidence CRISPR-Cas9 KO and lentiviral OE in cancer cells, Co-IP, ubiquitination assay, p53 half-life measurement, mouse xenograft

    PMID:31533005

    Open questions at the time
    • Whether LNX1 directly ubiquitinates p53 or only facilitates MDM2-dependent ubiquitination was not fully resolved
    • Physiological relevance outside cancer cell lines was not examined
  13. 2022 Medium

    A non-degradative ubiquitination function was defined: LNX1 performs non-degrading ubiquitination of RhoC (but not RhoA) to promote RhoC activity, with LIS1 acting as a negative regulator of this process, revealing isoform-specific Rho regulation.

    Evidence In vitro ubiquitination, RhoGDI interaction assay, RhoC activity assay, LIS1 OE/KD

    PMID:36192543

    Open questions at the time
    • The ubiquitin chain type on RhoC was not identified
    • In vivo validation of the LIS1–LNX1–RhoC axis was not performed
  14. 2025 Medium

    Behavioral dissection of single and double LNX knockouts clarified isoform-specific roles: neuronal LNX1p70 functions as a stabilizing scaffold for shared partners while LNX2 promotes their degradation, and Lnx1 loss specifically affects anxiety behavior, body weight, and pup ultrasonic vocalizations.

    Evidence Single and double LNX1/LNX2 KO mice, comprehensive behavioral battery, body weight analysis

    PMID:40269869

    Open questions at the time
    • Molecular substrates driving anxiety and vocalization phenotypes were not identified
    • Whether LNX1 scaffold and LNX2 E3 functions are competitive or complementary at the same synapse remains untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include how LNX1 E3 ligase and scaffold functions are coordinated at individual synapses, which substrates drive the behavioral phenotypes observed in knockout mice, and whether LNX1 variants contribute to human neurodevelopmental or psychiatric conditions.
  • No human genetic association studies for LNX1 have been reported
  • Chain-type specificity across different substrates is incompletely characterized
  • Structural basis of PDZ domain substrate selection is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0060090 molecular adaptor activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 2
Partners
EPHB1EPHB2ERBB2GJD2MDM2NUMBPPFIA1UBE2N
Complex memberships
LNX1-NMDAR-EphB2 postsynaptic complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LNX was identified as a novel Numb PTB domain-interacting protein via yeast two-hybrid screen. The interaction is mediated by the sequence motif LDNPAY in LNX, which binds the Numb PTB domain independent of tyrosine phosphorylation. LNX contains a RING finger domain and four PDZ domains. Tyrosine phosphorylation of the LDNPAY motif can generate a binding site for other PTB domain-containing proteins such as SHC. Yeast two-hybrid screen, mutational analysis, peptide competition experiments The Journal of biological chemistry High 9535908
2001 LNX2 (and the related LNX1) bind to mammalian Numb and Numblike via NPXY motifs. LNX proteins form oligomers through PDZ domain interactions with PDZ-binding motifs in their C-termini and via homophilic RING finger oligomerization, suggesting they serve as molecular scaffolds that localize Numb to specific subcellular sites. Protein interaction assays, in situ hybridization, oligomerization studies Molecular and cellular neurosciences Medium 11922143
2001 Human LNX was cloned and shown to contain four PDZ domains and an NPXY motif for Numb PTB domain binding, mapping to chromosome 4q12. cDNA cloning, sequence analysis, radiation hybrid mapping Biochemical genetics Low 11521506
2002 LNX functions as a RING-type E3 ubiquitin ligase that targets Numb for ubiquitin-dependent proteasomal degradation. The isolated RING finger domain acts as an E2-dependent E3 ligase in vitro; mutation of a conserved RING cysteine abolishes activity. A region including the Numb PTB domain-binding site and the first PDZ domain is required for Numb ubiquitylation. Wild-type but not mutant LNX causes proteasome-dependent Numb degradation and enhances Notch signaling. In vitro ubiquitin ligase assay, site-directed mutagenesis, in vivo ubiquitination, proteasome inhibition, Notch signaling reporter assay The EMBO journal High 11782429
2002 LNX (LNX1) interacts with the Coxsackievirus and adenovirus receptor (CAR) intracellular tail via the second PDZ domain of LNX. Efficient CAR binding requires both the consensus PDZ-binding motif at the CAR C-terminus and upstream sequences. CAR and LNX colocalize in mammalian cells. Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation, colocalization imaging The Journal of biological chemistry Medium 12468544
2004 The Np9 protein of human endogenous retrovirus K interacts with LNX (E3 ubiquitin ligase), involving N- and C-terminal domains of both proteins. This interaction alters subcellular localization of LNX. Np9 is itself unstable and degraded via the proteasome; ectopic Numb stabilizes Np9, suggesting Np9 may affect tumorigenesis through the LNX/Numb/Notch pathway. Yeast two-hybrid, co-immunoprecipitation, proteasome inhibition assay, subcellular localization Journal of virology Medium 15367597
2005 LNX1 is specifically expressed in perisynaptic Schwann cells (but not myelinating Schwann cells) at the neuromuscular junction and directly interacts with ErbB2. LNX1 protein levels are inversely correlated with responsiveness of perisynaptic Schwann cells to neuregulin-1, and LNX1 staining disappears upon denervation while ErbB2 reappears, suggesting LNX1 regulates neuregulin-1/ErbB signaling by promoting ErbB2 degradation. Immunostaining, direct protein interaction assay, developmental expression profiling, denervation model Molecular and cellular neurosciences Medium 16122940
2005 Human LNX interacts with SKIP (Ski interacting protein) via its PDZ domains. Co-immunoprecipitation confirmed LNX-SKIP interaction in HEK293 cells. LNX affects subcellular localization of Numb, suggesting LNX functions as a molecular anchor localizing Numb to the subcellular site of its interaction with Notch. Yeast two-hybrid, co-immunoprecipitation, subcellular localization assay The international journal of biochemistry & cell biology Medium 16002321
2009 Lnx-like (Lnx-l, ortholog of LNX1 in zebrafish) functions as a critical regulator of dorso-ventral axis formation. Lnx-l was identified as an E3 ubiquitin ligase for Bozozok (Boz), a homeodomain transcriptional repressor. Lnx-l induces K48-linked polyubiquitylation of Boz leading to proteasomal degradation. Dorsalization by Boz overexpression is suppressed by Lnx-l; Lnx-l cannot counteract Boz lacking the Lnx-l binding motif. Depletion of Lnx-l causes embryonic dorsalization rescued by Boz attenuation. Antisense morpholino knockdown, K48-polyubiquitylation assay, genetic epistasis in zebrafish, domain mapping Nature cell biology High 19668196
2009 LNX interacts with RhoC via its first PDZ domain, as identified by yeast two-hybrid and confirmed by co-immunoprecipitation in mammalian cells. Co-expression of LNX causes RhoC to relocalize from cytoplasm to nucleus. Co-expression of RhoC reduces LNX-induced AP-1 transcriptional activity, suggesting LNX and RhoC form a complex that modulates AP-1-mediated transcription. Yeast two-hybrid, co-immunoprecipitation, subcellular localization, AP-1 transcriptional reporter assay Molecular biology reports Medium 19701800
2010 Lnx-2b (zebrafish LNX ortholog) restricts gsc expression to the dorsal mesoderm by limiting Nodal and Bozozok activity. Overexpression of Boz together with depletion of Lnx-2b (but not either alone) causes robust gsc expression in all blastomeres, demonstrating that maternally deposited Lnx-2b restricts organizer expansion through ubiquitin-mediated control of Boz. Morpholino knockdown, single-cell injection, epistasis analysis in zebrafish Biochemical and biophysical research communications Medium 20971071
2010 Knockdown of LNX by siRNA in HEK293 cells causes G0/G1 cell cycle arrest. Transcriptomic analysis revealed downregulation of β-catenin, MAPK, NFκB, c-Myc-dependent pathways and upregulation of p53 and TGF-β-dependent pathways, suggesting LNX participates in cell cycle regulation through multiple signaling cascades. siRNA knockdown, flow cytometry cell cycle analysis, expression microarray, qRT-PCR Molecular biology reports Low 21104141
2011 Human protein array screening of 8,000 proteins with isolated LNX1 PDZ domains identified 53 potential binding partners. Integration with other methods assembled 220 LNX1 interacting proteins. Six novel LNX1 binding partners were confirmed: KCNA4, PAK6, PLEKHG5, PKC-alpha1, TYK2, and PBK. LNX1 is proposed to function as a signalling scaffold. Human protein array, co-immunoprecipitation, bioinformatic analysis PloS one Medium 22087225
2011 Phylogenetic analysis revealed that LNX PDZ domains are closely related to the four C-terminal PDZ domains of MUPP1. Novel interactions of LNX1 and LNX2 with three known MUPP1 ligands were identified by yeast two-hybrid assays, demonstrating conservation of binding specificity between LNX and MUPP1 PDZ domains. Phylogenetic analysis, yeast two-hybrid interaction assays BMC evolutionary biology Low 21827680
2012 A proteomic strategy integrating peptide library screening and in vitro ubiquitination assays identified multiple LNX substrates. The substrate recognition mechanism involves LNX PDZ domains binding C-termini of target proteins. Two novel endogenous substrates, PBK and BCR, were confirmed in vivo. LNX1-mediated ubiquitination and degradation of PBK inhibits cell proliferation and enhances sensitivity to doxorubicin-induced apoptosis. Random peptide library yeast two-hybrid, in vitro ubiquitination assay, in vivo ubiquitination, cell proliferation assay, apoptosis assay Journal of proteome research High 22889411
2014 LNX1 protein expression in brain was demonstrated for the first time. Cell-type-specific expression of LNX isoforms was clarified in CNS and PNS. The 5' UTR of Lnx1_variant 2 mRNA (generating LNX1p70) strongly suppresses protein production via upstream open reading frames (uORFs) and a sequence element that decreases mRNA levels and translational efficiency. LNX1p80 protein levels are regulated by proteasomal degradation. These mechanisms explain the very low levels of LNX1 in vivo. Western blot, luciferase reporter assays, uORF analysis, proteasome inhibition Gene Medium 25200495
2016 Mice lacking both LNX1 (in CNS) and LNX2 (globally) are healthy with unaltered Numb protein levels and no neuroanatomical defects indicative of NUMB dysfunction, demonstrating that LNX1/LNX2 are not essential for NUMB regulation in vivo. Double knockout mice exhibit decreased anxiety-related behaviour. Proteomic analysis identified LNX1/LNX2 interactions with presynaptic active zone proteins ERC1, ERC2, LIPRIN-αs (PPFIA1, PPFIA3), and F-BAR domain proteins FCHSD2 and SRGAP2. LNX1/LNX2 double knockout mouse, behavioural testing (open field, elevated plus maze), proteomics/mass spectrometry Molecular neurobiology High 27889896
2017 Proteomic analysis of the LNX1 interactome by affinity purification/mass spectrometry identified many novel LNX1-interacting proteins, with many mapping to PDZ2 and showing specificity for LNX1 over LNX2. PPFIA1 (liprin-α1), KLHL11, KIF7, and ERC2 are ubiquitination substrates of LNX1. LNX1 ubiquitination of liprin-α1 requires a PDZ-binding motif with a C-terminal cysteine binding LNX1 PDZ2. The neuronal LNX1p70 isoform (lacking the RING domain) can promote ubiquitination of PPFIA1 and KLHL11 by recruiting other E3 ligases (MID2/TRIM1, TRIM27) as a scaffold. Affinity purification/mass spectrometry, in vitro ubiquitination assay, co-immunoprecipitation, domain mapping PloS one High 29121065
2018 The crystal structure of the LNX1 ubiquitination domain (Zn-RING-Zn) in complex with Ubc13~Ubiquitin was determined. The RING domain is flanked by two zinc-finger motifs, both required for ubiquitination activity. In the heterodimeric complex, ubiquitin from one monomer shares more buried surface area with LNX1 from the other monomer—a unique and essential feature for catalysis. Ubc13/Ube2V2 was identified as a functional E2 for LNX1 in vitro. Dimeric LNX1 recruits ubiquitin-loaded Ubc13 for Ub transfer. Crystal structure determination, in vitro ubiquitination assay, mutagenesis Journal of molecular biology High 29496391
2018 LNX1 and LNX2 colocalize with connexin36 (Cx36)-containing gap junctions at electrical synapses in adult mouse brain. LNX1 and LNX2 directly interact with Cx36 via their second PDZ domain (confirmed by pull-down). Co-transfection of E3-ligase-competent LNX1/LNX2 with Cx36 leads to loss of Cx36-containing gap junctions between cells, whereas ligase-inactive isoforms do not, indicating LNX-mediated ubiquitination of Cx36 promotes its internalization at electrical synapses. Immunofluorescence colocalization, co-immunoprecipitation, PDZ pull-down, cotransfection with ligase-active vs. inactive isoforms, LNX null mice The European journal of neuroscience High 30295974
2018 Postsynaptic LNX1 in hippocampal CA3 neurons is essential for mossy fiber (MF) axon targeting during the postnatal period. Lnx1 deletion causes defective synaptic arrangement and aberrant presynaptic terminals. EphB1 and EphB2 receptors are novel LNX1-binding proteins forming a multiprotein complex stabilized on the CA3 membrane by LNX1, which prevents proteasomal degradation of EphB receptors. EphB1 and EphB2 independently transduce distinct signals controlling MF pruning and targeting. Constitutively active EphB2 kinase rescues MF terminal structure in Lnx1 mutant mice. Lnx1 knockout mice, MF axon tracing, co-immunoprecipitation, proteasome inhibition assay, constitutively active EphB2 rescue experiment The Journal of cell biology High 30185604
2019 LNX1 is an E3 ubiquitin ligase for NEK6; miR-325-3p targets LNX1 mRNA, reducing LNX1 levels, and thereby prevents proteasomal degradation of NEK6 in macrophages infected with M. tuberculosis. Accumulation of NEK6 activates STAT3 signaling, inhibiting apoptosis and promoting intracellular bacterial survival. Cell and mouse models, miRNA overexpression/knockdown, LNX1 overexpression/knockdown, western blot for NEK6 protein levels, STAT3 signaling assay, bacterial survival assay mBio Medium 32487755
2019 LDOC1 forms a protein complex with phospho-JAK2 and LNX1, targeting pJAK2 for ubiquitin-dependent proteasomal degradation. LDOC1 acts as a bridge between pJAK2 and LNX1 E3 ubiquitin ligase; LDOC1 deficiency attenuates LNX1-pJAK2 interaction, reducing pJAK2 ubiquitination and activating STAT3 signaling. Co-immunoprecipitation, immunofluorescence confocal microscopy, ubiquitination assay, LDOC1 KD/OE in lung cancer cells Cancers Medium 30634502
2019 E3 ubiquitin ligases LNX1 and LNX2 ubiquitinate the presynaptic glycine transporter GlyT2. The RING-finger domain of LNX1/2 ubiquitinates a cytoplasmic C-terminal lysine cluster in GlyT2 (K751, K773, K787, K791), regulating GlyT2 expression and transport activity. Genetic deletion of LNX2 in spinal cord neurons increases GlyT2 expression. LNX2 is required for PKC-mediated control of GlyT2 transport. Unbiased screening, in vitro ubiquitination assay, site-directed mutagenesis of GlyT2 lysines, LNX2 knockout neurons, transport activity assay Scientific reports High 31628376
2019 A hippocampal Lnx1-NMDAR-EphB2 multiprotein complex is required for initial social memory in juvenile mice. Lnx1 deficiency causes NMDAR hypofunction with decreased GluN2B in the postsynaptic density, disruption of the Lnx1-NMDAR-EphB2 complex, impaired neuronal activity in CA3, and social memory deficits. Specific restoration of Lnx1 or EphB2 in CA3 rescues synaptic function and social memory. Lnx1 knockout mice, co-immunoprecipitation, PSD fractionation, stereotaxic viral rescue, electrophysiology, behavioral testing Molecular psychiatry High 31772302
2019 LNX1 interacts with p53 and MDM2, and increases p53 ubiquitination in an MDM2-dependent manner, thereby decreasing p53 half-life and inhibiting p53-dependent transcription. LNX1 knockout (CRISPR) in p53 wild-type cancer cells increases p53 stability and activates p53 transcription. LNX1 is required for efficient tumor growth in cell culture and mouse xenograft models. CRISPR-Cas9 knockout, lentiviral overexpression, co-immunoprecipitation, ubiquitination assay, p53 half-life measurement, xenograft tumor model FASEB journal High 31533005
2019 In zebrafish, glycine signaling suppresses lnx1 expression; reduced Lnx1 stabilizes Numb protein and reduces Notch activity (measured as her4.1 expression), promoting neural stem cell (NSC) differentiation. Lnx1 overexpression increases NSC proliferation and causes neural tube closure defects. Knockdown of lnx1 blocks these effects of glycine signaling, placing lnx1 in the glycine→Lnx1→Numb→Notch pathway controlling NSC proliferation. Zebrafish morpholino knockdown, lnx1 overexpression, Notch activity reporter, in situ hybridization, neural tube phenotype analysis Frontiers in molecular neuroscience Medium 30833887
2020 LNX1 upregulation after temozolomide (TMZ) therapy in glioblastoma leads to Numb degradation, activation of Notch1 (increased NICD), and expansion of glioma stem cell (GSC) populations. LNX1 overexpression activates Notch1 and increases GSC populations; LNX1 knockdown reduces NICD, decreases stemness after TMZ, and prolongs median survival in a mouse model. This places LNX1 as a regulator of chemotherapy-induced stemness via the Numb/Notch1 axis. GSEA on PDX cells, LNX1 OE/KD in PDX lines, Notch1 signaling measurement (NICD western), GSC population assay, mouse survival model Cancers Medium 33255632
2021 LNX1 contributes to cell cycle progression; LNX1 knockout delays cell cycle, downregulates cyclin D1 and cyclin E1, and upregulated LNX1 increases S and G2/M populations. LNX1 upregulation activates cell cycle progression and increases resistance to cisplatin-mediated cell death. CRISPR-Cas9 KO, lentiviral overexpression, flow cytometry, western blot for cyclins Cancers Medium 34439220
2022 LNX1 performs non-degrading ubiquitination (NDU) of RhoC (but not RhoA), promoting RhoC activity. LIS1 (PAFAH1B1) negatively regulates LNX1-mediated ubiquitination of RhoC by inhibiting LNX1's effects on RhoGDI-RhoC interaction. This LIS1-LNX1-RhoC module represents an evolutionarily acquired function present only in vertebrates, providing a mechanism for isoform-specific Rho regulation. In vitro ubiquitination assay, RhoGDI interaction assay, LIS1 overexpression/knockdown, RhoC activity assay Scientific reports Medium 36192543
2022 HO-1 controls LNX1 expression in hepatic macrophages; LNX1 expression is strongly suppressed in HO-1-deficient macrophages. LNX1 drives M2-like macrophage polarization; Notch1 (downstream target of LNX1-mediated Numb degradation) is increased in HO-1-deficient macrophages. Transient LNX1 overexpression in HO-1-deficient macrophages treated with heme rescues M2-like polarization, defining a HO-1→LNX1→Notch1 pathway in macrophage polarization and liver fibrosis. RiboTag RNA-seq, LNX1 overexpression in HO-1-deficient macrophages, Notch1 western blot, macrophage polarization assay iScience Medium 36093061
2022 Lnx1 stabilizes EphB receptors at the postsynaptic membrane by preventing their internalization. Loss of Lnx1 promotes EphB receptor internalization from the cell surface, leading to abnormal dendritic spine development and impaired synaptogenesis. Constitutively active EphB2 intracellular signaling rescues synaptogenesis in Lnx1 mutant mice. Lnx1 knockout mice, receptor internalization assay, dendritic spine morphology analysis, constitutively active EphB2 rescue Frontiers in molecular neuroscience Medium 35531068
2025 Neuronal LNX1 isoforms (LNX1p70, which lack the RING catalytic domain) act as stabilizing scaffolds for shared interaction partners, while LNX2 promotes their ubiquitination and degradation. Single and double LNX1/LNX2 knockout behavioral analysis shows LNX2 plays a more prominent role in altered dark-light emergence and risk-taking behavior, while LNX1 loss contributes to anxiety phenotypes and determines body weight. Lnx1 knockout affects ultrasonic vocalizations of pups, revealing a role in social communication. Single and double LNX1/LNX2 knockout mice, behavioral battery (open field, EPM, dark-light, marble burying, novel object recognition, ultrasonic vocalizations), body weight analysis Behavioral and brain functions Medium 40269869

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
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
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2010 MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Molecular cell 388 20864041
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2009 A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease. PLoS genetics 205 19132087
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2002 LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. The EMBO journal 156 11782429
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2014 Large-scale interaction profiling of PDZ domains through proteomic peptide-phage display using human and viral phage peptidomes. Proceedings of the National Academy of Sciences of the United States of America 114 24550280
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2014 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nature communications 111 24722188
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1998 The mammalian numb phosphotyrosine-binding domain. Characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein, LNX. The Journal of biological chemistry 108 9535908
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2004 Mpdz is a quantitative trait gene for drug withdrawal seizures. Nature neuroscience 96 15208631
2013 A Y2H-seq approach defines the human protein methyltransferase interactome. Nature methods 93 23455924
2002 Congenic mapping of alcohol and pentobarbital withdrawal liability loci to a <1 centimorgan interval of murine chromosome 4: identification of Mpdz as a candidate gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 91 11978849
2016 Pooled-matrix protein interaction screens using Barcode Fusion Genetics. Molecular systems biology 89 27107012
2002 The Coxsackievirus and adenovirus receptor (CAR) forms a complex with the PDZ domain-containing protein ligand-of-numb protein-X (LNX). The Journal of biological chemistry 82 12468544
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2004 Np9 protein of human endogenous retrovirus K interacts with ligand of numb protein X. Journal of virology 76 15367597
2013 Mutation in MPDZ causes severe congenital hydrocephalus. Journal of medical genetics 72 23240096
2018 An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. Nature genetics 61 29892012
2015 Phospho-tyrosine dependent protein-protein interaction network. Molecular systems biology 61 25814554
2017 Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO molecular medicine 57 28500065
2001 The Lnx family proteins function as molecular scaffolds for Numb family proteins. Molecular and cellular neurosciences 57 11922143
2020 MicroRNA-325-3p Facilitates Immune Escape of Mycobacterium tuberculosis through Targeting LNX1 via NEK6 Accumulation to Promote Anti-Apoptotic STAT3 Signaling. mBio 45 32487755
2019 Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus. EMBO molecular medicine 38 30518636
2005 LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2. Molecular and cellular neurosciences 35 16122940
2018 MPDZ promotes DLL4-induced Notch signaling during angiogenesis. eLife 34 29620522
2017 Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene. Acta neuropathologica communications 34 28460636
2005 Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas. The international journal of biochemistry & cell biology 32 16002321
2011 Molecular evolution of the LNX gene family. BMC evolutionary biology 31 21827680
2009 Sequence variations of the human MPDZ gene and association with alcoholism in subjects with European ancestry. Alcoholism, clinical and experimental research 29 19175764
2012 Proteomics strategy to identify substrates of LNX, a PDZ domain-containing E3 ubiquitin ligase. Journal of proteome research 26 22889411
2011 Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa. Investigative ophthalmology & visual science 25 21862650
2009 Organizer restriction through modulation of Bozozok stability by the E3 ubiquitin ligase Lnx-like. Nature cell biology 24 19668196
2021 MPDZ as a novel epigenetic silenced tumor suppressor inhibits growth and progression of lung cancer through the Hippo-YAP pathway. Oncogene 22 34108620
2019 Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer. Cancers 22 30634502
2019 DAPLE and MPDZ bind to each other and cooperate to promote apical cell constriction. Molecular biology of the cell 21 31268831
2011 Biochemical and computational analysis of LNX1 interacting proteins. PloS one 21 22087225
2018 Retrograde regulation of mossy fiber axon targeting and terminal maturation via postsynaptic Lnx1. The Journal of cell biology 18 30185604
2016 The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia. BMC genomics 18 27129385
2013 Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption. Addiction biology 18 24118405
2018 E3 ubiquitin ligases LNX1 and LNX2 localize at neuronal gap junctions formed by connexin36 in rodent brain and molecularly interact with connexin36. The European journal of neuroscience 17 30295974
2018 LNX1/LNX2 proteins: functions in neuronal signalling and beyond. Neuronal signaling 16 32714586
2009 LNX (Ligand of Numb-protein X) interacts with RhoC, both of which regulate AP-1-mediated transcriptional activation. Molecular biology reports 16 19701800
2004 Potential pleiotropic effects of Mpdz on vulnerability to seizures. Genes, brain, and behavior 16 14960011
1999 Identification, sequence, and mapping of the mouse multiple PDZ domain protein gene, Mpdz. Genomics 16 10395806
2020 LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population during Temozolomide Therapy in Glioblastoma. Cancers 15 33255632
2019 Observation of nine previously reported and 10 non-reported SLC4A11 mutations among 20 Iranian CHED probands and identification of an MPDZ mutation as possible cause of CHED and FECD in one family. The British journal of ophthalmology 15 31420327
2019 E3 ubiquitin ligases LNX1 and LNX2 are major regulators of the presynaptic glycine transporter GlyT2. Scientific reports 15 31628376
2019 Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory. Molecular psychiatry 15 31772302
2016 Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice. Molecular neurobiology 15 27889896
2018 Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus. BMC medical genetics 14 29499638
2018 Structure of LNX1:Ubc13~Ubiquitin Complex Reveals the Role of Additional Motifs for the E3 Ligase Activity of LNX1. Journal of molecular biology 13 29496391
2014 Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability. Gene 13 25200495
2010 Lnx-2b restricts gsc expression to the dorsal mesoderm by limiting Nodal and Bozozok activity. Biochemical and biophysical research communications 13 20971071
2021 ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment. European journal of human genetics : EJHG 12 34135477
2019 Glycine Regulates Neural Stem Cell Proliferation During Development via Lnx1-Dependent Notch Signaling. Frontiers in molecular neuroscience 12 30833887
2017 Proteomic analysis reveals novel ligands and substrates for LNX1 E3 ubiquitin ligase. PloS one 12 29121065
2018 Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus. The British journal of ophthalmology 11 30002070
2001 Identification of a human LNX protein containing multiple PDZ domains. Biochemical genetics 11 11521506
2008 Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors. Cancer genetics and cytogenetics 10 18940473
2022 Heme oxygenase-1 mitigates liver injury and fibrosis via modulation of LNX1/Notch1 pathway in myeloid cells. iScience 9 36093061
2020 The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family. Molecules (Basel, Switzerland) 9 33333989
2014 Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal. Genes, brain, and behavior 9 25109596
2022 Genomic analysis of paired IDHwt glioblastomas reveals recurrent alterations of MPDZ at relapse after radiotherapy and chemotherapy. Journal of the neurological sciences 8 35259554
2019 LNX1 contributes to tumor growth by down-regulating p53 stability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 31533005
2010 A global genomic view on LNX siRNA-mediated cell cycle arrest. Molecular biology reports 7 21104141
2022 Novel Compound Heterozygous Variations in MPDZ Gene Caused Isolated Bilateral Macular Coloboma in a Chinese Family. Cells 6 36429029
2012 Profiling retinal biochemistry in the MPDZ mutant retinal dysplasia and degeneration chick: a model of human RP and LCA. Investigative ophthalmology & visual science 5 22159006
2024 Prenatal phenotype of a homozygous nonsense MPDZ variant in a fetus with severe congenital hydrocephalus. Prenatal diagnosis 4 38498110
2024 Expanding the spectrum of phenotypes for MPDZ: Report of four unrelated families and review of the literature. Clinical genetics 3 38857973
2023 Retinal manifestations in autosomal recessive MPDZ maculopathy: report of two cases and literature review. Ophthalmic genetics 3 36594712
2022 Activation of RhoC by regulatory ubiquitination is mediated by LNX1 and suppressed by LIS1. Scientific reports 3 36192543
2023 PATJ and MPDZ are required for trophectoderm lineage specification in early mouse embryos. Reproduction (Cambridge, England) 2 37318097
2021 LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance. Cancers 2 34439220
2024 Expanding the phenotypic spectrum of MPDZ gene variants: A case report with prenatally detected Dandy-Walker malformation and single ventricle heart. Prenatal diagnosis 1 38818866
2022 Evaluating the association between MPDZ-NF1B rs1324183 and keratoconus in an independent northwestern Chinese population. BMC ophthalmology 1 35305607
2022 Scaffold Protein Lnx1 Stabilizes EphB Receptor Kinases for Synaptogenesis. Frontiers in molecular neuroscience 1 35531068
2005 [Molecular cloning and identify expression of the novel human LNX gene in gliomas]. Zhonghua yi xue za zhi 1 16324299
2025 Differential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout mice. Behavioral and brain functions : BBF 0 40269869
2024 Identification of potential substrates of LNX1 in chicken cells. Poultry science 0 39693965