Affinage

L1CAM

Neural cell adhesion molecule L1 · UniProt P32004

Length
1257 aa
Mass
140.0 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

L1CAM is an immunoglobulin-superfamily cell adhesion molecule essential for nervous system development, where its function is required for neuronal migration, axon growth, and myelination, and whose loss-of-function mutations cause X-linked hydrocephalus, MASA syndrome, and SPG1 (PMID:7920659, PMID:24489698, PMID:30842511). At the growth cone, L1CAM transduces adhesion into directional motility through asymmetric grip/slip dynamics on laminin that generate traction force for haptotaxis (PMID:29483251), and it couples to the cytoskeleton via MAP-kinase-dependent phosphorylation of its cytoplasmic FIGQY motif, which controls ankyrin B binding and neuronal growth, and via direct binding to MAP2c through its intracellular domain (PMID:16597699, PMID:22503709). L1CAM is processed by sequential proteolysis: ADAM10 sheds the ectodomain and presenilin/gamma-secretase then liberates a nuclear L1-ICD that drives gene regulation, including upregulation of NBS1 via c-Myc to enhance MRN-dependent ATM-Chk2 checkpoint signaling and radioresistance (PMID:19260824, PMID:21297581); this shedding, restricted by the third fibronectin type III domain, is specifically required for myelination but not axonal outgrowth (PMID:30842511). Surface levels of L1CAM are controlled post-translationally by mono-ubiquitination-driven lysosomal degradation, by N-glycosylation that governs lipid-microdomain association and plasmin susceptibility, and by alpha-synuclein-dependent protection from lysosomal turnover (PMID:20940017, PMID:34380733, PMID:37286800). In cancer, L1CAM and its shed/soluble ectodomain drive invasion, metastasis, stemness, and chemoresistance by acting as a ligand for FGFR1 (engaging SRC-STAT3 and FAK) and by activating integrin alpha5beta1 and EGFR signaling through ERK/AKT, with transcription regulated by beta-catenin-TCF-induced ADAM10, KLF12/TRIM27, ADAMTS1, and TGFbeta inputs (PMID:17699774, PMID:23212305, PMID:34645505, PMID:28939985, PMID:38924996, PMID:38263290).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1991 Medium

    Established human L1CAM as a functional neurite-growth-promoting adhesion molecule and pinpointed the most conserved Ig and FNIII domains as candidate functional regions.

    Evidence Neurite growth assay on human L1CAM substrate plus cross-species sequence comparison

    PMID:1769655

    Open questions at the time
    • Did not define the binding partners engaged by the conserved domains
    • Functional importance inferred from conservation, not direct mutagenesis
  2. 1994 High

    Demonstrated that L1CAM function is essential for human nervous system development by linking loss-of-function mutations to X-linked hydrocephalus, MASA, and SPG1.

    Evidence Mutational analysis in patient cohorts with functional cell-surface expression assays

    PMID:7920659

    Open questions at the time
    • Did not resolve which downstream molecular activities of L1CAM are lost in disease
    • Genotype-phenotype relationships across syndromes not mechanistically explained
  3. 1998 Medium

    Showed that even a synonymous coding change can disrupt L1CAM by creating a cryptic splice site, broadening the mutational mechanisms causing hydrocephalus.

    Evidence DNA sequencing and RT-PCR of affected fetal RNA confirming in-frame exon 8 deletion

    PMID:9643285

    Open questions at the time
    • Functional consequence of the 23-amino-acid deletion on protein folding/adhesion not tested
    • Single mutation; generalizability unknown
  4. 2006 High

    Connected extracellular signaling to cytoskeletal coupling by showing MAP-kinase-dependent FIGQY phosphorylation controls ankyrin B binding and thereby L1CAM-mediated neuronal growth.

    Evidence Intramolecular BRET phosphorylation reporter, MAP kinase and ankyrin-binding inhibitors, neuronal growth assays

    PMID:16597699

    Open questions at the time
    • Identity of the kinase acting directly on FIGQY not established
    • Rescue by ankyrin-binding inhibitors only partial, implying additional effectors
  5. 2007 High

    Placed L1CAM in a Wnt-driven metastatic program, identifying ADAM10 as a beta-catenin-TCF target that sheds L1CAM and enhances colon cancer liver metastasis.

    Evidence Stable L1CAM transfection, in vivo mouse liver metastasis, ADAM10 overexpression, microarray analysis

    PMID:17699774

    Open questions at the time
    • The receptor(s) transducing the pro-metastatic L1CAM signal not defined here
    • Causal contribution of shedding vs full-length L1CAM to metastasis not separated
  6. 2008 Medium

    Revealed an endothelial role for L1CAM in tumor vasculature, mediating tumor-cell adhesion and transendothelial migration via neuropilin-1.

    Evidence Cytokine stimulation, anti-L1CAM and anti-neuropilin-1 blocking antibodies, tube formation and transmigration assays

    PMID:18931829

    Open questions at the time
    • Direct L1CAM-neuropilin-1 binding not biochemically demonstrated
    • In vivo relevance to metastasis not tested
  7. 2009 High

    Defined the regulated intramembrane proteolysis cascade (ADAM10 then gamma-secretase) that releases a nuclear-signaling L1-ICD, establishing L1CAM as a source of nuclear gene-regulatory signaling.

    Evidence Dominant-negative PS1, gamma-secretase inhibitors, biochemical fractionation, recombinant L1-ICD overexpression in carcinoma cells

    PMID:19260824

    Open questions at the time
    • Direct transcriptional targets of L1-ICD not identified in this study
    • Mechanism of L1-ICD nuclear import not resolved
  8. 2010 Medium

    Demonstrated post-translational control of L1CAM surface availability through mono-ubiquitination-driven lysosomal degradation and trafficking.

    Evidence Biochemical ubiquitination assays, subcellular fractionation, lysosomal inhibitors, trafficking analysis

    PMID:20940017

    Open questions at the time
    • The E3 ligase responsible was not identified
    • Physiological/disease contexts regulating this turnover not defined
  9. 2010 High

    Identified L1cam as a Sox10-regulated modifier gene in enteric nervous system development, controlling neural crest migration and survival.

    Evidence Two-locus complementation crosses (L1cam x Sox10/Ret/Gdnf heterozygotes), aganglionosis scoring, migration and cell-death analysis

    PMID:20696247

    Open questions at the time
    • Molecular mechanism linking L1cam to crest cell survival not defined
    • Direct evidence for Sox10 acting on the L1cam promoter not shown here
  10. 2011 High

    Connected nuclear L1-ICD signaling to DNA-damage checkpoint control, showing it upregulates NBS1 via c-Myc to drive MRN/ATM-Chk2 signaling and radioresistance in glioblastoma stem cells.

    Evidence RNAi knockdown, ectopic NBS1 rescue, checkpoint activation assays in glioblastoma stem cells

    PMID:21297581

    Open questions at the time
    • Direct DNA binding of L1-ICD vs indirect action via c-Myc not fully resolved
    • Generality beyond glioblastoma stem cells untested
  11. 2011 Medium

    Distinguished isoform-specific oncogenic activity, showing full-length but not the exon-2/27-deleted splice variant promotes metastasis via elevated MMP-2/MMP-9.

    Evidence Isoform-specific overexpression, in vivo lung/liver metastasis assays, zymography, invasion assays

    PMID:21541352

    Open questions at the time
    • Mechanism by which deleted exons abolish activity not defined
    • Receptor coupling to MMP induction not mapped
  12. 2012 High

    Identified FGFR1 as a receptor for the soluble L1 ectodomain driving glioma motility and proliferation, establishing a ligand-receptor mode of L1CAM action distinct from adhesion.

    Evidence Dominant-negative FGFR1, shRNA, L1-FGFR blocking peptide, PD173074, time-lapse motility and cell-cycle assays

    PMID:23212305

    Open questions at the time
    • Stoichiometry/structure of the L1-FGFR1 interaction not defined
    • Downstream signaling branches not fully mapped in this study
  13. 2012 Medium

    Showed L1CAM physically binds ErbB/EGFR receptors via Ig domains and potentiates neuregulin responses, broadening its receptor crosstalk repertoire.

    Evidence Reciprocal Co-IP in heterologous systems and developing brain, Ig-domain mapping, neuregulin response assays

    PMID:22815787

    Open questions at the time
    • Functional consequence in vivo development not established
    • Direct vs complex-mediated binding not fully resolved
  14. 2012 High

    Demonstrated L1CAM promotes neurite outgrowth via direct intracellular binding to MAP2c and MAPK-dependent MAP2 induction, linking adhesion to microtubule organization.

    Evidence ELISA direct-binding assay, Co-IP, L1-knockout mice, MAPK inhibitors, neurite outgrowth assays

    PMID:22503709

    Open questions at the time
    • Binding interface on the L1 intracellular domain not mapped
    • Relative contributions of direct binding vs MAP2 induction not quantified
  15. 2014 Medium

    Defined the cell-biological role of L1cam in radial migration, required for intermediate-zone locomotion and terminal somal translocation during corticogenesis.

    Evidence In utero electroporation of shRNA, time-lapse imaging in brain slices, quantitative morphometry

    PMID:24489698

    Open questions at the time
    • Molecular effectors coupling L1cam to soma movement not identified
    • Single-gene knockdown; modifier interactions not examined
  16. 2017 Medium

    Established integrin alpha5beta1/MAPK/ERK/AP1 as an L1CAM oncogenic pathway driving ezrin expression in esophageal squamous cell carcinoma.

    Evidence L1CAM knockdown/overexpression, in vitro/in vivo tumorigenesis, GSEA, pathway inhibition

    PMID:28939985

    Open questions at the time
    • Direct L1CAM-integrin engagement not biochemically shown
    • Role of ezrin as the sole effector not exclusive
  17. 2017 Medium

    Revealed a paracrine mechanism in which fibroblast-expressed L1CAM, driven by Mint3/HIF-1, stimulates integrin alpha5beta1/ERK signaling in adjacent cancer cells.

    Evidence Mint3 depletion in MEFs, co-injection tumor assays, L1CAM knockdown, pathway inhibition

    PMID:28504692

    Open questions at the time
    • Contact-dependent ligand-receptor identity not biochemically confirmed
    • Relevance to human stromal contexts not tested
  18. 2018 High

    Provided biophysical mechanism for L1CAM-driven directional motility through asymmetric grip/slip states generating traction force on laminin, with disruption in an L1CAM-syndrome patient.

    Evidence Single-molecule imaging on growth cones, traction force microscopy, laminin vs polylysine comparison, patient-derived cells

    PMID:29483251

    Open questions at the time
    • Molecular clutch components linking L1 to substrate not fully identified
    • How disease mutation alters grip/slip mechanistically not detailed
  19. 2018 Medium

    Linked L1CAM to cellular senescence, induced by TGFbeta and p16INK4a and repressed by RAS/MAPK, conferring increased adhesion and migration on senescent cells.

    Evidence Senescent-cell proteome profiling, pharmacological senescence induction, TGFbeta/Ras/p16 modulation, adhesion/migration assays

    PMID:29615539

    Open questions at the time
    • Functional consequence of senescent L1CAM in vivo unknown
    • Transcriptional mechanism of induction not resolved
  20. 2019 High

    Showed FNIII-domain conformation gates ADAM10 shedding and that shedding is specifically required for myelination, dissociating it from axonal outgrowth and ventricular development.

    Evidence Zebrafish l1camb knockdown with proteinase-resistant and soluble L1cam rescue variants, in vivo phenotyping

    PMID:30842511

    Open questions at the time
    • Mammalian validation of the myelination-specific requirement not shown here
    • Target receptor of shed L1 in myelination not identified
  21. 2019 High

    Identified a transmembrane-less L1CAM isoform (L1-deltaTM) generated by NOVA2-mediated exon skipping that drives angiogenesis via FGFR1.

    Evidence Splicing analysis, NOVA2 manipulation, direct NOVA2-pre-mRNA binding, FGFR1 inhibition, in vivo angiogenesis and tumor vasculature analysis

    PMID:30829570

    Open questions at the time
    • Quantitative contribution of L1-deltaTM vs shed ectodomain to FGFR1 activation not separated
    • Regulation of NOVA2 in tumors not defined
  22. 2019 Medium

    Demonstrated L1CAM-decorated exosomes promote glioblastoma motility, proliferation, and invasion through FAK and FGFR, extending L1CAM signaling to extracellular vesicle delivery.

    Evidence Exosome isolation/characterization, motility and cell-cycle assays, chick embryo invasion model, FAK and FGFR inhibitors

    PMID:31426278

    Open questions at the time
    • Direct exosomal L1-receptor engagement not biochemically shown
    • In vivo mammalian tumor relevance untested
  23. 2021 High

    Established that L1CAM drives ovarian cancer stemness and tumor initiation by physically binding and activating FGFR1, triggering SRC-mediated STAT3 activation.

    Evidence L1CAM-FGFR1 Co-IP, STAT3 inhibition rescue, gain/loss in patient-derived cancer stem cells, in vivo tumor initiation, neutralizing antibody

    PMID:34645505

    Open questions at the time
    • Structural basis of L1-FGFR1 complex not resolved
    • Whether membrane vs soluble L1 drives this axis not separated
  24. 2021 Medium

    Linked N-glycosylation (via CWH43) to L1CAM lipid-microdomain association, plasmin cleavage susceptibility, CSF shedding, and nuclear translocation, tying glycosylation to signaling output.

    Evidence CWH43-deletion mice and HeLa cells, glycosylation and microdomain analysis, plasmin cleavage, CSF L1CAM, nuclear translocation assays

    PMID:34380733

    Open questions at the time
    • Direct effect of glycosylation on specific adhesion/signaling interactions not dissected
    • Physiological significance of CSF shedding changes unclear
  25. 2022 Medium

    Showed L1CAM enables early dissemination of fallopian tube carcinoma precursors by upregulating integrins/fibronectin and activating AKT/ERK to support anchorage-independent survival and cohesive ovarian invasion.

    Evidence Gain/loss-of-function in fallopian tube secretory cells, tumor-ovary co-culture invasion model, AKT/ERK readouts, anchorage-independent survival assays

    PMID:36509990

    Open questions at the time
    • Receptor mediating integrin/fibronectin upregulation not defined
    • In vivo human metastatic relevance not directly tested
  26. 2023 Medium

    Identified alpha-synuclein as a stabilizer of L1CAM that protects it from lysosomal degradation, increasing surface L1CAM and melanoma motility independent of transcription.

    Evidence SNCA CRISPR knockout and overexpression, motility and lysosomal degradation assays, mRNA/protein analysis

    PMID:37286800

    Open questions at the time
    • Whether alpha-synuclein binds L1CAM directly not established
    • Mechanism diverting L1CAM from lysosomes not defined
  27. 2024 Medium

    Mapped a transcriptional control axis in which TRIM27 ubiquitinates and inactivates the L1CAM repressor KLF12, derepressing L1CAM to drive cisplatin resistance and metastasis.

    Evidence ChIP showing KLF12 binding to the L1CAM promoter, K326 ubiquitination mapping, L1CAM-depletion rescue, cisplatin resistance and metastasis assays

    PMID:38924996

    Open questions at the time
    • Whether K33-linked ubiquitination is the sole mode of KLF12 regulation unclear
    • Generality beyond esophageal squamous cell carcinoma untested
  28. 2024 Medium

    Defined an ADAMTS1-L1CAM-EGFR signaling axis driving EMT and lymph node metastasis in oral squamous cell carcinoma.

    Evidence ADAMTS1 knockdown/overexpression in OSCC and xenografts, in vivo lymph node metastasis, EGFR/EMT marker analysis, apigenin inhibition

    PMID:38263290

    Open questions at the time
    • Mechanism by which ADAMTS1 raises L1CAM levels not defined
    • Direct L1CAM-EGFR engagement not biochemically confirmed in this context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct L1CAM signaling modes (membrane adhesion, soluble ectodomain ligand activity, exosomal display, and nuclear L1-ICD) are coordinated and selectively engaged in development versus cancer remains unresolved.
  • No unified structural model of L1CAM-receptor complexes (FGFR1, EGFR, integrins)
  • Context-specific switching between adhesion and ligand/signaling roles not defined
  • Tissue-specific regulation of shedding and isoform choice incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3
Partners
ADAM10ANK2EGFRFGFR1ITGA5MAP2NRP1SNCA

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Mutations in the L1CAM gene cause X-linked hydrocephalus (HSAS), MASA syndrome, and SPG1, demonstrating that L1CAM protein function is essential for nervous system development; two HSAS mutations were identified that abolish cell surface expression of L1CAM, representing functional null mutations. Mutational analysis in patient cohorts; functional assessment of cell surface expression loss Nature genetics High 7920659
2009 L1CAM undergoes sequential proteolytic processing: first, ADAM10 cleaves L1CAM at the membrane to generate an L1-32 fragment; then presenilin/gamma-secretase performs regulated intramembrane proteolysis to release a 28 kDa intracellular domain (L1-ICD) that translocates to the nucleus and mediates gene regulation. Inhibition of either ADAM10 or gamma-secretase blocks nuclear translocation and L1-dependent gene regulation. Dominant-negative PS1 overexpression, gamma-secretase inhibitors, fluorescence and biochemical fractionation, recombinant L1-ICD overexpression in carcinoma cells The Biochemical journal High 19260824
2011 L1CAM regulates DNA damage checkpoint responses and radioresistance of glioblastoma stem cells through nuclear translocation of the L1-ICD, which upregulates NBS1 expression via c-Myc, thereby enhancing MRE11-RAD50-NBS1 (MRN) complex activity and ATM-Chk2 checkpoint signaling. Ectopic NBS1 expression rescued checkpoint activation lost upon L1CAM knockdown. RNA interference knockdown, ectopic NBS1 rescue experiments, checkpoint activation assays, nuclear translocation analysis in glioblastoma stem cells The EMBO journal High 21297581
2007 L1CAM expression in colon cancer cells confers metastatic capacity and induces liver metastasis in a mouse spleen-injection model. ADAM10, identified as a novel beta-catenin-TCF target gene, cleaves the L1CAM extracellular domain and enhances metastasis. L1CAM induces a specific gene program in colon cancer cells also elevated in human colorectal carcinoma tissue. Stable transfection of L1CAM in colon cancer cells, in vivo mouse liver metastasis assay, ADAM10 overexpression, DNA microarray analysis Cancer research High 17699774
2006 MAP kinase pathway-dependent phosphorylation of the FIGQY motif in the L1CAM cytoplasmic domain regulates its interaction with ankyrin B, and this modulation of ankyrin binding controls L1CAM-mediated neuronal growth. MAP kinase pathway inhibitors block L1CAM-mediated neuronal growth, and this blockade is partially rescued by inhibitors of L1CAM-ankyrin binding. Intramolecular BRET reporter assay for FIGQY phosphorylation, MAP kinase pathway inhibitors, ankyrin binding inhibitors, neuronal growth assays Molecular biology of the cell High 16597699
2012 L1CAM promotes neurite outgrowth by directly binding microtubule-associated protein 2c (MAP2c) via its intracellular domain (as shown by ELISA binding assay), and by enhancing MAP2 expression through the MAPK pathway. L1-deficient mice show reduced MAP2c levels; combined deficiency in both L1 and MAP2 reduces neurite outgrowth in vitro. ELISA binding assay (direct binding of MAP2c to L1 intracellular domain), co-immunoprecipitation of MAP2 isoforms with L1, L1-knockout mice, MAPK inhibitors, in vitro neurite outgrowth assays Molecular and cellular neurosciences High 22503709
2012 L1CAM physically binds ErbB receptors (including erbB1/EGFR) through Ig-like domains in its extracellular region, and this interaction enhances erbB receptor response to neuregulins. L1CAM-erbB binding was demonstrated in heterologous systems and in the mammalian developing brain. Co-immunoprecipitation in heterologous systems and developing brain tissue, binding domain mapping with Ig-like domain constructs PloS one Medium 22815787
2010 L1cam acts as a modifier gene in enteric nervous system development: loss of L1cam combined with heterozygous Sox10 loss significantly increases the incidence of aganglionosis by perturbing neural crest cell migration in the gut and causing excessive neural crest cell death prior to gut entry. Sox10 regulates L1cam expression. Two-locus complementation genetic crosses (L1cam knockout × Ret, Gdnf, Sox10 heterozygotes), in vivo aganglionosis scoring, neural crest cell migration analysis, cell death quantification Neurobiology of disease High 20696247
2010 L1CAM is ubiquitinated at the plasma membrane and in early endosomes; mono-ubiquitination enhances its lysosomal degradation and regulates intracellular trafficking, thereby controlling L1CAM re-appearance at the cell surface. Biochemical ubiquitination assays, subcellular fractionation, lysosomal degradation inhibitors, trafficking analysis FEBS letters Medium 20940017
2012 L1CAM stimulates glioma cell motility and proliferation through fibroblast growth factor receptor (FGFR) activation. Soluble L1 ectodomain (L1LE) acts as a ligand for FGFR1 on glioma cells; dominant-negative FGFR1 or L1 peptide blocking L1-FGFR interaction abolished glioma cell migration; combined shutdown of L1 expression and FGFR activity completely terminated cell migration in vitro. Dominant-negative FGFR1, shRNA knockdown of L1, L1-FGFR interaction-blocking peptide, FGFR1 chemical inhibitor PD173074, time-lapse motility assays, cell cycle analysis Clinical & experimental metastasis High 23212305
2019 ADAM10-mediated shedding of L1cam is regulated by its fibronectin type III (FNIII) domains; specifically, the third FNIII domain maintains a conformation restricting access to the membrane-proximal cleavage site. Metalloproteinase-mediated shedding is required for efficient myelination but not for axonal outgrowth or ventricular system development, as shown by rescue experiments with proteinase-resistant and soluble L1cam variants in zebrafish. Zebrafish l1camb knockdown, rescue experiments with proteinase-resistant and soluble L1cam variants, in vivo axonal outgrowth and myelination phenotype analysis Scientific reports High 30842511
2019 Endothelial cells express a novel L1CAM isoform (L1-ΔTM) lacking the transmembrane domain, generated by NOVA2 splicing factor-mediated skipping of the transmembrane domain exon. L1-ΔTM is secreted as a soluble protein that promotes angiogenesis through FGFR1 signaling via autocrine and paracrine activities. Alternative splicing analysis, NOVA2 knockdown/overexpression, direct NOVA2 binding to L1CAM pre-mRNA, FGFR1 inhibition assays, in vivo angiogenesis models, ovarian cancer vasculature analysis eLife High 30829570
2017 L1CAM promotes oncogenicity in esophageal squamous cell carcinoma by upregulating ezrin expression through activation of integrin α5β1/MAPK/ERK/AP1 signaling. L1CAM knockdown decreased cell growth, migration, and invasiveness, while overexpression had opposite effects; ezrin was identified as a key downstream effector. L1CAM knockdown and overexpression, in vitro and in vivo tumorigenesis assays, gene expression microarray/GSEA analysis, mechanistic pathway inhibition studies Journal of molecular medicine (Berlin, Germany) Medium 28939985
2017 Fibroblast-expressed L1CAM, induced by Mint3-mediated HIF-1 activation, stimulates ERK signaling via integrin α5β1 in adjacent cancer cells, promoting cancer cell proliferation in a cell-cell contact-dependent manner and enhancing tumor growth in vivo. Mint3 depletion in mouse embryonic fibroblasts, co-injection tumor assays in mice, gene expression analysis, L1CAM knockdown, pathway inhibition Oncogenesis Medium 28504692
2021 L1CAM promotes ovarian cancer stemness and tumor initiation by physically interacting with and activating FGFR1, which in turn induces SRC-mediated STAT3 activation. STAT3 inhibition prevented L1CAM-dependent stemness and tumor initiation; an L1CAM-neutralizing antibody blocked these activities. Co-immunoprecipitation of L1CAM-FGFR1 complex, STAT3 inhibition rescue assays, gain/loss-of-function in patient-derived cancer stem cells, in vivo tumor initiation assays, antibody-mediated neutralization Journal of experimental & clinical cancer research : CR High 34645505
2011 Full-length L1CAM (FL-L1CAM), but not the tumor-associated splice variant lacking exons 2 and 27 (SV-L1CAM), promotes experimental lung and liver metastasis. FL-L1CAM correlates with increased invasive potential and elevated MMP-2 and MMP-9 expression and activity. Selective overexpression of each isoform in tumor cells, in vivo mouse metastasis assays (lung/liver), MMP activity assays (zymography), in vitro invasion assays PloS one Medium 21541352
2021 CWH43 deletion decreases N-glycosylation of L1CAM, reduces its association with cell membrane lipid microdomains, increases L1CAM cleavage by plasmin, and increases shedding of cleaved L1CAM in cerebrospinal fluid. CWH43 deletion also decreased L1CAM nuclear translocation, suggesting decreased intracellular signaling. CWH43 mutant mice and human HeLa cells with CWH43 deletion, N-glycosylation analysis, lipid microdomain fractionation, plasmin cleavage assays, CSF L1CAM measurement, nuclear translocation assays Proceedings of the National Academy of Sciences of the United States of America Medium 34380733
2014 L1cam is required for cell locomotion in the intermediate zone and terminal translocation of the soma through the primitive cortical zone during radial migration in murine corticogenesis. L1cam-knockdown neurons showed decreased locomotion velocity, longer and more undulated leading processes, and decreased somal movement during terminal translocation. In utero electroporation of shRNA targeting L1cam, time-lapse analysis of neuronal migration in brain slices, quantitative curvature index analysis PloS one Medium 24489698
2019 L1CAM-decorated exosomes stimulate glioblastoma cell motility, proliferation, and invasiveness. The motility and proliferation-promoting effects of L1-decorated exosomes are reduced by inhibitors of focal adhesion kinase (FAK) and fibroblast growth factor receptor (FGFR), placing L1CAM action upstream of these kinases. Exosome isolation and L1CAM decoration characterization, SuperScratch motility assay, DNA cell cycle analysis, chick embryo brain tumor invasion model, FAK and FGFR chemical inhibitors International journal of molecular sciences Medium 31426278
2008 L1CAM expression on tumor-derived endothelial cells is upregulated by TNF-α, IFN-γ, and TGF-β1. L1CAM on endothelium mediates selective tumor cell adhesion and transendothelial migration; antibodies to L1CAM and its ligand neuropilin-1 blocked tube formation and SDF-1β-induced transmigration of tumor endothelial cells. Cytokine stimulation of endothelial cells, anti-L1CAM and anti-neuropilin-1 antibody blocking assays, tube formation assay, transmigration assay, tumor cell adhesion to endothelial monolayers Journal of molecular medicine (Berlin, Germany) Medium 18931829
2022 L1CAM is required for early dissemination of fallopian tube carcinoma precursors to the ovary: L1CAM upregulates integrins and fibronectin in malignant cells and activates AKT and ERK pathways, increasing cell survival under anchorage-independent conditions and enabling cohesive invasion of the ovary. L1CAM gain/loss-of-function in fallopian tube secretory cells, tumor-ovary co-culture invasion model, pathway analysis (AKT, ERK activation), anchorage-independent survival assays Communications biology Medium 36509990
2023 Alpha-synuclein promotes L1CAM expression and localization to the plasma membrane by protecting L1CAM from lysosomal degradation. Knockout of SNCA in melanoma cells led to a 75% reduction in motility and significant decreases in L1CAM and N-cadherin expression; the reduction in L1CAM was not due to transcriptional effects but rather increased lysosomal degradation of L1CAM. SNCA knockout by CRISPR in melanoma cell lines, stable SNCA overexpression in neuroblastoma cells, motility assays, lysosomal degradation assays, mRNA and protein expression analysis Scientific reports Medium 37286800
2018 L1CAM is induced during cellular senescence by TGFβ signaling and is suppressed by RAS/MAPK(Erk) signaling; it is also induced by p16INK4a-mediated CDK inhibition. Senescent cells with enhanced surface L1CAM showed increased adhesion to extracellular matrix and faster migration. Proteome profiling of senescent cells, pharmacological induction of senescence, TGFβ treatment, Ras expression, p16INK4a modulation, cell adhesion and migration assays Aging Medium 29615539
2018 L1-CAM undergoes grip and slip states on adhesive substrates; the ratio of grip state is higher on laminin than on polylysine, accompanied by increased traction force. Asymmetric grip/slip of L1-CAM under the growth cone generates directional force for laminin-induced haptotaxis. This mechanism is disrupted in an L1CAM syndrome patient with corpus callosum agenesis. Single-molecule imaging of L1-CAM on growth cones, traction force microscopy, laminin vs polylysine substrate comparison, patient-derived cell analysis Proceedings of the National Academy of Sciences of the United States of America High 29483251
2024 KLF12 binds directly to the L1CAM promoter and represses its transcription; TRIM27 ubiquitinates KLF12 at K326 via K33-linked polyubiquitination, reducing KLF12 transcriptional activity and consequently increasing L1CAM expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss in esophageal squamous cell carcinoma. Chromatin immunoprecipitation (ChIP) assay showing KLF12 binding to L1CAM promoter, ubiquitination site mapping (K326), rescue experiments with L1CAM depletion, cisplatin resistance and metastasis assays Drug resistance updates Medium 38924996
2024 The ADAMTS1 metalloprotease activates an ADAMTS1-L1CAM-EGFR signaling axis in oral squamous cell carcinoma: ADAMTS1 increases L1CAM levels, which activates EGFR, leading to EMT and enhanced invasiveness and lymph node metastasis. ADAMTS1 knockdown and overexpression in OSCC cells and xenografts, in vivo lymph node metastasis assay, mechanistic pathway analysis (EGFR activation, EMT markers), pharmacological inhibition by apigenin Cell death & disease Medium 38263290
1991 Human L1CAM supports neurite growth in vitro and shows 92% amino acid identity to mouse L1cam. Comparison across species identifies the second Ig domain and second fibronectin type III domain as the most conserved and likely functionally important domains. Neurite growth assay on human L1CAM substrate, full coding region cloning and sequencing, cross-species sequence comparison Genomics Medium 1769655
2020 L1cam deletion in adult hippocampal stem/progenitor cells increases differentiation of progenitors into new neurons, increases dendritic arbor complexity in immature neurons, and accelerates age-related decline in hippocampal neurogenesis; deletion in neurons leads to increased anxiety-related behavior. Conditional knockout using multiple Cre-driver lines in mice, BrdU/EdU lineage tracing, morphological analysis of dendritic complexity, behavioral assays Stem cell research Medium 32971459
1998 A silent C924T mutation (G308G) in exon 8 of L1CAM creates a novel 5' splice site, resulting in an in-frame deletion of 69 bp (23 amino acids) from exon 8, causing X-linked hydrocephalus. RT-PCR of affected fetal RNA confirmed aberrant splicing. DNA sequencing, splice site consensus sequence analysis, RT-PCR of affected fetal RNA confirming in-frame deletion Journal of medical genetics Medium 9643285

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nature genetics 347 7920659
2012 L1CAM: a major driver for tumor cell invasion and motility. Cell adhesion & migration 187 22796939
2007 Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer research 175 17699774
2015 L1CAM in human cancer. International journal of cancer 150 26111503
1991 Molecular structure and functional testing of human L1CAM: an interspecies comparison. Genomics 148 1769655
2001 Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. Human mutation 147 11438988
2011 L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. The EMBO journal 145 21297581
1998 Byr4 and Cdc16 form a two-component GTPase-activating protein for the Spg1 GTPase that controls septation in fission yeast. Current biology : CB 143 9742395
2010 L1CAM malfunction in the nervous system and human carcinomas. Cellular and molecular life sciences : CMLS 124 20237819
2003 The L1CAM extracellular region: a multi-domain protein with modular and cooperative binding modes. Frontiers in bioscience : a journal and virtual library 116 12957823
2009 L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer letters 110 19144458
2022 L1CAM-associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization. Journal of extracellular biology 96 35492832
2010 Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Annals of surgical oncology 90 20162456
2009 Nuclear translocation and signalling of L1-CAM in human carcinoma cells requires ADAM10 and presenilin/gamma-secretase activity. The Biochemical journal 89 19260824
2016 Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility. Clinical cancer research : an official journal of the American Association for Cancer Research 87 27390347
2008 L1-CAM in cancerous tissues. Expert opinion on biological therapy 85 18847309
2005 Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiology of disease 85 15905095
2020 Long Noncoding RNA POU3F3 and α-Synuclein in Plasma L1CAM Exosomes Combined with β-Glucocerebrosidase Activity: Potential Predictors of Parkinson's Disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 81 32236821
2016 L1CAM expression in endometrial carcinomas: an ENITEC collaboration study. British journal of cancer 81 27505134
2006 The adhesion molecule L1 (CD171) promotes melanoma progression. International journal of cancer 76 16506207
2024 Single-extracellular vesicle (EV) analyses validate the use of L1 Cell Adhesion Molecule (L1CAM) as a reliable biomarker of neuron-derived EVs. Journal of extracellular vesicles 75 38868956
2016 L1CAM: Cell adhesion and more. Progress in histochemistry and cytochemistry 67 27267927
2010 Linking L1CAM-mediated signaling to NF-κB activation. Trends in molecular medicine 60 21195665
2019 CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC cancer 56 31500597
2019 A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing. eLife 54 30829570
2019 Exosomal L1CAM Stimulates Glioblastoma Cell Motility, Proliferation, and Invasiveness. International journal of molecular sciences 54 31426278
2015 L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets. Trends in pharmacological sciences 53 26478212
2012 Role of L1CAM for axon sprouting and branching. Cell and tissue research 51 22370595
2006 MAP kinase pathway-dependent phosphorylation of the L1-CAM ankyrin binding site regulates neuronal growth. Molecular biology of the cell 51 16597699
2012 L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor. Clinical & experimental metastasis 49 23212305
2010 An updated and upgraded L1CAM mutation database. Human mutation 49 19953645
2019 L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing. Scientific reports 48 30842511
2021 L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling. Journal of experimental & clinical cancer research : CR 44 34645505
2006 L1 (CD171) is highly expressed in gastrointestinal stromal tumors. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 43 16400320
2005 Identification of L1CAM, Jagged2 and Neuromedin U as ovarian cancer-associated antigens. Oncology reports 42 15706405
2002 Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease? American journal of medical genetics 42 11857550
2020 Different Shades of L1CAM in the Pathophysiology of Cancer Stem Cells. Journal of clinical medicine 41 32429448
2009 L1-CAM as a target for treatment of cancer with monoclonal antibodies. Anticancer research 41 20044598
2014 Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. Acta biomaterialia 40 25308870
2020 Recent insights into the role of L1CAM in cancer initiation and progression. International journal of cancer 38 32588424
2016 Temporal expression of CD184(CXCR4) and CD171(L1CAM) identifies distinct early developmental stages of human retinal ganglion cells in embryonic stem cell derived retina. Experimental eye research 38 27867005
2012 L1CAM increases MAP2 expression via the MAPK pathway to promote neurite outgrowth. Molecular and cellular neurosciences 38 22503709
2008 Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration. Journal of molecular medicine (Berlin, Germany) 37 18931829
2016 Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation. Cellular oncology (Dordrecht, Netherlands) 34 26883759
2008 L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis. Human reproduction (Oxford, England) 34 18332088
2010 Elevated L1CAM expression in precursor lesions and primary and metastastic tissues of pancreatic ductal adenocarcinoma. Oncology reports 33 20811670
2020 Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4+ CAR T Cell Efficacy. Frontiers in immunology 32 32296437
2014 L1CAM is expressed in triple-negative breast cancers and is inversely correlated with androgen receptor. BMC cancer 31 25510351
2010 L1cam acts as a modifier gene during enteric nervous system development. Neurobiology of disease 31 20696247
2018 Increased L1CAM (CD171) levels are associated with glioblastoma and metastatic brain tumors. Medicine 30 30235708
2017 L1CAM drives oncogenicity in esophageal squamous cell carcinoma by stimulation of ezrin transcription. Journal of molecular medicine (Berlin, Germany) 30 28939985
2016 Proteome analysis identifies L1CAM/CD171 and DPP4/CD26 as novel markers of human skin mast cells. Allergy 30 27091730
2021 Nodal-induced L1CAM/CXCR4 subpopulation sustains tumor growth and metastasis in colorectal cancer derived organoids. Theranostics 29 33897875
2017 Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients. British journal of cancer 29 28751757
2003 Adhesion molecules CD171 (L1CAM) and CD24 are expressed by primary neuroendocrine carcinomas of the skin (Merkel cell carcinomas). Journal of cutaneous pathology 29 12834484
2012 L1CAM binds ErbB receptors through Ig-like domains coupling cell adhesion and neuregulin signalling. PloS one 28 22815787
2016 L1CAM: amending the "low-risk" category in endometrial carcinoma. Journal of cancer research and clinical oncology 27 27695947
1999 Regions of Byr4, a regulator of septation in fission yeast, that bind Spg1 or Cdc16 and form a two-component GTPase-activating protein with Cdc16. The Journal of biological chemistry 27 10196225
1991 Physical mapping of the loci Gabra3, DXPas8, CamL1, and Rsvp in a region of the mouse X chromosome homologous to human Xq28. Genomics 27 1684949
2017 Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin α5β1 and tumour growth. Oncogenesis 25 28504692
2015 The role of L1cam in murine corticogenesis, and the pathogenesis of hydrocephalus. Pathology international 25 25641508
2015 miR-503 inhibits cell proliferation and invasion in glioma by targeting L1CAM. International journal of clinical and experimental medicine 25 26770450
2010 "CRASH"ing with the worm: insights into L1CAM functions and mechanisms. Developmental dynamics : an official publication of the American Association of Anatomists 25 20225255
2010 Expression of L1CAM, COX-2, EGFR, c-KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets? Histopathology 25 20459551
1998 A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS). Journal of medical genetics 25 9643285
2018 Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis. Proceedings of the National Academy of Sciences of the United States of America 24 29483251
2020 Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM. Cancers 23 33228199
2019 Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis. The Journal of clinical endocrinology and metabolism 23 31504653
2008 L1 (CAM) (CD171) in ovarian serous neoplasms. European journal of gynaecological oncology 23 18386459
2024 Isolation and quantification of L1CAM-positive extracellular vesicles on a chip as a potential biomarker for Parkinson's Disease. Journal of extracellular vesicles 22 38898558
2014 L1cam is crucial for cell locomotion and terminal translocation of the Soma in radial migration during murine corticogenesis. PloS one 22 24489698
2008 Neurotrophins 3 and 4 differentially regulate NCAM, L1 and N-cadherin expression during peripheral nerve regeneration. Biotechnology and applied biochemistry 22 17640175
2022 Functional Diversity of Neuronal Cell Adhesion and Recognition Molecule L1CAM through Proteolytic Cleavage. Cells 19 36231047
2011 Full-length L1CAM and not its Δ2Δ27 splice variant promotes metastasis through induction of gelatinase expression. PloS one 19 21541352
1998 Byr4, a dosage-dependent regulator of cytokinesis in S. pombe, interacts with a possible small GTPase pathway including Spg1 and Cdc16. Molecules and cells 19 9638658
2024 L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 18 38460672
2023 Knocking out alpha-synuclein in melanoma cells downregulates L1CAM and decreases motility. Scientific reports 18 37286800
2010 L1CAM ubiquitination facilitates its lysosomal degradation. FEBS letters 18 20940017
2023 L1CAM immunocapture generates a unique extracellular vesicle population with a reproducible miRNA fingerprint. RNA biology 17 37042019
2024 Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma. Cell death & disease 16 38263290
2022 L1CAM is required for early dissemination of fallopian tube carcinoma precursors to the ovary. Communications biology 16 36509990
2020 A novel nonsense mutation in the L1CAM gene responsible for X-linked congenital hydrocephalus. The journal of gene medicine 16 32128973
2018 Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence. Aging 16 29615539
2017 The Pleiotropic Role of L1CAM in Tumor Vasculature. International journal of molecular sciences 16 28134764
2013 The immunohistochemical expression of CD24 and CD171 adhesion molecules in borderline ovarian tumors. Polish journal of pathology : official journal of the Polish Society of Pathologists 16 24166603
2004 L1 (CD171) as a novel biomarker for ovarian and endometrial carcinomas. Expert review of molecular diagnostics 16 15225093
2025 Most L1CAM Is not Associated with Extracellular Vesicles in Human Biofluids and iPSC-Derived Neurons. Molecular neurobiology 15 40210837
2024 KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 15 38924996
2023 Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma. International journal of molecular sciences 15 36768928
2021 High-risk endometrial cancer proteomic profiling reveals that FBXW7 mutation alters L1CAM and TGM2 protein levels. Cancer 15 33872388
2017 L1 cell adhesion molecule (L1CAM) is a strong predictor for locoregional recurrences in cervical cancer. Oncotarget 15 29152102
2024 Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer's Disease Models. International journal of molecular sciences 14 38542381
2018 L1 Cell Adhesion Molecule (L1CAM) expression in endometrioid endometrial carcinomas: A possible pre-operative surrogate of lymph vascular space invasion. PloS one 14 30557309
2017 L1CAM expression associates with poor outcome in endometrioid, but not in clear cell ovarian carcinoma. Gynecologic oncology 14 28625395
2023 Viral delivery of L1CAM promotes axonal extensions by embryonic cerebral grafts in mouse brain. Stem cell reports 13 36963389
2021 Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus. Proceedings of the National Academy of Sciences of the United States of America 13 34380733
2020 L1cam curbs the differentiation of adult-born hippocampal neurons. Stem cell research 13 32971459
2018 L1CAM Immunopositivity in Anaplastic Supratentorial Ependymomas: Correlation With Clinical and Histological Parameters. International journal of surgical pathology 13 30251576
2022 L1CAM expression as a predictor of platinum response in high-risk endometrial carcinoma. International journal of cancer 12 35429348
1990 Linkage of a gene for neural cell adhesion molecule, L1 (CamL1) to the Rsvp region of the mouse X chromosome. Genomics 12 1964443

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