Affinage

Showing HEPACAM — GLIALCAM is a alias.

HEPACAM

Hepatic and glial cell adhesion molecule · UniProt Q14CZ8

Length
416 aa
Mass
46.0 kDa
Annotated
2026-06-10
72 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HEPACAM encodes GlialCAM (hepaCAM), an IgG-like transmembrane cell adhesion molecule predominantly expressed in CNS astrocytes and oligodendrocytes at cell-cell contact sites, where it organizes glial junctional protein complexes that govern ion and water homeostasis (PMID:18293412, PMID:21419380). GlialCAM functions as the obligate auxiliary subunit of two partner proteins: it is a direct binding partner and trafficking chaperone for MLC1, required to target MLC1 to astrocytic junctions and stabilize it at the plasma membrane, with MLC1 reciprocally controlling GlialCAM surface levels in vivo so that the two act as an interdependent functional unit in a common pathway (PMID:21419380, PMID:23793458, PMID:24824219, PMID:31752924); and it is an auxiliary subunit of the ClC-2 chloride channel, binding ClC-2, clustering it at glial junctions, and activating it by stabilizing the open configuration of the common (slow) gate (PMID:22405205, PMID:25185546). Structure-function dissection assigns distinct activities to distinct domains: the extracellular Ig domain mediates homo-dimerization and junctional targeting and binds MLC1 and ClC-2, the C-terminus is required for junctional targeting, and the first residues of the transmembrane segment are essential for ClC-2 activation but dispensable for targeting, thereby separating targeting from functional activation (PMID:26033718, PMID:31960914). Through these complexes GlialCAM controls astrocytic volume regulation, and its loss in mice produces astrocyte swelling and intramyelinic edema with abolished MLC1 and reduced ClC-2 expression (PMID:28695146). Beyond ion homeostasis, GlialCAM stabilizes connexin-43 at junctions to support astrocyte gap-junction coupling, regulates astrocyte territorial self-organization and the synaptic excitation/inhibition balance during cortical development, and on astroglial exosomes drives axon growth and neuroprotection against excitotoxicity (PMID:27819278, PMID:34171291, PMID:37620511, PMID:39602529). Loss of GlialCAM/MLC1 complex function causes megalencephalic leukoencephalopathy with subcortical cysts (MLC), and disease-causing mutations act by disrupting homo-complex formation, mislocalizing the complex, and uncoupling its partners (PMID:21624973, PMID:31960914). GlialCAM is also a molecular-mimicry target of EBV EBNA1 recognized by a cross-reactive CSF autoantibody, linking it to multiple sclerosis (PMID:35073561). In non-glial epithelial and tumor contexts, hepaCAM engages F-actin and caveolin-1, mediates cell-matrix adhesion and motility, and acts as a tumor suppressor by inducing p53/p21-dependent senescence and c-Myc degradation (PMID:19142852, PMID:19059381, PMID:18845560, PMID:21618595).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2008 Medium

    Establishing where HEPACAM acts: defining its glial cell-type expression and developmental regulation provided the cellular context for all later mechanistic work in the brain.

    Evidence LacZ knock-in reporter mouse, double-label immunofluorescence, and in situ hybridization across postnatal development

    PMID:18293412

    Open questions at the time
    • Reporter expression does not define molecular function
    • Did not identify binding partners or channels
  2. 2008 Medium

    Pre-glial work first assigned hepaCAM a tumor-suppressive and adhesion role, raising the question of how a single adhesion molecule controls proliferation, motility, and surface organization.

    Evidence Biochemical glycosylation/dimerization assays, caveolin-1 fractionation and Co-IP, F-actin co-sedimentation, and senescence assays in MCF7 and carcinoma cells

    PMID:15917256 PMID:18293412 PMID:18845560 PMID:19059381

    Open questions at the time
    • These functions were defined in non-glial cell lines
    • Mechanistic link between adhesion and growth control left open
    • Connection to the glial complex not yet made
  3. 2011 High

    The central discovery: identifying GlialCAM as a direct MLC1 binding partner required for MLC1 junctional localization explained how MLC disease mutations act, unifying two MLC genes into one molecular pathway.

    Evidence Quantitative proteomics of affinity-purified MLC1, Co-IP, co-localization, and disease-mutation analysis in astrocytes and post-mortem brain

    PMID:21419380 PMID:21624973

    Open questions at the time
    • Did not establish what channel activity the complex controls
    • Stoichiometry and structural basis of homo/hetero-complexes unresolved
  4. 2012 High

    Identifying GlialCAM as an auxiliary subunit of the ClC-2 chloride channel revealed a concrete ion-channel function and showed disease mutations abolish ClC-2 targeting to glial junctions.

    Evidence Co-IP, electrophysiology, immunofluorescence co-localization, and disease-mutation analysis in heterologous cells

    PMID:22405205

    Open questions at the time
    • Did not resolve which GlialCAM domain activates versus targets the channel
    • Relationship between ClC-2 and MLC1/VRAC currents unclear
  5. 2013 High

    Demonstrating GlialCAM acts as a chaperone stabilizing MLC1 at the membrane and rescuing VRAC currents and vacuolation defined the functional consequence of the complex for astrocytic volume regulation.

    Evidence siRNA knockdown and overexpression in HeLa and primary astrocytes, patch-clamp electrophysiology, and vacuolation assays

    PMID:23793458

    Open questions at the time
    • Whether GlialCAM directly gates VRAC or acts indirectly not resolved
    • In vivo relevance of the chaperone role untested at this stage
  6. 2014 High

    In vivo genetics and biophysical dissection established mutual interdependence of GlialCAM and MLC1 for localization and ClC-2 modulation, and separated GlialCAM's targeting activity from its channel-activating activity.

    Evidence Glialcam and Mlc1 knockout mice and zebrafish, oligodendrocyte electrophysiology, CLC channel mutant electrophysiology, and cross-species localization studies

    PMID:24647135 PMID:24824219 PMID:25185546

    Open questions at the time
    • Molecular basis of common-gate stabilization not structurally defined
    • How MLC1 controls GlialCAM surface levels mechanistically unknown
  7. 2015 High

    Domain-mapping assigned the extracellular Ig domain to dimerization/partner binding/targeting, the C-terminus to targeting, and the transmembrane N-terminus to channel activation, providing a structure-function logic for the molecule.

    Evidence Domain-deletion mutagenesis with electrophysiology, Co-IP, and junctional targeting assays

    PMID:26033718

    Open questions at the time
    • No atomic structure of the complex
    • Cytoplasmic tail interactors not yet identified
  8. 2016 Medium

    Linking hepaCAM to connexin-43 stabilization extended its role beyond ion channels to gap-junction maintenance, showing it prevents Cx43 lysosomal degradation at junctions.

    Evidence Reciprocal Co-IP, co-localization, lysosomal/proteasomal inhibitor experiments, and disease-mutation analysis

    PMID:27819278

    Open questions at the time
    • Single lab, mechanism of degradation protection not fully defined
    • In vivo requirement for Cx43 stabilization not tested here
  9. 2017 High

    Glialcam-null mice tied the molecular defects to a primary astrocytic volume-regulation pathology with aquaporin-4 redistribution and progressive intramyelinic edema, anchoring the MLC mechanism in vivo.

    Evidence Glialcam-null mouse immunohistochemistry, western blot, MRI, and histology

    PMID:28695146

    Open questions at the time
    • Causal sequence linking ion/water imbalance to edema not fully dissected
    • Cell-autonomous versus circuit effects not separated
  10. 2018 Medium

    Clarifying that GlialCAM/MLC1 modulates LRRC8/VRAC indirectly via signaling rather than direct interaction refined the mechanism of volume-regulated current control.

    Evidence siRNA knockdown, Xenopus oocyte expression, electrophysiology with negative interaction data, and ERK/LRRC8C phosphorylation western blots

    PMID:30076890

    Open questions at the time
    • The signaling intermediary between MLC1 and VRAC not identified
    • ERK pathway link correlative
  11. 2019 High

    Developmental and epistasis studies showed the complex assembles at perivascular endfeet in a defined postnatal window and that GlialCAM and MLC1 act as a single functional unit, with MLC1 able to reach junctions independently when overexpressed.

    Evidence Gliovascular-unit fractionation with developmental Co-IP timecourse, and double-knockout zebrafish/mouse epistasis with rescue experiments

    PMID:30684007 PMID:31752924

    Open questions at the time
    • Trigger for timed assembly unknown
    • Relationship to blood-brain barrier maturation correlative
  12. 2020 Medium

    A crosslinking-based structural model of GlialCAM homo-interactions explained why different MLC mutations are dominant or recessive by mapping them to distinct cis and trans Ig-domain interfaces.

    Evidence Nanobody biochemistry, cysteine crosslinking, double-mutant analysis, and computational docking

    PMID:31960914

    Open questions at the time
    • No crystal structure of the homo-complex
    • Model from a single lab
  13. 2021 High

    Conditional astrocyte deletion revealed developmental roles in astrocyte territory competition, gap-junction coupling, and excitation/inhibition balance, broadening HEPACAM function beyond ion homeostasis to circuit assembly.

    Evidence Astrocyte-specific conditional knockout with mosaic analysis, live imaging, dye coupling, and synaptic electrophysiology; plus interactome screen identifying GPRC5B/GPR37L1

    PMID:34100078 PMID:34171291

    Open questions at the time
    • Whether E/I imbalance is secondary to coupling defects unresolved
    • GPCR-MLC interaction mechanism not yet defined at this stage
  14. 2022 High

    Identifying molecular mimicry between EBV EBNA1 and GlialCAM connected the protein to multiple sclerosis autoimmunity, with a structurally defined cross-reactive autoantibody.

    Evidence Single-cell B-cell repertoire sequencing, protein microarray, affinity measurements, EBNA1-Fab crystal structure, and EBNA1-immunization MS mouse model

    PMID:35073561

    Open questions at the time
    • Causal contribution of anti-GlialCAM antibodies to human MS not established
    • Role of GlialCAM post-translational modification in patients unclear
  15. 2023 High

    Exosome studies established that surface GlialCAM on astroglial exosomes is necessary and sufficient to stimulate axon growth, defining a non-junctional, secreted mode of action.

    Evidence Exosome reporter mice, Hepacam knockout, size-exclusion exosome isolation, and in vivo axon-growth assays; plus GBM proliferation/invasion analyses

    PMID:37620511 PMID:37722850

    Open questions at the time
    • Neuronal receptor for exosomal GlialCAM unknown
    • How ApoE inhibits the effect mechanistically unresolved
  16. 2024 High

    Extending exosome function, surface HepaCAM was shown to mediate astrocyte-exosome neuroprotection against excitotoxicity, with inflammatory cytokines suppressing this pathway.

    Evidence Exosome reporter mice, proteomics, and excitotoxicity assays in mouse and human iPSC-derived motor neurons

    PMID:39602529

    Open questions at the time
    • Molecular target on motor neurons not identified
    • Relevance to human neurodegeneration not established
  17. 2025 Medium

    Mechanistic studies of GPRC5B signaling and cytoplasmic-tail function added a GPCR/β-arrestin signaling axis and tied the tail to MAPK/cytoskeletal networks, Cx43, and ClC-2 association in vivo.

    Evidence β-arrestin 2 recruitment and constitutive-activity assays with Co-IP, plus cytoplasmic-tail truncation mouse with proximity proteomics and behavior; cholesterol-biosynthesis study via SREBP2

    PMID:41314544 PMID:41605409

    Open questions at the time
    • GPRC5B downstream effectors in astrocytes undefined
    • Causal chain from cytoplasmic-tail interactome to phenotype incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GlialCAM integrates its distinct activities — junctional channel assembly, exosomal neuroprotection/axon growth, GPCR signaling, and tumor suppression — into a coherent astrocyte program, and the high-resolution structure of the GlialCAM/MLC1/ClC-2 complex, remain unresolved.
  • No atomic structure of the assembled glial complex
  • Neuronal/exosomal receptors for GlialCAM unidentified
  • Unified model linking junctional and secreted functions absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2
Partners
ACTBCAV1CLCN2GJA1GPR37L1GPRC5BKCNQ2MLC1
Complex memberships
GlialCAM/ClC-2 channel complexGlialCAM/MLC1 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 GlialCAM (encoded by HEPACAM) is a direct binding partner of MLC1, identified by quantitative proteomic analysis of affinity-purified MLC1. GlialCAM is required for proper localization of MLC1 to astrocytic junctions; mutant GlialCAM disrupts localization of MLC1-GlialCAM complexes at astrocytic junctions. GlialCAM also localizes in myelin. Quantitative proteomic analysis of affinity-purified MLC1, co-localization experiments, functional analysis of disease-causing mutations in heterologous cells and primary astrocytes American journal of human genetics High 21419380
2011 MLC1 and GlialCAM form homo- and hetero-complexes. MLC-causing mutations in GLIALCAM mainly reduce formation of GlialCAM homo-complexes, leading to a trafficking defect that prevents GlialCAM from reaching cell junctions and co-traffics MLC1 away from junctions. MLC1 is not necessary for GlialCAM expression or targeting. Co-immunoprecipitation, heterologous cell transfection, primary astrocyte experiments, post-mortem brain analysis Human molecular genetics High 21624973
2012 GlialCAM is an auxiliary subunit of the ClC-2 Cl− channel. GlialCAM binds ClC-2, targets it to cell-cell junctions in Bergmann glia and astrocyte endfeet, increases ClC-2-mediated currents, and changes its functional properties. Disease-causing GLIALCAM mutations abolish targeting of ClC-2 to cell junctions. Co-immunoprecipitation, electrophysiology, immunofluorescence co-localization, disease mutation analysis in heterologous cells Neuron High 22405205
2013 GlialCAM acts as a chaperone for MLC1: GlialCAM ablation causes intracellular accumulation and reduced plasma membrane expression of MLC1, while GlialCAM overexpression increases stability of mutant MLC1 variants. Reduction in GlialCAM results in defective activation of volume-regulated anion currents (VRAC) and augmented vacuolation, phenocopying MLC1 mutations. GlialCAM overexpression with MLC1 mutants can reactivate VRAC currents and reverse vacuolation. siRNA knockdown, overexpression in HeLa cells and primary astrocytes, patch-clamp electrophysiology, cell vacuolation assay Human molecular genetics High 23793458
2014 In vivo, GlialCAM is important for targeting both MLC1 and ClC-2 to specialized glial domains and for modifying ClC-2 biophysical properties specifically in oligodendrocytes. Unexpectedly, MLC1 is also crucial for proper localization of GlialCAM and ClC-2 and for changing ClC-2 currents in vivo, revealing a mutual interdependence. ClC-2 is not required for MLC1 or GlialCAM localization. Loss-of-function Glialcam and Mlc1 mouse models, in vivo localization studies, electrophysiology in oligodendrocytes, myelin vacuolation histology Nature communications High 24647135
2014 GlialCAM activates CLC channels by stabilizing the open configuration of the common (slow) gate. GlialCAM clusters all CLC channels tested at cell contacts in vitro. GlialCAM slows deactivation kinetics of CLC-Ka/barttin and increases CLC-0 currents by opening the common gate. GlialCAM targets common-gate-deficient CLC-2 mutant to cell contacts without altering function, dissociating targeting from functional activation. Electrophysiology with CLC channel mutants, heterologous cell expression, functional analysis of common-gate-deficient mutants Biophysical journal High 25185546
2014 MLC1 regulates glial surface levels of GlialCAM in an evolutionarily conserved manner. In mlc1−/− zebrafish and Mlc1−/− mice, GlialCAM is mislocalized. In vitro, impaired GlialCAM localization in Mlc1−/− astrocytes occurs in the presence of elevated potassium (mimicking neuronal activity). In human MLC patient brain biopsy, GLIALCAM is also mislocalized in Bergmann glia. Zebrafish mlc1 knockout generation and characterization, mouse Mlc1 knockout primary astrocyte cultures, human post-mortem brain biopsy analysis, immunofluorescence Human molecular genetics High 24824219
2015 The extracellular domain of GlialCAM is necessary for its targeting to cell junctions and for interactions with itself (homo-dimerization), MLC1, and ClC-2. The C-terminus of GlialCAM is required for targeting to junctions but not for biochemical interaction. The first three residues of the transmembrane segment of GlialCAM are essential for ClC-2 current activation but not for targeting or biochemical interaction. Domain deletion mutagenesis combined with functional electrophysiology, co-immunoprecipitation, and cell junction targeting assays The Journal of physiology High 26033718
2005 HepaCAM is an N-linked glycoprotein that forms homodimers through cis-interaction on the cell surface. Its subcellular localization is density-dependent: in spread cells it localizes to protrusions; in confluent cells it accumulates at cell-cell contacts. The cytoplasmic domain of hepaCAM is essential for cell-matrix adhesion and cell motility functions but not for surface localization or dimer formation. Biochemical analysis (glycosylation, phosphorylation), cytoplasmic domain-truncated mutants transfected into MCF7 cells, cell adhesion and motility assays, immunocytochemistry The Journal of biological chemistry Medium 15917256
2009 HepaCAM directly binds F-actin. HepaCAM co-sediments with F-actin, and is partially insoluble in Triton X-100 in a manner dependent on intact F-actin. Disruption of F-actin decreases hepaCAM detergent insolubility and disturbs its localization. Both the extracellular and cytoplasmic domains are required for stable actin association; an intact protein is needed for this interaction and for hepaCAM-mediated cell adhesion and motility. Triton X-100 solubility assay, co-immunoprecipitation, F-actin co-sedimentation assay, domain-deletion mutants, cell adhesion and motility assays Journal of cellular physiology Medium 19142852
2008 HepaCAM partially localizes in lipid rafts/caveolae and associates with caveolin-1 (Cav-1). The first extracellular immunoglobulin domain of hepaCAM is required for binding Cav-1. Co-expression with Cav-1 induces hepaCAM expression and distributes hepaCAM to intracellular Cav-1-positive caveolar structures. Sucrose density gradient fractionation (lipid raft isolation), co-localization, co-immunoprecipitation, deletion mutant analysis Biochemical and biophysical research communications Medium 19059381
2008 HepaCAM/GlialCAM is predominantly expressed in CNS glial cells, particularly CNPase-positive oligodendrocytes and astrocytes at cell contact sites. Expression is upregulated during postnatal brain development concomitant with MBP, and GlialCAM co-localizes with GAP43 in oligodendrocyte growth cone-like structures. LacZ reporter assay showed expression prominent in white matter tracts and ependymal cells. LacZ knock-in reporter mouse, double-label immunofluorescence, in situ hybridization, developmental expression analysis Glia Medium 18293412
2016 HepaCAM associates with connexin 43 (Cx43) and enhances Cx43 localization to plasma membrane junctions. HepaCAM stabilizes Cx43 protein by preventing its lysosomal degradation (not proteasomal). MLC-causing mutations in hepaCAM or neutralization of hepaCAM by antibodies disrupts hepaCAM–Cx43 association at cellular junctions. Co-immunoprecipitation, immunofluorescence co-localization, lysosomal and proteasomal inhibitor experiments, disease-mutation analysis Scientific reports Medium 27819278
2017 Glialcam-null mice show abolished MLC1 expression in astrocytes, reduced ClC-2 expression, and increased expression and redistribution of aquaporin-4. GlialCAM loss causes early astrocyte swelling at perivascular processes followed by progressive intramyelinic edema, supporting astrocytic volume regulation defect as primary cellular pathology. Glialcam-null mouse model, immunohistochemistry, western blot, MRI, histology Annals of clinical and translational neurology High 28695146
2018 GlialCAM/MLC1 modulates LRRC8/VRAC currents indirectly. MLC1 cannot potentiate VRAC when LRRC8A is knocked down, but MLC1 and LRRC8A do not co-localize or interact, and MLC1 does not potentiate LRRC8-mediated VRAC currents in Xenopus oocytes. Astrocytes lacking MLC1 show increased ERK phosphorylation and altered phosphorylation of the VRAC subunit LRRC8C, suggesting indirect modulation via signal transduction. siRNA knockdown, Xenopus oocyte expression, electrophysiology, co-localization and co-immunoprecipitation (negative result for direct interaction), western blot for ERK and LRRC8C phosphorylation Neurobiology of disease Medium 30076890
2019 The MLC1/GlialCAM complex assembles at astrocyte perivascular endfeet between postnatal days 10 and 15 in mice, after aquaporin-4 channel formation, and this maturation correlates temporally with blood-brain barrier maturation markers Claudin-5 and P-gP. Purified gliovascular unit preparation, co-immunoprecipitation, western blot developmental timecourse, immunofluorescence Brain structure & function Medium 30684007
2019 GlialCAM and MLC1 form a functional unit; in both zebrafish and mice, loss of both proteins does not aggravate the leukodystrophy phenotype compared to single knockouts, indicating they act in a common pathway. In Glialcam-null mouse astrocytes, overexpressed MLC1 can localize to cell-cell junctions independently of GlialCAM. Double knockout generation in zebrafish (glialcama−/−/mlc1−/−) and mice, MRI, histology, protein localization by immunofluorescence, overexpression rescue experiment Orphanet journal of rare diseases High 31752924
2020 A structural model of GlialCAM homo-interactions was developed using biochemistry combined with a nanobody, double-mutants, and cysteine crosslinking. Dominant mutations affect different GlialCAM-GlialCAM interacting surfaces in the first Ig domain, in either cis (same cell) or trans (neighboring cells) configurations, explaining the dominant vs. recessive character of different disease mutations. Nanobody-based biochemistry, cysteine crosslinking, double-mutant analysis, computer docking structural modeling Human molecular genetics Medium 31960914
2021 HepaCAM regulates astrocyte competition for territory and morphological complexity in the developing mouse cortex. Conditional deletion of Hepacam from developing astrocytes significantly impairs gap junction coupling between astrocytes and disrupts the balance between synaptic excitation and inhibition. Conditional knockout mouse (astrocyte-specific Hepacam deletion), mosaic analysis, live imaging, electrophysiology (excitation/inhibition balance), dye coupling assay Neuron High 34171291
2021 The GlialCAM brain interactome includes transporters, ion channels, and G-protein-coupled receptors including GPRC5B and GPR37L1. GPRC5B and GPR37L1 directly interact with MLC proteins. Inactivation of Gpr37l1 upregulates MLC proteins without altering their localization; reduction of GPRC5B downregulates MLC proteins, leading to impaired ClC-2 and VRAC activation. MLC1-GPCR interaction is dynamically regulated by osmolarity and potassium concentration changes. Proteomic interactome screen, co-immunoprecipitation validation, in vivo mouse Gpr37l1 knockout, siRNA knockdown of GPRC5B in primary astrocytes, electrophysiology Human molecular genetics Medium 34100078
2022 Molecular mimicry exists between EBV transcription factor EBNA1 and CNS protein GlialCAM. A CSF-derived cross-reactive antibody was identified that binds both EBNA1 and GlialCAM; molecular mimicry is facilitated by a post-translational modification of GlialCAM. The crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment was determined. EBNA1 immunization exacerbates disease in a mouse model of MS. Single-cell B cell repertoire sequencing, protein microarray, affinity measurements, crystal structure of EBNA1 epitope-Fab complex, in vivo mouse MS model (EBNA1 immunization) Nature High 35073561
2023 Surface expression of glial HepaCAM on astroglial exosomes is necessary and sufficient to mediate the axon-stimulating effect of astroglial exosomes on cortical pyramidal neurons. ApoE strongly inhibits the stimulatory effect of astroglial exosomes on axon growth. Size-exclusion chromatography exosome isolation, cell-type-specific exosome reporter mice, biochemical and genetic studies (Hepacam KO), in vivo exosome spreading assay Nature communications High 37620511
2023 GlialCAM high expression promotes cell-cell adhesion and a proliferative GBM cell state. GBM cells with low GlialCAM display enhanced invasion. RNAi-mediated inhibition of GlialCAM activates pro-invasive extracellular matrix adhesion and signaling pathways. GlialCAM regulates a functional axis with MLC1 and aquaporin-4 that controls proliferation vs. invasive states. Human tumor specimens, primary GBM spheroids, RNAi knockdown, gene expression profiling, single-cell transcriptomic cross-referencing The Journal of neuroscience Medium 37722850
2024 Surface expression of HepaCAM on astrocyte exosomes preferentially mediates their neuroprotective effect against excitotoxicity. Inflammatory cytokines (ITC: IL-1α/TNF-α/C1q) reduce astrocyte exosome secretion and abolish their neuroprotective effect. SOD1G93A expression partially reduces this neuroprotection. Cell-type-specific exosome reporter mice, selective exosome isolation, proteomic characterization, genetic analysis (HepaCAM), excitotoxicity assays with mouse spinal and human iPSC-derived motor neurons Science advances High 39602529
2025 GPRC5B exhibits constitutive activity that is inhibited by MLC1, likely through interference with GPRC5B oligomerization. GlialCAM enhances β-arrestin 2 recruitment to GPRC5B, leading to GlialCAM mislocalization from cell-cell junctions. MLC-associated GPRC5B mutants show enhanced maturation, increased plasma membrane stability, and increased affinity for GlialCAM; coexpression with these mutants does not induce GlialCAM mislocalization. GPRC5B constitutive activity assays, β-arrestin 2 recruitment assay, co-immunoprecipitation, plasma membrane fractionation, cell junction localization imaging The Journal of biological chemistry Medium 41314544
2025 Deletion of the GlialCAM cytoplasmic tail in glial cells causes white matter vacuolization and behavioral deficits (motor coordination, muscle strength, memory). Proteomic analysis identified cytoplasmic tail interactors linked to MAPK signaling and cytoskeletal regulatory networks. Mutant mice show reduced association of hepaCAM with Connexin 43 and CLC-2, and activation of astrocytes and microglia. Cytoplasmic domain truncation mouse model, single-cell transcriptomics, spatial in situ profiling, proximity-based proteomics, behavioral testing, histology bioRxivpreprint Medium 41394633
2025 Dominant MLC-causing missense mutations in hepaCAM dramatically disrupt hepaCAM distribution throughout the astrocyte in vivo. Mutant hepaCAM shows decreased association with Connexin 43 and CLC-2 and altered association with previously undescribed potential interactors including KCNQ2. Viral tools for astrocyte-specific expression in developing mouse cortex, proximity-based proteomics (BioID or similar), immunofluorescence localization bioRxivpreprint Medium 40894676
2008 HepaCAM induces cellular senescence via a p53/p21-dependent pathway in MCF7 cells. The cytoplasmic domain is required, as hCAM-tailless mutant does not cause senescence. siRNA knockdown of p53 in hepaCAM-expressing cells reduces p21 and alleviates senescence. Stable transfection, colony formation assay, β-galactosidase senescence assay, siRNA p53 knockdown, western blot Carcinogenesis Medium 18845560
2011 HepaCAM causes G1 phase arrest in renal cell carcinoma 786-0 cells by promoting c-Myc degradation via increased phosphorylation of c-Myc at T58, leading to proteasomal degradation. This occurs post-transcriptionally (c-Myc mRNA unchanged). A proteasomal inhibitor (MG132) abrogates this effect. Ectopic hepaCAM expression, flow cytometry cell cycle analysis, c-Myc inhibitor treatment, RT-PCR (mRNA unchanged), western blot phosphorylation analysis, MG132 proteasome inhibitor Journal of cellular biochemistry Medium 21618595
2026 HepaCAM is essential for normal memory function in mice by maintaining synaptic protein levels and synaptic spine density. HepaCAM promotes neuronal function by modulating SREBP2-dependent cholesterol biosynthesis in astrocytes and facilitating its secretion. The interaction of hepaCAM with ClC-2 is required for hepaCAM's regulatory role in cholesterol biosynthesis. Hippocampal knockdown of hepaCAM reduces synaptic proteins, spine density, and impairs memory. HepaCAM knockdown in mouse hippocampus, cholesterol biosynthesis assay, SREBP2 pathway analysis, synaptic protein western blot, spine density morphometry, memory behavioral tests Brain research Medium 41605409
2010 HepaCAM is cleaved in MCF7 cells generating a fragment containing mainly the cytoplasmic domain. Cleavage is promoted by calcium influx independent of PKC, and involves proteasome, calpain-1, and cathepsin B. When the cytoplasmic domain is cleaved, hepaCAM loses its ability to promote cell-ECM adhesion, migration, and growth inhibition. Biochemical cleavage detection, pharmacological inhibitors (PMA, calcium ionophore, proteasome inhibitor MG132, cysteine protease inhibitors), cell adhesion and migration assays International journal of oncology Medium 20514407

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 674 35073561
2011 Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. American journal of human genetics 149 21419380
2012 GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron 123 22405205
2014 Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nature communications 101 24647135
2021 HepaCAM controls astrocyte self-organization and coupling. Neuron 94 34171291
2011 Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Human molecular genetics 86 21624973
2005 Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma. Journal of hepatology 69 15885354
2008 GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. Glia 61 18293412
2013 Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Human molecular genetics 55 23793458
2005 Structural and functional analyses of a novel ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells. The Journal of biological chemistry 54 15917256
2014 Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening. BMC medical genetics 48 24580998
2017 Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model. Annals of clinical and translational neurology 47 28695146
2008 Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells. Carcinogenesis 43 18845560
2020 Long noncoding RNA HOTAIR regulates the invasion and metastasis of prostate cancer by targeting hepaCAM. British journal of cancer 39 33024272
2014 Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans. Human molecular genetics 38 24824219
2018 GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy. Neurobiology of disease 35 30076890
2017 Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b. Cellular signalling 35 28093267
2016 HepaCAM associates with connexin 43 and enhances its localization in cellular junctions. Scientific reports 33 27819278
2023 Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation. Nature communications 30 37620511
2019 Postnatal development of the astrocyte perivascular MLC1/GlialCAM complex defines a temporal window for the gliovascular unit maturation. Brain structure & function 28 30684007
2014 GlialCAM, a CLC-2 Cl(-) channel subunit, activates the slow gate of CLC chloride channels. Biophysical journal 28 25185546
2011 HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma. Journal of cellular biochemistry 26 21618595
2009 The immunoglobulin-like cell adhesion molecule hepaCAM modulates cell adhesion and motility through direct interaction with the actin cytoskeleton. Journal of cellular physiology 24 19142852
2021 Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins. Human molecular genetics 23 34100078
2014 Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer. The Prostate 23 24811146
2018 HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro. International journal of oncology 21 29658567
2017 Overexpression of HepaCAM inhibits bladder cancer cell proliferation and viability through the AKT/FoxO pathway. Journal of cancer research and clinical oncology 20 28229220
2015 Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy. The Journal of physiology 20 26033718
2015 5-azacytidine inhibits the proliferation of bladder cancer cells via reversal of the aberrant hypermethylation of the hepaCAM gene. Oncology reports 20 26677113
2013 Expanding the spectrum of megalencephalic leukoencephalopathy with subcortical cysts in two patients with GLIALCAM mutations. Neurogenetics 20 24202401
2015 Expression of hepaCAM inhibits bladder cancer cell proliferation via a Wnt/β-catenin-dependent pathway in vitro and in vivo. Cancer biology & therapy 19 26192362
2012 Exploration of the correlations between interferon-γ in patient serum and HEPACAM in bladder transitional cell carcinoma, and the interferon-γ mechanism inhibiting BIU-87 proliferation. The Journal of urology 19 22906662
2010 Functional significance of the hepaCAM gene in bladder cancer. BMC cancer 19 20205955
2013 hepaCAM and p-mTOR closely correlate in bladder transitional cell carcinoma and hepaCAM expression inhibits proliferation via an AMPK/mTOR dependent pathway in human bladder cancer cells. The Journal of urology 18 23669565
2014 Renal tumor-derived exosomes inhibit hepaCAM expression of renal carcinoma cells in a p-AKT-dependent manner. Neoplasma 17 24645843
2009 The immunoglobulin-like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373-MG cells. Journal of cellular biochemistry 17 19507233
2007 Purification of the extracellular domain of the membrane protein GlialCAM expressed in HEK and CHO cells and comparison of the glycosylation. Protein expression and purification 17 18082421
2014 Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy. Human mutation 16 25044933
2008 Detection and identification of plasma proteins that bind GlialCAM using ProteinChip arrays, SELDI-TOF MS, and nano-LC MS/MS. Proteomics 14 18203261
2024 In-depth analysis of serum antibodies against Epstein-Barr virus lifecycle proteins, and EBNA1, ANO2, GlialCAM and CRYAB peptides in patients with multiple sclerosis. Frontiers in immunology 13 39742283
2020 Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies. Human molecular genetics 13 31960914
2014 HepaCAM inhibits clear cell renal carcinoma 786-0 cell proliferation via blocking PKCε translocation from cytoplasm to plasma membrane. Molecular and cellular biochemistry 13 24515280
2010 Expression of hepaCAM and its effect on proliferation of tumor cells in renal cell carcinoma. Urology 13 20110109
2016 The SMAD2/3 pathway is involved in hepaCAM-induced apoptosis by inhibiting the nuclear translocation of SMAD2/3 in bladder cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 26873485
2014 GlialCAM, a glial cell adhesion molecule implicated in neurological disease. Advances in neurobiology 12 25300132
2010 Expression and clinical significance of hepaCAM and VEGF in urothelial carcinoma. World journal of urology 12 20593288
2010 Exon 2 methylation inhibits hepaCAM expression in transitional cell carcinoma of the bladder. Urologia internationalis 12 20628239
2019 Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit. Orphanet journal of rare diseases 11 31752924
2014 Risk factors for hepatitis C transmission in HIV patients, Hepacam study, ANRS 12267 Cambodia. AIDS and behavior 11 23612943
2016 Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect. Metabolic brain disease 10 27389245
2016 Overexpression of Hepatocyte Cell Adhesion Molecule (hepaCAM) Inhibits the Proliferation, Migration, and Invasion in Colorectal Cancer Cells. Oncology research 10 28244854
2008 Interaction of the immunoglobulin-like cell adhesion molecule hepaCAM with caveolin-1. Biochemical and biophysical research communications 10 19059381
2021 STAT3 phosphorylation is required for the HepaCAM-mediated inhibition of castration-resistant prostate cancer cell viability and metastasis. The Prostate 8 33909312
2019 Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models. World journal of pediatrics : WJP 8 31372844
2023 Glial Cell Adhesion Molecule (GlialCAM) Determines Proliferative versus Invasive Cell States in Glioblastoma. The Journal of neuroscience : the official journal of the Society for Neuroscience 7 37722850
2015 HEPACAM inhibited the growth and migration of cancer cells in the progression of non-small cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 7 26392113
2024 Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model. Science advances 5 39602529
2018 HepaCAM Regulates Warburg Effect of Renal Cell Carcinoma via HIF-1α/NF-κB Signaling Pathway. Urology 5 30528714
2022 HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation. International journal of oncology 4 35191516
2021 HepaCAM shapes astrocyte territories, stabilizes gap-junction coupling, and influences neuronal excitability. Neuron 4 34352210
2019 HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain. Molecular medicine reports 4 30664187
2010 The immunoglobulin-like cell adhesion molecule hepaCAM is cleaved in the human breast carcinoma MCF7 cells. International journal of oncology 4 20514407
2012 [Analysis of HEPACAM mutations in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts]. Zhonghua er ke za zhi = Chinese journal of pediatrics 3 23324143
2026 Loss of hepaCAM inhibits cholesterol biosynthesis and impairs learning and memory in mice. Brain research 1 41605409
2026 Recognition mechanisms of multiple sclerosis antibody MS with antigens EBNA1 and GlialCAM via molecular dynamics simulations. Physical chemistry chemical physics : PCCP 0 41528339
2026 [Expression of Concern] 5‑Azacytidine inhibits the proliferation of bladder cancer cells via reversal of the aberrant hypermethylation of the hepaCAM gene. Oncology reports 0 41930589
2025 Dominant MLC-causing mutations alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. bioRxiv : the preprint server for biology 0 40894676
2025 Regulation of the orphan G-protein-coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy. The Journal of biological chemistry 0 41314544
2025 GlialCAM Cytoplasmic Signaling in Oligodendrocytes and Astrocytes is Essential for White Matter Homeostasis in the Brain. bioRxiv : the preprint server for biology 0 41394633
2023 Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation. bioRxiv : the preprint server for biology 0 36824898
2022 [Corrigendum] HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain. Molecular medicine reports 0 35616141
2020 [Analysis of a child with megalencephalic leukoencephalopathy with subcortical cyst type 2B caused by HEPACAM variant]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 32335882

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