Affinage

ICAM5

Intercellular adhesion molecule 5 · UniProt Q9UMF0

Length
924 aa
Mass
97.1 kDa
Annotated
2026-06-10
24 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ICAM-5 (telencephalin) is a somatodendritic immunoglobulin-superfamily adhesion molecule that couples neuronal integrin signaling to dendritic spine maturation and immune modulation in the telencephalon (PMID:10741396, PMID:23015592). Through its N-terminal Ig domains it binds the leukocyte integrin LFA-1 (CD11a/CD18)—with the first domain essential for the interaction and a second non-integrin binding site in the sixth domain—thereby mediating T-cell adhesion to hippocampal neurons (PMID:10741396); crystallographic analysis of the LFA-1 αL I-domain bound to ICAM-5 D1–D2 reveals an unusually mobile α7 helix indicative of low-energy integrin conformational change (PMID:18691975), while the curved D1–D4 architecture supports charge-based homophilic adhesion distinct from ICAM-1 (PMID:25004970). ICAM-5 restrains spine maturation by keeping dendritic filopodia immature: its cytoplasmic tail competes with the NMDA receptor subunit GluN1 for α-actinin binding, and its loss or tail deletion frees GluN1/α-actinin association to drive cytoskeletal reorganization (PMID:25572420). Upon NMDA receptor activation, MMP-2/MMP-9 cleave the ICAM-5 ectodomain, releasing it from the actin cytoskeleton; the soluble ectodomain then engages neuronal β1 integrins—which co-immunoprecipitate with ICAM-5 via its first two Ig domains—to promote filopodial elongation, surface insertion and Ser845 phosphorylation of the GluA1 AMPAR subunit, increased mEPSC frequency, and elevated network excitability (PMID:17682049, PMID:23015592, PMID:23844251, PMID:22912716). The shed ectodomain additionally acts on immune cells, attenuating TCR-driven T-cell activation (PMID:18223167), serving as a 'don't-eat-me' and anti-inflammatory signal to microglia (PMID:29311819), and conferring neuroprotection in autoimmune neuroinflammation (PMID:30915022). ICAM-5 expression and trafficking are tightly controlled: FMRP binds the ICAM5 coding-sequence mRNA, and ICAM5 overexpression in Fmr1-null mice produces spine abnormalities and cognitive deficits reversible by ICAM5 knockdown (PMID:31882402), while calsyntenin-1 co-transports ICAM-5 and limits its synaptic surface accumulation (PMID:31680833). ICAM-5 also functions outside the nervous system as an entry receptor co-opted by enterovirus D68 through lipid-raft translocation (PMID:32101770) and is an aberrantly activated, MAPK/ERK- and JNK-driven oncogenic effector in thyroid carcinoma downstream of DNMT1/DNMT3a-mediated promoter hypermethylation (PMID:38228798).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Established ICAM-5 as a functional adhesion receptor for leukocyte integrins, defining how immune cells dock onto telencephalic neurons.

    Evidence Domain-deletion constructs and antibody-blocking T-cell adhesion assays on hippocampal neurons

    PMID:10741396

    Open questions at the time
    • Did not address the physiological consequence of neuron-T-cell adhesion in vivo
    • Nature of the non-integrin domain-6 binding partner unresolved
  2. 2007 High

    Showed that activity-dependent proteolytic shedding converts membrane ICAM-5 into a soluble effector that reshapes dendritic structure, linking NMDA receptor signaling to spine remodeling.

    Evidence MMP inhibitors, MMP-2/9 siRNA and knockout mice, NMDA stimulation and live imaging of hippocampal neurons

    PMID:17682049

    Open questions at the time
    • Receptor mediating the soluble ectodomain's effect not yet identified
    • Precise cleavage site not mapped
  3. 2008 High

    Resolved the structural basis of ICAM-5/LFA-1 recognition, revealing integrin allosteric mobility relevant to adhesion signaling.

    Evidence X-ray crystallography of the αL I-domain bound to ICAM-5 D1–D2

    PMID:18691975

    Open questions at the time
    • Structure used a high-affinity engineered I-domain rather than physiological state
    • Does not address homophilic or β1 integrin binding modes
  4. 2008 Medium

    Demonstrated that shed ICAM-5 feeds back onto the immune system to dampen T-cell activation, extending its role beyond adhesion to immunomodulation.

    Evidence T-cell activation flow cytometry, cytokine mRNA measurement, and purified sICAM-5 stimulation

    PMID:18223167

    Open questions at the time
    • Receptor on T cells transducing the sICAM-5 signal not defined
    • In vivo relevance to neuroimmune crosstalk untested
  5. 2012 High

    Identified β1 integrins as the neuronal receptor for shed ICAM-5 and connected the ICAM-5/β1 axis to synaptic contact formation and excitability.

    Evidence Reciprocal Co-IP from mouse brain, domain mapping, mEPSC recordings, multielectrode arrays, antibody perturbation and ICAM5 KO neurons

    PMID:22912716 PMID:23015592

    Open questions at the time
    • Whether membrane vs soluble ICAM-5 engages β1 integrins in cis or trans not fully resolved
    • Downstream integrin signaling intermediates not mapped
  6. 2013 Medium

    Defined the molecular output of ICAM-5/β1 signaling as selective GluA1 surface insertion and phosphorylation, providing a mechanism for potentiated glutamatergic transmission.

    Evidence mEPSC recordings, surface biotinylation, immunostaining and exogenous ectodomain application

    PMID:23844251

    Open questions at the time
    • Kinase responsible for Ser845 phosphorylation not identified
    • Link to long-term plasticity in vivo not established
  7. 2014 High

    Revealed ICAM-5's curved multidomain architecture and electrostatic homophilic adhesion mode, distinguishing it mechanistically from ICAM-1.

    Evidence X-ray crystallography of D1–D4 in three space groups with electrostatic and crystal-packing analysis

    PMID:25004970

    Open questions at the time
    • Functional consequence of homophilic adhesion in neurons not tested
    • D5 position inferred from modeling only
  8. 2015 Medium

    Explained how membrane ICAM-5 negatively gates spine maturation, via cytoplasmic competition with GluN1 for α-actinin.

    Evidence Co-IP, cytoplasmic-tail deletion constructs, ICAM-5 KO neurons, peptide internalization and F-actin staining

    PMID:25572420

    Open questions at the time
    • Stoichiometry and direct vs indirect α-actinin binding not quantified
    • How NMDA signaling switches α-actinin partner preference mechanistically unclear
  9. 2017 Medium

    Extended the soluble ICAM-5 signaling repertoire to microglia, identifying it as a 'don't-eat-me' and anti-inflammatory cue.

    Evidence Microglial adhesion and phagocytosis assays, cytokine ELISA and ICAM-5-coated surface experiments

    PMID:29311819

    Open questions at the time
    • Microglial receptor for sICAM-5 not identified
    • In vivo relevance to synaptic pruning untested
  10. 2019 High

    Placed ICAM5 downstream of FMRP translational control and demonstrated its causal contribution to fragile-X-like cognitive and spine phenotypes.

    Evidence FMRP-mRNA binding (RIP), in vivo AAV-shRNA knockdown with Morris water maze and fear conditioning, spine morphology in Fmr1 KO mice

    PMID:31882402

    Open questions at the time
    • Whether FMRP represses ICAM5 translation directly vs affecting stability not distinguished
    • Circuit-level basis of behavioral rescue unresolved
  11. 2019 Medium

    Identified calsyntenin-1 as a trafficking partner that controls ICAM-5 synaptic surface abundance and links its mislocalization to fragile-X spine defects.

    Evidence Co-IP, live-cell co-transport imaging, shRNA knockdown, surface biotinylation and spine analysis in Fmr1 KO neurons

    PMID:31680833

    Open questions at the time
    • Molecular determinants of the CLSTN1/ICAM-5 cargo interaction not mapped
    • Directionality (anterograde vs retrograde) of transport not resolved
  12. 2019 Medium

    Established a neuroprotective role for ICAM-5 in progressive neuroinflammation, with soluble ICAM-5 ameliorating autoimmune demyelinating disease.

    Evidence ICAM-5 KO EAE model, intrathecal sICAM-5 administration, clinical scoring and flow cytometry

    PMID:30915022

    Open questions at the time
    • Cellular target of intrathecal sICAM-5 in the EAE context not pinpointed
    • Mechanistic overlap with the microglial anti-inflammatory pathway not directly tested
  13. 2020 Medium

    Demonstrated a pathogen-hijacked function of ICAM-5 as an EV-D68 entry receptor dependent on lipid-raft translocation.

    Evidence Lipid raft fractionation, confocal co-localization, MβCD disruption with cholesterol rescue and viral entry assays

    PMID:32101770

    Open questions at the time
    • Domain of ICAM-5 engaging the virus not mapped
    • Signal driving raft translocation upon infection unknown
  14. 2024 Medium

    Identified GPM6a as a cis/trans interaction partner of ICAM-5 cooperating in neurite and filopodia outgrowth.

    Evidence Reciprocal Co-IP, cell aggregation assays, co-localization and co-overexpression in N2a cells and hippocampal neurons

    PMID:39352694

    Open questions at the time
    • Endogenous (non-overexpression) interaction not confirmed
    • Whether GPM6a modulates ICAM-5 shedding or integrin signaling untested
  15. 2024 Medium

    Revealed an oncogenic, MAPK-driven role for aberrantly activated ICAM5 in thyroid carcinoma controlled by DNMT-mediated promoter methylation.

    Evidence DNMT1/DNMT3a shRNA knockdown with ICAM5 overexpression rescue, ERK/JNK inhibitors, proliferation/migration/invasion assays and xenografts

    PMID:38228798

    Open questions at the time
    • Mechanism by which promoter hypermethylation paradoxically activates transcription not explained
    • Whether ICAM5's adhesion/integrin functions contribute to oncogenesis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptors transducing soluble ICAM-5 signals on immune and microglial cells, and the molecular link between its synaptic adhesion roles and its oncogenic MAPK signaling, remain undefined.
  • No identified microglial or T-cell receptor for sICAM-5
  • No unifying mechanism connecting neuronal and carcinoma functions
  • In vivo significance of homophilic adhesion not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0098772 molecular function regulator activity 2 GO:0001618 virus receptor activity 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
ACTN1CLSTN1FMR1GPM6AGRIN1ITGALITGB1ITGB2

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ICAM-5 binds the leukocyte integrin CD11a/CD18 (LFA-1) through its first immunoglobulin domain; deletion of the first domain abolishes binding, and monoclonal antibodies against the first domain completely block the interaction. The sixth domain also supports leukocyte binding through a non-integrin mechanism. T-cell binding to hippocampal neurons is blocked by antibodies against both CD11a/CD18 and ICAM-5. Protein domain deletion constructs, monoclonal antibody blocking assays, T-cell adhesion assay to hippocampal neurons European journal of immunology High 10741396
2007 NMDA receptor activation promotes MMP-2- and MMP-9-dependent cleavage of ICAM-5 from hippocampal neurons, disrupting its actin cytoskeletal association. Soluble ICAM-5 promotes elongation of dendritic filopodia from wild-type but not ICAM-5-deficient neurons, and ICAM-5 deficiency causes retraction of thin spine heads in response to NMDA stimulation. MMP inhibitors, siRNA knockdown of MMP-2/9, MMP-2/9 knockout mice, NMDA/AMPA stimulation of hippocampal neurons, immunoblotting, live imaging The Journal of cell biology High 17682049
2008 Crystal structure of a high-affinity LFA-1 alphaL I domain bound to the N-terminal two domains of ICAM-5 reveals an unusual alpha7 helix mobility: the alpha7 helix swings out and inserts into a neighboring I domain in an upside-down orientation, implying low energy cost for large-scale integrin conformational changes during signaling. X-ray crystallography of alphaL I domain / ICAM-5 D1–D2 complex Molecular cell High 18691975
2008 Soluble ICAM-5 (sICAM-5) attenuates TCR-mediated T-cell activation, reducing expression of CD69, CD40L, and CD25 (IL-2R), and promotes TGF-β1 and IFN-γ mRNA expression but not TNF. The effect is most pronounced in naive (CD45ROLow) T cells and early in priming; activated T cells promote ICAM-5 cleavage from neurons to generate sICAM-5. T-cell activation assays (flow cytometry for activation markers), cytokine mRNA measurement, stimulation with purified sICAM-5 Blood Medium 18223167
2012 β1 integrins are binding partners for ICAM-5; they co-immunoprecipitate with ICAM-5 from mouse brain and the binding region maps to the first two Ig domains of ICAM-5. Ablation of ICAM-5 increases synaptic contact formation and mEPSC frequency. Antibodies against ICAM-5 or β1 integrins alter spine maturation. ICAM-5 ectodomain cleavage is increased or decreased when the ICAM-5/β1 integrin interaction is weakened or potentiated, respectively. Co-immunoprecipitation from mouse brain, electrophysiology (mEPSC recordings), antibody perturbation, ICAM5 knockout neurons Journal of cell science High 23015592
2012 The ICAM-5 ectodomain stimulates β1 integrin-dependent increases in spike counts and burst number in hippocampal networks. A β1 integrin blocking antibody mimics the effect of MMP inhibition on cLTP-evoked neuronal activity changes, supporting that MMP-dependent shedding of ICAM-5 acts via β1 integrins to regulate neuronal excitability. Multielectrode array recordings, MMP inhibitors, β1 integrin blocking antibody, exogenous soluble ICAM-5 ectodomain application PloS one Medium 22912716
2013 The ICAM-5 ectodomain increases mEPSC frequency (but not amplitude) and stimulates increased membrane/surface expression of GluA1 (but not GluA2) AMPAR subunits along dendrites, as well as GluA1 phosphorylation at serine 845, via a β1 integrin-dependent mechanism. Single-cell electrophysiology (mEPSC recordings), biotinylation/precipitation surface assays, immunostaining, exogenous ICAM-5 ectodomain application PloS one Medium 23844251
2014 Crystal structure of ICAM-5 D1–D4 and modeled D1–D5 fragment reveals a curved molecule with pronounced interdomain bends at D2/D3 and D3/D4. ICAM-5 mediates homotypic (homophilic) interactions through charge-based (electrostatic) intermolecular contacts between N-terminal and C-terminal moieties, in contrast to ICAM-1. X-ray crystallography in three space groups, electrostatic surface analysis, crystal packing analysis Acta crystallographica. Section D, Biological crystallography High 25004970
2015 ICAM-5 cytoplasmic domain competes with GluN1 (NMDA receptor subunit) for binding to α-actinin; deletion of the ICAM-5 cytoplasmic tail or gene ablation increases GluN1/α-actinin association, while internalization of ICAM-5 peptide disrupts the GluN1/α-actinin interaction. NMDA treatment decreases α-actinin binding to ICAM-5 and increases it to GluN1. ICAM-5 is thus a negative regulator of spine maturation by preventing actin cytoskeleton reorganization via α-actinin. Co-immunoprecipitation, domain deletion constructs, ICAM-5 KO neurons, peptide internalization assays, F-actin staining Biology open Medium 25572420
2017 Soluble ICAM-5 released from NMDA-treated neurons binds microglia, promotes downregulation of microglia adhesion and phagocytosis, reduces secretion of TNF-α and IL-1β, and induces IL-10 secretion from LPS-stimulated microglia, acting as a 'don't-eat-me' signal and anti-inflammatory agent. Microglia adhesion and phagocytosis assays, cytokine ELISA, ICAM-5-coated surface adhesion experiments, NMDA stimulation of neurons Frontiers in molecular neuroscience Medium 29311819
2019 FMRP directly binds ICAM5 mRNA at its coding sequence, as shown by biochemical binding assays. In Fmr1 KO mice, ICAM5 is excessively expressed and correlates with dendritic spine morphological abnormalities. In vivo knockdown of ICAM5 in the dentate gyrus rescues impaired spatial/fear memory and anxiety-like behaviors in Fmr1 KO mice. Biochemical FMRP-mRNA binding assay (RIP), in vivo AAV-shRNA knockdown, behavioral tests (Morris water maze, fear conditioning), dendritic spine morphology analysis The Journal of neuroscience High 31882402
2019 Calsyntenin-1 (CLSTN1) co-localizes and co-transports with ICAM-5 in cortical neurons. shRNA-mediated downregulation of CLSTN1 increases ICAM-5 surface accumulation at synaptic membranes and affects dendritic spine maturation. Normalization of CLSTN1 in Fmr1 KO neurons reduces ICAM-5 synaptic surface abundance and rescues aberrant spine phenotypes. Co-immunoprecipitation, live-cell imaging (co-transport), shRNA knockdown, surface biotinylation, dendritic spine morphology analysis in Fmr1 KO neurons Frontiers in neuroscience Medium 31680833
2019 Intrathecal application of soluble sICAM-5 ameliorates EAE disease symptoms and the ICAM-5 KO mouse shows a more severe EAE disease course in the chronic phase, indicating a neuroprotective function of ICAM-5 in progressive neurodegeneration. LFA-1/ICAM-1 contacts between APCs and Th17 cells are not affected by ICAM-5. ICAM-5 knockout mouse EAE model, intrathecal sICAM-5 administration, clinical scoring, flow cytometry Frontiers in neurology Medium 30915022
2020 EV-D68 infection facilitates translocation of its receptor ICAM-5 into lipid rafts, and viral particles co-localize with ICAM-5 in rafts. Methyl-β-cyclodextrin disrupts lipid rafts and abolishes this co-localization, thereby blocking EV-D68 entry without affecting initial viral attachment to the cell membrane. Lipid raft fractionation, confocal co-localization, MβCD treatment, cholesterol rescue, viral entry/infection assays Antiviral research Medium 32101770
2024 GPM6a interacts with ICAM-5 in both cis and trans configurations in cell lines (co-immunoprecipitation and cell aggregation assays). The two proteins co-localize on dendritic shafts of hippocampal neurons, and their co-overexpression additively enhances neurite length, neurite number in N2a cells, and filopodia formation in neurons. Co-immunoprecipitation, cell aggregation assay, immunostaining co-localization, overexpression in N2a cells and hippocampal neurons Journal of neurochemistry Medium 39352694
2024 DNMT1 and DNMT3a induce promoter hypermethylation of ICAM5 in thyroid carcinoma cells, paradoxically activating its transcription. ICAM5 overexpression activates MAPK/ERK and MAPK/JNK signaling; ERK or JNK inhibition blocks oncogenic effects of ICAM5. Knockdown of DNMT1 or DNMT3a decreases ICAM5 expression and suppresses malignant properties, which are rescued by ICAM5 re-overexpression. shRNA knockdown of DNMT1/DNMT3a, ICAM5 overexpression rescue, pharmacological ERK/JNK inhibitors, proliferation/migration/invasion assays, in vivo xenograft Functional & integrative genomics Medium 38228798

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. The Journal of cell biology 150 17682049
2012 Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries. Annals of the rheumatic diseases 54 22523428
2012 Interactions between ICAM-5 and β1 integrins regulate neuronal synapse formation. Journal of cell science 54 23015592
2000 Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CD11a/CD18. European journal of immunology 52 10741396
2008 Shedded neuronal ICAM-5 suppresses T-cell activation. Blood 49 18223167
2012 MMPs and soluble ICAM-5 increase neuronal excitability within in vitro networks of hippocampal neurons. PloS one 43 22912716
2013 Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1. PloS one 37 23844251
2002 Release of soluble ICAM-5, a neuronal adhesion molecule, in acute encephalitis. Neurology 35 11839847
2008 An unusual allosteric mobility of the C-terminal helix of a high-affinity alphaL integrin I domain variant bound to ICAM-5. Molecular cell 33 18691975
2014 ICAM-5: a neuronal dendritic adhesion molecule involved in immune and neuronal functions. Advances in neurobiology 28 25300135
2012 Structure, Expression, and Function of ICAM-5. Comparative and functional genomics 27 22312318
2020 Methyl-β-cyclodextrin inhibits EV-D68 virus entry by perturbing the accumulation of virus particles and ICAM-5 in lipid rafts. Antiviral research 22 32101770
2000 Release of the neuronal glycoprotein ICAM-5 in serum after hypoxic-ischemic injury. Annals of neurology 22 11026442
2017 Neuronal ICAM-5 Inhibits Microglia Adhesion and Phagocytosis and Promotes an Anti-inflammatory Response in LPS Stimulated Microglia. Frontiers in molecular neuroscience 21 29311819
2016 Icam5 Expression Exhibits Sex Differences in the Neonatal Pituitary and Is Regulated by Estradiol and Bisphenol A. Endocrinology 21 26789235
2019 Neuronal ICAM-5 Plays a Neuroprotective Role in Progressive Neurodegeneration. Frontiers in neurology 15 30915022
2019 Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome. Frontiers in neuroscience 14 31680833
1998 Mapping of the ICAM-5 (telencephalin) gene, a neuronal member of the ICAM family, to a location between ICAM-1 and ICAM-3 on human chromosome 19p13.2. Genomics 14 9828136
2019 ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 31882402
2024 DNMT1/DNMT3a-mediated promoter hypermethylation and transcription activation of ICAM5 augments thyroid carcinoma progression. Functional & integrative genomics 7 38228798
2014 Crystal structures of an ICAM-5 ectodomain fragment show electrostatic-based homophilic adhesions. Acta crystallographica. Section D, Biological crystallography 7 25004970
2015 ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin. Biology open 6 25572420
2025 Tumor cell exosome circ-0023919 promotes EMT through the miR-197-5p/ICAM5 axis and enhances the drug resistance of colorectal cancer to 5-fu. Experimental cell research 3 41397666
2024 Combined additive effects of neuronal membrane glycoprotein GPM6a and the intercellular cell adhesion molecule ICAM5 on neuronal morphogenesis. Journal of neurochemistry 2 39352694

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