{"gene":"ICAM5","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Protein domain deletion constructs, monoclonal antibody blocking assays, T-cell adhesion assay to hippocampal neurons","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain deletion mutagenesis combined with antibody blocking in cell-based adhesion assays, multiple orthogonal methods in single study","pmids":["10741396"],"is_preprint":false},{"year":2007,"finding":"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.","method":"MMP inhibitors, siRNA knockdown of MMP-2/9, MMP-2/9 knockout mice, NMDA/AMPA stimulation of hippocampal neurons, immunoblotting, live imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mice, pharmacological inhibitors, siRNA, and functional spine morphology assays across multiple models","pmids":["17682049"],"is_preprint":false},{"year":2008,"finding":"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.","method":"X-ray crystallography of alphaL I domain / ICAM-5 D1–D2 complex","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mechanistic interpretation of integrin allostery, single rigorous paper with structural resolution","pmids":["18691975"],"is_preprint":false},{"year":2008,"finding":"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.","method":"T-cell activation assays (flow cytometry for activation markers), cytokine mRNA measurement, stimulation with purified sICAM-5","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional assays with defined readouts, single lab, two orthogonal methods (flow cytometry + mRNA)","pmids":["18223167"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation from mouse brain, electrophysiology (mEPSC recordings), antibody perturbation, ICAM5 knockout neurons","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from brain tissue, electrophysiology, domain mapping, and KO functional readout in single study","pmids":["23015592"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Multielectrode array recordings, MMP inhibitors, β1 integrin blocking antibody, exogenous soluble ICAM-5 ectodomain application","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional MEA recordings with pharmacological tools, single lab, multiple orthogonal perturbations","pmids":["22912716"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Single-cell electrophysiology (mEPSC recordings), biotinylation/precipitation surface assays, immunostaining, exogenous ICAM-5 ectodomain application","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology + biochemical surface assay + imaging), single lab","pmids":["23844251"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography in three space groups, electrostatic surface analysis, crystal packing analysis","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure in three space groups with functional interpretation of homophilic adhesion, single rigorous structural study","pmids":["25004970"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, domain deletion constructs, ICAM-5 KO neurons, peptide internalization assays, F-actin staining","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain deletions and KO validation, multiple orthogonal approaches, single lab","pmids":["25572420"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Microglia adhesion and phagocytosis assays, cytokine ELISA, ICAM-5-coated surface adhesion experiments, NMDA stimulation of neurons","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (adhesion, phagocytosis, cytokine secretion), single lab, orthogonal readouts","pmids":["29311819"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Biochemical FMRP-mRNA binding assay (RIP), in vivo AAV-shRNA knockdown, behavioral tests (Morris water maze, fear conditioning), dendritic spine morphology analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct FMRP-mRNA binding demonstrated biochemically, in vivo KD with cognitive behavioral rescue, multiple orthogonal methods","pmids":["31882402"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, live-cell imaging (co-transport), shRNA knockdown, surface biotinylation, dendritic spine morphology analysis in Fmr1 KO neurons","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue in KO neurons with multiple approaches, single lab","pmids":["31680833"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ICAM-5 knockout mouse EAE model, intrathecal sICAM-5 administration, clinical scoring, flow cytometry","journal":"Frontiers in neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined phenotype and rescue by intrathecal sICAM-5, single lab","pmids":["30915022"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Lipid raft fractionation, confocal co-localization, MβCD treatment, cholesterol rescue, viral entry/infection assays","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation plus functional entry assay with cholesterol rescue, single lab, multiple methods","pmids":["32101770"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, cell aggregation assay, immunostaining co-localization, overexpression in N2a cells and hippocampal neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP plus functional cell assays, single lab, two orthogonal binding methods","pmids":["39352694"],"is_preprint":false},{"year":2024,"finding":"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.","method":"shRNA knockdown of DNMT1/DNMT3a, ICAM5 overexpression rescue, pharmacological ERK/JNK inhibitors, proliferation/migration/invasion assays, in vivo xenograft","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiment (DNMT KD + ICAM5 OE), pathway inhibitors, in vitro and in vivo assays, single lab","pmids":["38228798"],"is_preprint":false}],"current_model":"ICAM-5 (telencephalin) is a somatodendritic adhesion molecule that binds leukocyte/neuronal β1 and β2 (LFA-1/CD11a-CD18) integrins via its N-terminal Ig domains, maintains dendritic filopodia in an immature state by competing with GluN1 for α-actinin binding, and is cleaved by MMP-2/9 upon NMDA receptor activation, whereupon the soluble ectodomain engages β1 integrins to promote spine maturation, GluA1 surface insertion, and increased glutamatergic transmission, while also suppressing T-cell activation, microglial phagocytosis, and neuroinflammation; its expression is regulated post-transcriptionally by FMRP binding to its coding sequence mRNA and spatially by calsyntenin-1-dependent trafficking."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10741396"],"confidence":"High","gaps":["Did not address the physiological consequence of neuron-T-cell adhesion in vivo","Nature of the non-integrin domain-6 binding partner unresolved"]},{"year":2007,"claim":"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","pmids":["17682049"],"confidence":"High","gaps":["Receptor mediating the soluble ectodomain's effect not yet identified","Precise cleavage site not mapped"]},{"year":2008,"claim":"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","pmids":["18691975"],"confidence":"High","gaps":["Structure used a high-affinity engineered I-domain rather than physiological state","Does not address homophilic or β1 integrin binding modes"]},{"year":2008,"claim":"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","pmids":["18223167"],"confidence":"Medium","gaps":["Receptor on T cells transducing the sICAM-5 signal not defined","In vivo relevance to neuroimmune crosstalk untested"]},{"year":2012,"claim":"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","pmids":["23015592","22912716"],"confidence":"High","gaps":["Whether membrane vs soluble ICAM-5 engages β1 integrins in cis or trans not fully resolved","Downstream integrin signaling intermediates not mapped"]},{"year":2013,"claim":"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","pmids":["23844251"],"confidence":"Medium","gaps":["Kinase responsible for Ser845 phosphorylation not identified","Link to long-term plasticity in vivo not established"]},{"year":2014,"claim":"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","pmids":["25004970"],"confidence":"High","gaps":["Functional consequence of homophilic adhesion in neurons not tested","D5 position inferred from modeling only"]},{"year":2015,"claim":"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","pmids":["25572420"],"confidence":"Medium","gaps":["Stoichiometry and direct vs indirect α-actinin binding not quantified","How NMDA signaling switches α-actinin partner preference mechanistically unclear"]},{"year":2017,"claim":"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","pmids":["29311819"],"confidence":"Medium","gaps":["Microglial receptor for sICAM-5 not identified","In vivo relevance to synaptic pruning untested"]},{"year":2019,"claim":"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","pmids":["31882402"],"confidence":"High","gaps":["Whether FMRP represses ICAM5 translation directly vs affecting stability not distinguished","Circuit-level basis of behavioral rescue unresolved"]},{"year":2019,"claim":"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","pmids":["31680833"],"confidence":"Medium","gaps":["Molecular determinants of the CLSTN1/ICAM-5 cargo interaction not mapped","Directionality (anterograde vs retrograde) of transport not resolved"]},{"year":2019,"claim":"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","pmids":["30915022"],"confidence":"Medium","gaps":["Cellular target of intrathecal sICAM-5 in the EAE context not pinpointed","Mechanistic overlap with the microglial anti-inflammatory pathway not directly tested"]},{"year":2020,"claim":"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","pmids":["32101770"],"confidence":"Medium","gaps":["Domain of ICAM-5 engaging the virus not mapped","Signal driving raft translocation upon infection unknown"]},{"year":2024,"claim":"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","pmids":["39352694"],"confidence":"Medium","gaps":["Endogenous (non-overexpression) interaction not confirmed","Whether GPM6a modulates ICAM-5 shedding or integrin signaling untested"]},{"year":2024,"claim":"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","pmids":["38228798"],"confidence":"Medium","gaps":["Mechanism by which promoter hypermethylation paradoxically activates transcription not explained","Whether ICAM5's adhesion/integrin functions contribute to oncogenesis untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,7,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,11,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,9,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,15]}],"complexes":[],"partners":["ITGAL","ITGB2","ITGB1","GRIN1","ACTN1","CLSTN1","GPM6A","FMR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMF0","full_name":"Intercellular adhesion molecule 5","aliases":["Telencephalin"],"length_aa":924,"mass_kda":97.1,"function":"Cell adhesion molecule that functions as a receptor ligand of the signaling receptor ITGAL:ITGB2/LFA-1 (lymphocyte-function associated (LFA) molecule 1) ensuring neuron cell-leukocyte adhesion (PubMed:8995416). Creates homophilic cell adhesion promoting dendritogenesis and arborization of hippocampal neurons (PubMed:10893271)","subcellular_location":"Cell membrane; Cell projection; Cell projection, uropodium; Cell projection, dendritic spine membrane","url":"https://www.uniprot.org/uniprotkb/Q9UMF0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ICAM5","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ICAM5","total_profiled":1310},"omim":[{"mim_id":"601852","title":"INTERCELLULAR ADHESION MOLECULE 5; ICAM5","url":"https://www.omim.org/entry/601852"},{"mim_id":"104311","title":"PRESENILIN 1; PSEN1","url":"https://www.omim.org/entry/104311"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":22.8}],"url":"https://www.proteinatlas.org/search/ICAM5"},"hgnc":{"alias_symbol":["TLN"],"prev_symbol":["TLCN"]},"alphafold":{"accession":"Q9UMF0","domains":[{"cath_id":"2.60.40.10","chopping":"37-118","consensus_level":"high","plddt":91.6623,"start":37,"end":118},{"cath_id":"2.60.40.10","chopping":"125-225","consensus_level":"medium","plddt":93.9644,"start":125,"end":225},{"cath_id":"2.60.40.10","chopping":"228-321","consensus_level":"medium","plddt":90.6122,"start":228,"end":321},{"cath_id":"2.60.40.10","chopping":"333-406","consensus_level":"high","plddt":91.2786,"start":333,"end":406},{"cath_id":"2.60.40.10","chopping":"411-490","consensus_level":"high","plddt":84.6061,"start":411,"end":490},{"cath_id":"2.60.40.10","chopping":"494-571","consensus_level":"high","plddt":85.269,"start":494,"end":571},{"cath_id":"2.60.40.10","chopping":"577-625_639-664","consensus_level":"high","plddt":84.8285,"start":577,"end":664},{"cath_id":"2.60.40.10","chopping":"666-743","consensus_level":"medium","plddt":83.8418,"start":666,"end":743},{"cath_id":"2.60.40.10","chopping":"745-830","consensus_level":"medium","plddt":85.8017,"start":745,"end":830}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMF0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMF0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMF0-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ICAM5","jax_strain_url":"https://www.jax.org/strain/search?query=ICAM5"},"sequence":{"accession":"Q9UMF0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMF0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMF0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMF0"}},"corpus_meta":[{"pmid":"17682049","id":"PMC_17682049","title":"Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17682049","citation_count":150,"is_preprint":false},{"pmid":"22523428","id":"PMC_22523428","title":"Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.","date":"2012","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22523428","citation_count":54,"is_preprint":false},{"pmid":"23015592","id":"PMC_23015592","title":"Interactions between ICAM-5 and β1 integrins regulate neuronal synapse formation.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23015592","citation_count":54,"is_preprint":false},{"pmid":"10741396","id":"PMC_10741396","title":"Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CD11a/CD18.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10741396","citation_count":52,"is_preprint":false},{"pmid":"18223167","id":"PMC_18223167","title":"Shedded neuronal ICAM-5 suppresses T-cell activation.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18223167","citation_count":49,"is_preprint":false},{"pmid":"22912716","id":"PMC_22912716","title":"MMPs and soluble ICAM-5 increase neuronal excitability within in vitro networks of hippocampal neurons.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22912716","citation_count":43,"is_preprint":false},{"pmid":"23844251","id":"PMC_23844251","title":"Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1.","date":"2013","source":"PloS 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Expression, and Function of ICAM-5.","date":"2012","source":"Comparative and functional genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22312318","citation_count":27,"is_preprint":false},{"pmid":"11026442","id":"PMC_11026442","title":"Release of the neuronal glycoprotein ICAM-5 in serum after hypoxic-ischemic injury.","date":"2000","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11026442","citation_count":22,"is_preprint":false},{"pmid":"32101770","id":"PMC_32101770","title":"Methyl-β-cyclodextrin inhibits EV-D68 virus entry by perturbing the accumulation of virus particles and ICAM-5 in lipid rafts.","date":"2020","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/32101770","citation_count":22,"is_preprint":false},{"pmid":"26789235","id":"PMC_26789235","title":"Icam5 Expression Exhibits Sex Differences in the Neonatal Pituitary and Is Regulated by Estradiol and Bisphenol 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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.\",\n      \"method\": \"Protein domain deletion constructs, monoclonal antibody blocking assays, T-cell adhesion assay to hippocampal neurons\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain deletion mutagenesis combined with antibody blocking in cell-based adhesion assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"10741396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"MMP inhibitors, siRNA knockdown of MMP-2/9, MMP-2/9 knockout mice, NMDA/AMPA stimulation of hippocampal neurons, immunoblotting, live imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mice, pharmacological inhibitors, siRNA, and functional spine morphology assays across multiple models\",\n      \"pmids\": [\"17682049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography of alphaL I domain / ICAM-5 D1–D2 complex\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mechanistic interpretation of integrin allostery, single rigorous paper with structural resolution\",\n      \"pmids\": [\"18691975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"T-cell activation assays (flow cytometry for activation markers), cytokine mRNA measurement, stimulation with purified sICAM-5\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional assays with defined readouts, single lab, two orthogonal methods (flow cytometry + mRNA)\",\n      \"pmids\": [\"18223167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from mouse brain, electrophysiology (mEPSC recordings), antibody perturbation, ICAM5 knockout neurons\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from brain tissue, electrophysiology, domain mapping, and KO functional readout in single study\",\n      \"pmids\": [\"23015592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Multielectrode array recordings, MMP inhibitors, β1 integrin blocking antibody, exogenous soluble ICAM-5 ectodomain application\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional MEA recordings with pharmacological tools, single lab, multiple orthogonal perturbations\",\n      \"pmids\": [\"22912716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell electrophysiology (mEPSC recordings), biotinylation/precipitation surface assays, immunostaining, exogenous ICAM-5 ectodomain application\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology + biochemical surface assay + imaging), single lab\",\n      \"pmids\": [\"23844251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography in three space groups, electrostatic surface analysis, crystal packing analysis\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure in three space groups with functional interpretation of homophilic adhesion, single rigorous structural study\",\n      \"pmids\": [\"25004970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion constructs, ICAM-5 KO neurons, peptide internalization assays, F-actin staining\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain deletions and KO validation, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"25572420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Microglia adhesion and phagocytosis assays, cytokine ELISA, ICAM-5-coated surface adhesion experiments, NMDA stimulation of neurons\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (adhesion, phagocytosis, cytokine secretion), single lab, orthogonal readouts\",\n      \"pmids\": [\"29311819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical FMRP-mRNA binding assay (RIP), in vivo AAV-shRNA knockdown, behavioral tests (Morris water maze, fear conditioning), dendritic spine morphology analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct FMRP-mRNA binding demonstrated biochemically, in vivo KD with cognitive behavioral rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31882402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging (co-transport), shRNA knockdown, surface biotinylation, dendritic spine morphology analysis in Fmr1 KO neurons\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue in KO neurons with multiple approaches, single lab\",\n      \"pmids\": [\"31680833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ICAM-5 knockout mouse EAE model, intrathecal sICAM-5 administration, clinical scoring, flow cytometry\",\n      \"journal\": \"Frontiers in neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined phenotype and rescue by intrathecal sICAM-5, single lab\",\n      \"pmids\": [\"30915022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Lipid raft fractionation, confocal co-localization, MβCD treatment, cholesterol rescue, viral entry/infection assays\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation plus functional entry assay with cholesterol rescue, single lab, multiple methods\",\n      \"pmids\": [\"32101770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, cell aggregation assay, immunostaining co-localization, overexpression in N2a cells and hippocampal neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP plus functional cell assays, single lab, two orthogonal binding methods\",\n      \"pmids\": [\"39352694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown of DNMT1/DNMT3a, ICAM5 overexpression rescue, pharmacological ERK/JNK inhibitors, proliferation/migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiment (DNMT KD + ICAM5 OE), pathway inhibitors, in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"38228798\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ICAM-5 (telencephalin) is a somatodendritic adhesion molecule that binds leukocyte/neuronal β1 and β2 (LFA-1/CD11a-CD18) integrins via its N-terminal Ig domains, maintains dendritic filopodia in an immature state by competing with GluN1 for α-actinin binding, and is cleaved by MMP-2/9 upon NMDA receptor activation, whereupon the soluble ectodomain engages β1 integrins to promote spine maturation, GluA1 surface insertion, and increased glutamatergic transmission, while also suppressing T-cell activation, microglial phagocytosis, and neuroinflammation; its expression is regulated post-transcriptionally by FMRP binding to its coding sequence mRNA and spatially by calsyntenin-1-dependent trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4]. Through its N-terminal Ig domains it binds the leukocyte integrin LFA-1 (CD11a/CD18)\\u2014with the first domain essential for the interaction and a second non-integrin binding site in the sixth domain\\u2014thereby mediating T-cell adhesion to hippocampal neurons [#0]; crystallographic analysis of the LFA-1 \\u03b1L I-domain bound to ICAM-5 D1\\u2013D2 reveals an unusually mobile \\u03b17 helix indicative of low-energy integrin conformational change [#2], while the curved D1\\u2013D4 architecture supports charge-based homophilic adhesion distinct from ICAM-1 [#7]. ICAM-5 restrains spine maturation by keeping dendritic filopodia immature: its cytoplasmic tail competes with the NMDA receptor subunit GluN1 for \\u03b1-actinin binding, and its loss or tail deletion frees GluN1/\\u03b1-actinin association to drive cytoskeletal reorganization [#8]. 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 \\u03b21 integrins\\u2014which co-immunoprecipitate with ICAM-5 via its first two Ig domains\\u2014to promote filopodial elongation, surface insertion and Ser845 phosphorylation of the GluA1 AMPAR subunit, increased mEPSC frequency, and elevated network excitability [#1, #4, #6, #5]. The shed ectodomain additionally acts on immune cells, attenuating TCR-driven T-cell activation [#3], serving as a 'don't-eat-me' and anti-inflammatory signal to microglia [#9], and conferring neuroprotection in autoimmune neuroinflammation [#12]. 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 [#10], while calsyntenin-1 co-transports ICAM-5 and limits its synaptic surface accumulation [#11]. ICAM-5 also functions outside the nervous system as an entry receptor co-opted by enterovirus D68 through lipid-raft translocation [#13] and is an aberrantly activated, MAPK/ERK- and JNK-driven oncogenic effector in thyroid carcinoma downstream of DNMT1/DNMT3a-mediated promoter hypermethylation [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established ICAM-5 as a functional adhesion receptor for leukocyte integrins, defining how immune cells dock onto telencephalic neurons.\",\n      \"evidence\": \"Domain-deletion constructs and antibody-blocking T-cell adhesion assays on hippocampal neurons\",\n      \"pmids\": [\"10741396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the physiological consequence of neuron-T-cell adhesion in vivo\", \"Nature of the non-integrin domain-6 binding partner unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"MMP inhibitors, MMP-2/9 siRNA and knockout mice, NMDA stimulation and live imaging of hippocampal neurons\",\n      \"pmids\": [\"17682049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating the soluble ectodomain's effect not yet identified\", \"Precise cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the structural basis of ICAM-5/LFA-1 recognition, revealing integrin allosteric mobility relevant to adhesion signaling.\",\n      \"evidence\": \"X-ray crystallography of the \\u03b1L I-domain bound to ICAM-5 D1\\u2013D2\",\n      \"pmids\": [\"18691975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure used a high-affinity engineered I-domain rather than physiological state\", \"Does not address homophilic or \\u03b21 integrin binding modes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that shed ICAM-5 feeds back onto the immune system to dampen T-cell activation, extending its role beyond adhesion to immunomodulation.\",\n      \"evidence\": \"T-cell activation flow cytometry, cytokine mRNA measurement, and purified sICAM-5 stimulation\",\n      \"pmids\": [\"18223167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on T cells transducing the sICAM-5 signal not defined\", \"In vivo relevance to neuroimmune crosstalk untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified \\u03b21 integrins as the neuronal receptor for shed ICAM-5 and connected the ICAM-5/\\u03b21 axis to synaptic contact formation and excitability.\",\n      \"evidence\": \"Reciprocal Co-IP from mouse brain, domain mapping, mEPSC recordings, multielectrode arrays, antibody perturbation and ICAM5 KO neurons\",\n      \"pmids\": [\"23015592\", \"22912716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether membrane vs soluble ICAM-5 engages \\u03b21 integrins in cis or trans not fully resolved\", \"Downstream integrin signaling intermediates not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the molecular output of ICAM-5/\\u03b21 signaling as selective GluA1 surface insertion and phosphorylation, providing a mechanism for potentiated glutamatergic transmission.\",\n      \"evidence\": \"mEPSC recordings, surface biotinylation, immunostaining and exogenous ectodomain application\",\n      \"pmids\": [\"23844251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Ser845 phosphorylation not identified\", \"Link to long-term plasticity in vivo not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed ICAM-5's curved multidomain architecture and electrostatic homophilic adhesion mode, distinguishing it mechanistically from ICAM-1.\",\n      \"evidence\": \"X-ray crystallography of D1\\u2013D4 in three space groups with electrostatic and crystal-packing analysis\",\n      \"pmids\": [\"25004970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of homophilic adhesion in neurons not tested\", \"D5 position inferred from modeling only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Explained how membrane ICAM-5 negatively gates spine maturation, via cytoplasmic competition with GluN1 for \\u03b1-actinin.\",\n      \"evidence\": \"Co-IP, cytoplasmic-tail deletion constructs, ICAM-5 KO neurons, peptide internalization and F-actin staining\",\n      \"pmids\": [\"25572420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct vs indirect \\u03b1-actinin binding not quantified\", \"How NMDA signaling switches \\u03b1-actinin partner preference mechanistically unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the soluble ICAM-5 signaling repertoire to microglia, identifying it as a 'don't-eat-me' and anti-inflammatory cue.\",\n      \"evidence\": \"Microglial adhesion and phagocytosis assays, cytokine ELISA and ICAM-5-coated surface experiments\",\n      \"pmids\": [\"29311819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Microglial receptor for sICAM-5 not identified\", \"In vivo relevance to synaptic pruning untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed ICAM5 downstream of FMRP translational control and demonstrated its causal contribution to fragile-X-like cognitive and spine phenotypes.\",\n      \"evidence\": \"FMRP-mRNA binding (RIP), in vivo AAV-shRNA knockdown with Morris water maze and fear conditioning, spine morphology in Fmr1 KO mice\",\n      \"pmids\": [\"31882402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FMRP represses ICAM5 translation directly vs affecting stability not distinguished\", \"Circuit-level basis of behavioral rescue unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified calsyntenin-1 as a trafficking partner that controls ICAM-5 synaptic surface abundance and links its mislocalization to fragile-X spine defects.\",\n      \"evidence\": \"Co-IP, live-cell co-transport imaging, shRNA knockdown, surface biotinylation and spine analysis in Fmr1 KO neurons\",\n      \"pmids\": [\"31680833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinants of the CLSTN1/ICAM-5 cargo interaction not mapped\", \"Directionality (anterograde vs retrograde) of transport not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a neuroprotective role for ICAM-5 in progressive neuroinflammation, with soluble ICAM-5 ameliorating autoimmune demyelinating disease.\",\n      \"evidence\": \"ICAM-5 KO EAE model, intrathecal sICAM-5 administration, clinical scoring and flow cytometry\",\n      \"pmids\": [\"30915022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular target of intrathecal sICAM-5 in the EAE context not pinpointed\", \"Mechanistic overlap with the microglial anti-inflammatory pathway not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a pathogen-hijacked function of ICAM-5 as an EV-D68 entry receptor dependent on lipid-raft translocation.\",\n      \"evidence\": \"Lipid raft fractionation, confocal co-localization, M\\u03b2CD disruption with cholesterol rescue and viral entry assays\",\n      \"pmids\": [\"32101770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain of ICAM-5 engaging the virus not mapped\", \"Signal driving raft translocation upon infection unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified GPM6a as a cis/trans interaction partner of ICAM-5 cooperating in neurite and filopodia outgrowth.\",\n      \"evidence\": \"Reciprocal Co-IP, cell aggregation assays, co-localization and co-overexpression in N2a cells and hippocampal neurons\",\n      \"pmids\": [\"39352694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-overexpression) interaction not confirmed\", \"Whether GPM6a modulates ICAM-5 shedding or integrin signaling untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an oncogenic, MAPK-driven role for aberrantly activated ICAM5 in thyroid carcinoma controlled by DNMT-mediated promoter methylation.\",\n      \"evidence\": \"DNMT1/DNMT3a shRNA knockdown with ICAM5 overexpression rescue, ERK/JNK inhibitors, proliferation/migration/invasion assays and xenografts\",\n      \"pmids\": [\"38228798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which promoter hypermethylation paradoxically activates transcription not explained\", \"Whether ICAM5's adhesion/integrin functions contribute to oncogenesis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 7, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 11, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 9, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGAL\", \"ITGB2\", \"ITGB1\", \"GRIN1\", \"ACTN1\", \"CLSTN1\", \"GPM6A\", \"FMR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}