{"gene":"CADM4","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2007,"finding":"Necl4 (CADM4) is expressed by myelinating Schwann cells along the internodes and serves as the glial binding partner for axonal Necl1 (CADM3); the heterophilic trans-interaction between Necl4 and Necl1 mediates Schwann cell adhesion to axons. Disruption of this interaction using soluble extracellular domains or expression of dominant-negative Necl4 in Schwann cells inhibits peripheral nervous system myelination.","method":"Soluble extracellular domain competition assay, dominant-negative overexpression in Schwann cells, co-culture myelination assay, immunofluorescence localization","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, dominant-negative inhibition, and in vitro myelination readout; independently replicated by multiple subsequent studies","pmids":["17558405"],"is_preprint":false},{"year":2013,"finding":"Genetic deletion of Cadm4 specifically in Schwann cells (DHH-Cre/Cadm4(fl/fl)) or expression of a dominant-negative Cadm4 lacking its cytoplasmic domain (Tg(mbp-Cadm4dCT)) causes focal hypermyelination (tomacula and myelin outfoldings), abnormal axon-glial contact, redistribution of ion channels along the axon, impaired motor function, and slower nerve conduction velocity; Cadm4's cytoplasmic domain is required for normal myelin unit growth and axonal membrane organization in the PNS.","method":"Conditional knockout (Cre/lox), dominant-negative transgenic mice, electron microscopy, immunostaining of ion channels, nerve conduction velocity measurements, behavioral assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (full KO, Schwann cell-specific KO, dominant-negative transgenic) with orthogonal functional and structural readouts in a single study","pmids":["23825401"],"is_preprint":false},{"year":2001,"finding":"TSLL2 (CADM4) encodes a transmembrane immunoglobulin superfamily protein; its expression is lost or markedly reduced in human glioma cell lines and some prostate cancer cell lines, and its cytoplasmic domain shows structural homology to the tumor suppressor TSLC1, suggesting functional relevance of this domain.","method":"cDNA cloning, structural homology analysis, expression analysis in cancer cell lines","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 4 / Weak — initial cloning and expression survey; no direct functional/mechanistic experiment performed on this protein","pmids":["11536053"],"is_preprint":false},{"year":2006,"finding":"TSLL2/CADM4 protein localizes to lateral membranes in polarized MDCK cells, forms homodimers, and induces Ca2+/Mg2+-independent cell aggregation upon overexpression, indicating homophilic trans-interaction. Introduction of TSLL2 into a prostate cancer cell line (PPC-1) strongly suppresses subcutaneous tumor formation in nude mice.","method":"Confocal microscopy of polarized cells, cell aggregation assay, homodimerization (pulldown/co-IP), xenograft tumor suppression assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment, cell aggregation functional assay, and in vivo tumor suppression assay in a single study; single lab","pmids":["16261159"],"is_preprint":false},{"year":2011,"finding":"CADM4 associates in cis with the actin-binding protein 4.1B (but not 4.1N) in normal human kidney proximal tubule lysates, as shown by immunoprecipitation. Introduction of CADM4 into a renal cell carcinoma line (786-O) suppresses tumor formation in nude mice, supporting a tumor suppressor function.","method":"Immunoprecipitation/Western blotting from human kidney lysates, xenograft tumor suppression assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP from native tissue plus in vivo tumor assay; single lab, two orthogonal methods","pmids":["21544807"],"is_preprint":false},{"year":2013,"finding":"Necl-4/CADM4 interacts in cis with ErbB3 through their extracellular regions, recruits PTPN13, and inhibits heregulin-induced activation of ErbB2/ErbB3 signaling. Additionally, Necl-4 interacts in cis with integrin α6β4 through extracellular regions and inhibits phorbol ester-induced disassembly of hemidesmosomes.","method":"Co-immunoprecipitation, pulldown assay, phosphorylation assays for ErbB2/ErbB3 downstream signaling, hemidesmosome disassembly assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP for binding partners and functional signaling readout; single lab","pmids":["23611113"],"is_preprint":false},{"year":2013,"finding":"In the CNS, genetic knockout of Necl-4/Cadm4 does not affect oligodendrocyte differentiation, myelin formation, or PNS myelination in developing mice, indicating that Cadm4 is dispensable for CNS and PNS axonal myelination under these conditions.","method":"Necl4 knockout mouse generation, immunostaining of myelin markers, electron microscopy of PNS and CNS myelin","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with structural and immunostaining readouts; single lab; contradicts PNS findings from other groups (NEGATIVE result noted)","pmids":["23700466"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, cadm4 knockdown dramatically expands the cardiac outflow tract (OFT) while overexpression greatly diminishes it; cadm4 limits the production of OFT progenitor cells and the duration of their accumulation at the arterial pole, placing Cadm4 as a regulator of second heart field deployment.","method":"Morpholino knockdown, mRNA overexpression, cardiac progenitor cell quantification, live imaging in zebrafish","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function in zebrafish with quantitative progenitor cell readout; single lab","pmids":["24813897"],"is_preprint":false},{"year":2015,"finding":"In confluent vascular endothelial cells, Necl-4/CADM4 is upregulated and localizes at cell-cell contact sites where it cis-interacts with VEGFR2, recruiting PTPN13 to inhibit VEGFR2 tyrosine phosphorylation and reduce cell movement and proliferation. In sparse cells, Necl-4 accumulates at leading edges where it inhibits ROCK via PTPN13, facilitating VEGF-induced Rac1 activation and ERK1/2 activation to enhance movement and proliferation.","method":"Co-immunoprecipitation (Necl-4 with VEGFR2), knockdown experiments, VEGFR2 phosphorylation assays, Rac1 and ROCK activity assays, cell migration and proliferation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding, knockdown with defined signaling readouts, multiple pathway components tested; single lab","pmids":["25893857"],"is_preprint":false},{"year":2017,"finding":"Necl-4/CADM4 enhances VEGF-induced activation of the PLCγ-c-Raf-MEK-ERK signaling pathway in endothelial cells without affecting VEGFR2 phosphorylation or internalization; this effect is independent of PTPN13 or ROCK.","method":"siRNA knockdown of Necl-4, phosphorylation assays for PLCγ, c-Raf, MEK, ERK and VEGFR2, VEGFR2 internalization assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple downstream phosphorylation readouts; single lab, single method type","pmids":["28601637"],"is_preprint":false},{"year":2018,"finding":"Cadm4/Necl-4 expressed by oligodendrocytes promotes formation of axoglial contact sites, but excessive adhesion via a membrane-bound extracellular domain (Cadm4dCT) prevents myelin elongation. Transgenic mice expressing Cadm4dCT in oligodendrocytes are hypomyelinated and show myelination of neuronal somata; these abnormalities require specific neuron-glial interaction and depend on axonal Cadm receptors (Cadm3/Necl-1 and Cadm2/Necl-3).","method":"Transgenic mouse overexpression, cultured oligodendrocyte-neuron co-culture, nanofiber culture, knockout of axonal Cadm receptors, electron microscopy, immunostaining","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (transgenic OE, axonal receptor KO), in vitro and in vivo readouts, orthogonal experiments distinguishing cell-autonomous vs. contact-dependent effects","pmids":["30551998"],"is_preprint":false},{"year":2018,"finding":"The cytoplasmic terminal region (CTR) of Necl-4/Cadm4 contains a PDZ-binding motif that directly binds the first PDZ domain of Par-3. Necl-4 and Par-3 colocalize along the inner (adaxonal) Schwann cell membrane and co-precipitate from Schwann cell lysates. Knockdown of Necl-4 perturbs Par-3 localization to the inner Schwann cell membrane in myelinating co-cultures, implicating Necl-1/Necl-4 interaction in recruiting Par-3 to establish Schwann cell radial polarity.","method":"Unbiased proteomic PDZ-domain screen with Necl-4 CTR, co-immunoprecipitation from Schwann cell lysates, immunofluorescence colocalization, siRNA knockdown in myelinating co-cultures","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic screen plus reciprocal co-IP plus functional KD with localization readout; multiple orthogonal methods in one study","pmids":["30585357"],"is_preprint":false},{"year":2022,"finding":"Cadm4 forms a complex with Mpp6 (Pals2), protein band 4.1G (Epb41l2), and Lin7 in Schmidt-Lanterman incisures (SLIs) of peripheral nerve myelin, as identified by mass spectrometry-based proteomics of purified myelin. This complex is increased in aged FA2H-deficient mouse sciatic nerves alongside increased SLI frequency.","method":"Mass spectrometry-based proteomics of purified myelin, quantitative protein analysis, SLI counting by electron/light microscopy","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS proteomics of purified myelin fractions identifies complex members; indirect evidence of complex enrichment; single study","pmids":["35445918"],"is_preprint":false},{"year":2024,"finding":"Cadm4 undergoes palmitoylation at cysteine-347 (C347), catalyzed by ZDHHC3, which is required for stable Cadm4 localization at the plasma membrane. Mutation C347A blocks palmitoylation, causes Cadm4 internalization and degradation. Cadm4-KI (C347A knock-in) mice show severe CNS myelin abnormalities (loss, demyelination, hypermyelination), impaired neuronal transmission, and cognitive deficits. Genetic deletion of ZDHHC3 reduces Cadm4 palmitoylation and causes CNS myelination defects phenocopying Cadm4-KI. Cadm4 may regulate oligodendrocyte differentiation via the WNT-β-Catenin pathway.","method":"Site-directed mutagenesis (C347A), palmitoylation assay, knock-in mouse model, ZDHHC3 knockout mice, plasma membrane fractionation, electron microscopy, electrophysiology, behavioral assays","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis identifies specific palmitoylation site, enzymatic writer (ZDHHC3) identified, two independent in vivo genetic models phenocopy each other, multiple orthogonal readouts","pmids":["39327467"],"is_preprint":false},{"year":2025,"finding":"Necl-4/CADM4 is expressed in GABAergic inhibitory neurons and localizes at GABAergic synapses on inhibitory neurons in the hippocampus. Genetic ablation of Necl-4 increases GABAergic synapse density on inhibitory neurons and enhances GABAergic synaptic currents, effects mediated through ErbB4 activation. This leads to high-frequency firing, excitotoxicity-mediated neuronal death, and hippocampal neuronal loss with synaptic degeneration.","method":"Necl-4 KO mouse, immunofluorescence of hippocampal neurons and cultured neurons, electrophysiology (mIPSC recording), ErbB4 activation assays, cell death assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with electrophysiological readout and ErbB4 pathway activation identified; single lab, multiple methods","pmids":["40728771"],"is_preprint":false}],"current_model":"CADM4 (Necl-4/SynCAM4) is a transmembrane immunoglobulin superfamily cell adhesion molecule that mediates heterophilic trans-interaction with axonal CADM3/Necl-1 to govern Schwann cell–axon contact and PNS myelination, with its cytoplasmic domain recruiting the polarity protein Par-3 to the adaxonal membrane; in the CNS, tightly regulated Cadm4-mediated axoglial adhesion is required for proper myelin targeting and wrapping by oligodendrocytes; Cadm4 plasma membrane stability is maintained by ZDHHC3-catalyzed palmitoylation at C347, loss of which causes severe CNS demyelination; additionally, Cadm4 cis-interacts with VEGFR2, ErbB3, and integrin α6β4 to modulate growth factor signaling and contact inhibition via PTPN13, and at GABAergic synapses on inhibitory neurons it restrains ErbB4-dependent synaptic strengthening to prevent excitotoxic neuronal death."},"narrative":{"mechanistic_narrative":"CADM4 (Necl-4/SynCAM4/TSLL2) is a transmembrane immunoglobulin-superfamily cell adhesion molecule that governs glia–axon contact during myelination and modulates contact-dependent growth factor signaling [PMID:17558405, PMID:23611113]. In the peripheral nervous system, CADM4 expressed by myelinating Schwann cells mediates heterophilic trans-adhesion to axonal CADM3/Necl-1, and disruption of this interaction inhibits myelination [PMID:17558405]; its cytoplasmic domain is required for normal myelin growth and axonal membrane organization, with loss producing focal hypermyelination, disordered ion channel distribution, and slowed nerve conduction [PMID:23825401]. This cytoplasmic domain carries a PDZ-binding motif that directly engages the first PDZ domain of Par-3, recruiting it to the adaxonal Schwann cell membrane to establish radial glial polarity [PMID:30585357]. In the CNS, oligodendroglial CADM4 promotes axoglial contact, and the balance of adhesion must be tightly regulated, as excessive adhesion blocks myelin elongation and mistargets myelin onto neuronal somata in a manner dependent on axonal Cadm receptors [PMID:30551998]. CADM4 plasma membrane stability requires ZDHHC3-catalyzed palmitoylation at cysteine-347; abolishing this modification triggers internalization and degradation and causes severe CNS demyelination, impaired transmission, and cognitive deficits [PMID:39327467]. Beyond myelination, CADM4 acts in cis with ErbB3, integrin α6β4, and VEGFR2 to restrain or shape growth factor signaling, in several cases by recruiting the phosphatase PTPN13 [PMID:23611113, PMID:25893857], and at hippocampal GABAergic synapses it restrains ErbB4-dependent synaptic strengthening to prevent excitotoxic neuronal death [PMID:40728771]. Reintroduction of CADM4 suppresses tumor formation in prostate and renal carcinoma xenografts, consistent with a tumor-suppressor role [PMID:16261159, PMID:21544807].","teleology":[{"year":2006,"claim":"Established that CADM4 is a functional adhesion molecule with homophilic trans-interaction capacity and an in vivo tumor-suppressing activity, moving it beyond a cloned sequence to a candidate functional protein.","evidence":"Polarized MDCK localization, cell aggregation assay, homodimerization pulldown, and prostate cancer xenograft suppression","pmids":["16261159"],"confidence":"Medium","gaps":["Homophilic adhesion later contrasts with heterophilic axon-glia adhesion; cis vs trans contexts not unified","Molecular basis of tumor suppression not defined"]},{"year":2007,"claim":"Defined CADM4's primary physiological role by showing it is the Schwann cell partner for axonal CADM3, mediating the adhesion required for PNS myelination.","evidence":"Soluble extracellular domain competition, dominant-negative overexpression, and co-culture myelination assay","pmids":["17558405"],"confidence":"High","gaps":["Cytoplasmic signaling downstream of adhesion not yet defined","Whether adhesion is purely structural or instructive unclear"]},{"year":2011,"claim":"Linked CADM4 to the actin cytoskeleton and reinforced tumor suppression, showing a cis association with protein 4.1B in native kidney tissue.","evidence":"Co-immunoprecipitation from human kidney lysates and renal carcinoma xenograft suppression","pmids":["21544807"],"confidence":"Medium","gaps":["Functional consequence of 4.1B binding not tested","Single lab, no reciprocal validation"]},{"year":2013,"claim":"Demonstrated that the CADM4 cytoplasmic domain is required for normal myelin unit growth and axonal membrane organization, distinguishing adhesion from intracellular signaling functions.","evidence":"Schwann cell-specific conditional knockout and cytoplasmic-domain-deleted dominant-negative transgenic mice with EM, ion channel immunostaining, and nerve conduction measurements","pmids":["23825401"],"confidence":"High","gaps":["Cytoplasmic effector mediating the phenotype not yet identified","Mechanism of ion channel redistribution unresolved"]},{"year":2013,"claim":"Identified CADM4 as a cis-acting brake on receptor signaling, binding ErbB3 and integrin α6β4 and recruiting PTPN13 to dampen heregulin signaling and stabilize hemidesmosomes.","evidence":"Reciprocal co-IP, pulldown, ErbB2/ErbB3 phosphorylation assays, and hemidesmosome disassembly assay","pmids":["23611113"],"confidence":"Medium","gaps":["Single lab without in vivo confirmation","Relevance to myelinating cells not tested"]},{"year":2013,"claim":"Raised a discrepancy regarding CADM4 requirement, with one knockout reporting it dispensable for both CNS and PNS myelination.","evidence":"Necl4 knockout mouse with myelin marker immunostaining and EM of PNS and CNS","pmids":["23700466"],"confidence":"Medium","gaps":["Negative result conflicts with PNS phenotypes from other groups","Knockout strategy and developmental window differences unresolved"]},{"year":2014,"claim":"Extended CADM4 function to organogenesis, showing it limits second heart field progenitor deployment to the cardiac outflow tract.","evidence":"Morpholino knockdown and mRNA overexpression with progenitor quantification and live imaging in zebrafish","pmids":["24813897"],"confidence":"Medium","gaps":["Molecular partners in heart field unknown","Conservation in mammalian heart development not tested"]},{"year":2015,"claim":"Showed CADM4 signaling is context-dependent, acting through VEGFR2 and PTPN13 to inhibit endothelial movement at confluence but promote it at sparse leading edges.","evidence":"Co-IP, knockdown, VEGFR2 phosphorylation, Rac1/ROCK activity, and migration/proliferation assays","pmids":["25893857"],"confidence":"Medium","gaps":["Switch mechanism between confluent and sparse states unclear","Single lab"]},{"year":2017,"claim":"Refined the VEGF signaling model by showing a PTPN13/ROCK-independent CADM4 enhancement of the PLCγ–c-Raf–MEK–ERK cascade.","evidence":"siRNA knockdown with PLCγ, c-Raf, MEK, ERK, and VEGFR2 phosphorylation and internalization assays","pmids":["28601637"],"confidence":"Medium","gaps":["Direct molecular link to PLCγ pathway not defined","Single method type"]},{"year":2018,"claim":"Established that CNS myelination requires tightly tuned CADM4 adhesion, with excessive oligodendroglial adhesion blocking myelin elongation and mistargeting myelin to somata via axonal Cadm receptors.","evidence":"Cadm4dCT transgenic mice, oligodendrocyte-neuron and nanofiber co-cultures, axonal Cadm receptor knockouts, EM and immunostaining","pmids":["30551998"],"confidence":"High","gaps":["Intracellular signal controlling elongation not identified","Reconciliation with the earlier dispensable-CNS result incomplete"]},{"year":2018,"claim":"Identified the cytoplasmic effector linking CADM4 adhesion to polarity, showing its PDZ-binding motif directly recruits Par-3 to the adaxonal membrane.","evidence":"Unbiased PDZ-domain proteomic screen, co-IP from Schwann cell lysates, colocalization, and siRNA knockdown with Par-3 localization readout","pmids":["30585357"],"confidence":"High","gaps":["Downstream polarity machinery beyond Par-3 not mapped","Link to ion channel phenotypes not established"]},{"year":2022,"claim":"Placed CADM4 in a defined membrane scaffold complex at Schmidt-Lanterman incisures with Mpp6, band 4.1G, and Lin7.","evidence":"Mass spectrometry proteomics of purified myelin with quantitative analysis and SLI counting","pmids":["35445918"],"confidence":"Medium","gaps":["Functional role of the complex not tested","Co-enrichment is indirect evidence of a stable complex"]},{"year":2024,"claim":"Defined a post-translational mechanism stabilizing CADM4, showing ZDHHC3-catalyzed palmitoylation at C347 maintains plasma membrane localization and is required for CNS myelin integrity.","evidence":"C347A mutagenesis, palmitoylation assays, knock-in and ZDHHC3-knockout mice that phenocopy, membrane fractionation, EM, electrophysiology, and behavioral assays","pmids":["39327467"],"confidence":"High","gaps":["Mechanistic link to WNT-β-catenin in oligodendrocyte differentiation not fully resolved","Regulation of palmitoylation dynamics unknown"]},{"year":2025,"claim":"Extended CADM4 to synaptic regulation, showing it restrains ErbB4-dependent GABAergic synapse strengthening on inhibitory neurons to prevent excitotoxic death.","evidence":"Necl-4 knockout mice, mIPSC recording, ErbB4 activation assays, and cell death assays in hippocampal neurons","pmids":["40728771"],"confidence":"Medium","gaps":["Direct CADM4–ErbB4 interaction not biochemically demonstrated","Single lab"]},{"year":null,"claim":"How CADM4's adhesion, cytoplasmic scaffolding (Par-3, 4.1 proteins), palmitoylation-dependent stability, and diverse cis-receptor signaling roles are integrated into a single regulatory logic across glia, endothelium, heart, and neurons remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of cis vs trans interactions","Discrepancy between dispensable and required myelination phenotypes not fully reconciled","Direct synaptic ErbB4 interaction unverified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8,13]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,9]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,10,14]}],"complexes":["Cadm4-Mpp6(Pals2)-band 4.1G(Epb41l2)-Lin7 complex (Schmidt-Lanterman incisures)"],"partners":["CADM3","CADM2","PARD3","ERBB3","ITGB4","KDR","PTPN13","ZDHHC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFZ8","full_name":"Cell adhesion molecule 4","aliases":["Immunoglobulin superfamily member 4C","IgSF4C","Nectin-like protein 4","NECL-4","TSLC1-like protein 2"],"length_aa":388,"mass_kda":42.8,"function":"Involved in the cell-cell adhesion. Has calcium- and magnesium-independent cell-cell adhesion activity. May have tumor-suppressor activity","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8NFZ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CADM4","classification":"Not Classified","n_dependent_lines":204,"n_total_lines":1208,"dependency_fraction":0.16887417218543047},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CADM4","total_profiled":1310},"omim":[{"mim_id":"619519","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2FF; CMT2FF","url":"https://www.omim.org/entry/619519"},{"mim_id":"609744","title":"CELL ADHESION MOLECULE 4; CADM4","url":"https://www.omim.org/entry/609744"},{"mim_id":"609743","title":"CELL ADHESION MOLECULE 3; CADM3","url":"https://www.omim.org/entry/609743"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":203.4}],"url":"https://www.proteinatlas.org/search/CADM4"},"hgnc":{"alias_symbol":["TSLL2","Necl-4","SynCAM4"],"prev_symbol":["IGSF4C"]},"alphafold":{"accession":"Q8NFZ8","domains":[{"cath_id":"2.60.40.10","chopping":"25-120","consensus_level":"high","plddt":94.7828,"start":25,"end":120},{"cath_id":"2.60.40.10","chopping":"127-220","consensus_level":"high","plddt":96.4123,"start":127,"end":220},{"cath_id":"2.60.40.10","chopping":"222-308","consensus_level":"high","plddt":94.0337,"start":222,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFZ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFZ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFZ8-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CADM4","jax_strain_url":"https://www.jax.org/strain/search?query=CADM4"},"sequence":{"accession":"Q8NFZ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFZ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFZ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFZ8"}},"corpus_meta":[{"pmid":"17558405","id":"PMC_17558405","title":"A central role for Necl4 (SynCAM4) in Schwann cell-axon interaction and myelination.","date":"2007","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17558405","citation_count":159,"is_preprint":false},{"pmid":"23825401","id":"PMC_23825401","title":"Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23825401","citation_count":64,"is_preprint":false},{"pmid":"11536053","id":"PMC_11536053","title":"Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane proteins.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11536053","citation_count":61,"is_preprint":false},{"pmid":"30551998","id":"PMC_30551998","title":"Axoglial Adhesion by Cadm4 Regulates CNS Myelination.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30551998","citation_count":56,"is_preprint":false},{"pmid":"21544807","id":"PMC_21544807","title":"Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21544807","citation_count":53,"is_preprint":false},{"pmid":"16261159","id":"PMC_16261159","title":"Cell adhesion and prostate tumor-suppressor activity of TSLL2/IGSF4C, an immunoglobulin superfamily molecule homologous to TSLC1/IGSF4.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16261159","citation_count":46,"is_preprint":false},{"pmid":"24813897","id":"PMC_24813897","title":"Cadm4 restricts the production of cardiac outflow tract progenitor cells.","date":"2014","source":"Cell 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membrane.","date":"2018","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/30585357","citation_count":15,"is_preprint":false},{"pmid":"22718847","id":"PMC_22718847","title":"Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas.","date":"2012","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22718847","citation_count":15,"is_preprint":false},{"pmid":"14659875","id":"PMC_14659875","title":"Isolation of the mouse Tsll1 and Tsll2 genes, orthologues of the human TSLC1-like genes 1 and 2 (TSLL1 and TSLL2).","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14659875","citation_count":12,"is_preprint":false},{"pmid":"27980052","id":"PMC_27980052","title":"Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma.","date":"2016","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27980052","citation_count":10,"is_preprint":false},{"pmid":"23559354","id":"PMC_23559354","title":"Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast.","date":"2013","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23559354","citation_count":8,"is_preprint":false},{"pmid":"28601637","id":"PMC_28601637","title":"Necl-4 enhances the PLCγ-c-Raf-MEK-ERK pathway without affecting internalization of VEGFR2.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28601637","citation_count":7,"is_preprint":false},{"pmid":"28561015","id":"PMC_28561015","title":"Necl 4 and RNase 5 Are Important Biomarkers for Gastric and Colon Adenocarcinomas.","date":"2017","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/28561015","citation_count":4,"is_preprint":false},{"pmid":"35445918","id":"PMC_35445918","title":"Age-Dependent Increase in Schmidt-Lanterman Incisures and a Cadm4-Associated Membrane Skeletal Complex in Fatty Acid 2-hydroxylase Deficient Mice: a Mouse Model of Spastic Paraplegia SPG35.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35445918","citation_count":3,"is_preprint":false},{"pmid":"40728771","id":"PMC_40728771","title":"Necl-4/CADM4 regulates GABAergic synaptic strength on GABAergic inhibitory neurons via ErbB4 activation and prevents neuronal impairments.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40728771","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12666,"output_tokens":4298,"usd":0.051234,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12175,"output_tokens":4484,"usd":0.086487,"stage2_stop_reason":"end_turn"},"total_usd":0.137721,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Necl4 (CADM4) is expressed by myelinating Schwann cells along the internodes and serves as the glial binding partner for axonal Necl1 (CADM3); the heterophilic trans-interaction between Necl4 and Necl1 mediates Schwann cell adhesion to axons. Disruption of this interaction using soluble extracellular domains or expression of dominant-negative Necl4 in Schwann cells inhibits peripheral nervous system myelination.\",\n      \"method\": \"Soluble extracellular domain competition assay, dominant-negative overexpression in Schwann cells, co-culture myelination assay, immunofluorescence localization\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, dominant-negative inhibition, and in vitro myelination readout; independently replicated by multiple subsequent studies\",\n      \"pmids\": [\"17558405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genetic deletion of Cadm4 specifically in Schwann cells (DHH-Cre/Cadm4(fl/fl)) or expression of a dominant-negative Cadm4 lacking its cytoplasmic domain (Tg(mbp-Cadm4dCT)) causes focal hypermyelination (tomacula and myelin outfoldings), abnormal axon-glial contact, redistribution of ion channels along the axon, impaired motor function, and slower nerve conduction velocity; Cadm4's cytoplasmic domain is required for normal myelin unit growth and axonal membrane organization in the PNS.\",\n      \"method\": \"Conditional knockout (Cre/lox), dominant-negative transgenic mice, electron microscopy, immunostaining of ion channels, nerve conduction velocity measurements, behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (full KO, Schwann cell-specific KO, dominant-negative transgenic) with orthogonal functional and structural readouts in a single study\",\n      \"pmids\": [\"23825401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TSLL2 (CADM4) encodes a transmembrane immunoglobulin superfamily protein; its expression is lost or markedly reduced in human glioma cell lines and some prostate cancer cell lines, and its cytoplasmic domain shows structural homology to the tumor suppressor TSLC1, suggesting functional relevance of this domain.\",\n      \"method\": \"cDNA cloning, structural homology analysis, expression analysis in cancer cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — initial cloning and expression survey; no direct functional/mechanistic experiment performed on this protein\",\n      \"pmids\": [\"11536053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TSLL2/CADM4 protein localizes to lateral membranes in polarized MDCK cells, forms homodimers, and induces Ca2+/Mg2+-independent cell aggregation upon overexpression, indicating homophilic trans-interaction. Introduction of TSLL2 into a prostate cancer cell line (PPC-1) strongly suppresses subcutaneous tumor formation in nude mice.\",\n      \"method\": \"Confocal microscopy of polarized cells, cell aggregation assay, homodimerization (pulldown/co-IP), xenograft tumor suppression assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment, cell aggregation functional assay, and in vivo tumor suppression assay in a single study; single lab\",\n      \"pmids\": [\"16261159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CADM4 associates in cis with the actin-binding protein 4.1B (but not 4.1N) in normal human kidney proximal tubule lysates, as shown by immunoprecipitation. Introduction of CADM4 into a renal cell carcinoma line (786-O) suppresses tumor formation in nude mice, supporting a tumor suppressor function.\",\n      \"method\": \"Immunoprecipitation/Western blotting from human kidney lysates, xenograft tumor suppression assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP from native tissue plus in vivo tumor assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"21544807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Necl-4/CADM4 interacts in cis with ErbB3 through their extracellular regions, recruits PTPN13, and inhibits heregulin-induced activation of ErbB2/ErbB3 signaling. Additionally, Necl-4 interacts in cis with integrin α6β4 through extracellular regions and inhibits phorbol ester-induced disassembly of hemidesmosomes.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, phosphorylation assays for ErbB2/ErbB3 downstream signaling, hemidesmosome disassembly assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP for binding partners and functional signaling readout; single lab\",\n      \"pmids\": [\"23611113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the CNS, genetic knockout of Necl-4/Cadm4 does not affect oligodendrocyte differentiation, myelin formation, or PNS myelination in developing mice, indicating that Cadm4 is dispensable for CNS and PNS axonal myelination under these conditions.\",\n      \"method\": \"Necl4 knockout mouse generation, immunostaining of myelin markers, electron microscopy of PNS and CNS myelin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with structural and immunostaining readouts; single lab; contradicts PNS findings from other groups (NEGATIVE result noted)\",\n      \"pmids\": [\"23700466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, cadm4 knockdown dramatically expands the cardiac outflow tract (OFT) while overexpression greatly diminishes it; cadm4 limits the production of OFT progenitor cells and the duration of their accumulation at the arterial pole, placing Cadm4 as a regulator of second heart field deployment.\",\n      \"method\": \"Morpholino knockdown, mRNA overexpression, cardiac progenitor cell quantification, live imaging in zebrafish\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function in zebrafish with quantitative progenitor cell readout; single lab\",\n      \"pmids\": [\"24813897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In confluent vascular endothelial cells, Necl-4/CADM4 is upregulated and localizes at cell-cell contact sites where it cis-interacts with VEGFR2, recruiting PTPN13 to inhibit VEGFR2 tyrosine phosphorylation and reduce cell movement and proliferation. In sparse cells, Necl-4 accumulates at leading edges where it inhibits ROCK via PTPN13, facilitating VEGF-induced Rac1 activation and ERK1/2 activation to enhance movement and proliferation.\",\n      \"method\": \"Co-immunoprecipitation (Necl-4 with VEGFR2), knockdown experiments, VEGFR2 phosphorylation assays, Rac1 and ROCK activity assays, cell migration and proliferation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding, knockdown with defined signaling readouts, multiple pathway components tested; single lab\",\n      \"pmids\": [\"25893857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Necl-4/CADM4 enhances VEGF-induced activation of the PLCγ-c-Raf-MEK-ERK signaling pathway in endothelial cells without affecting VEGFR2 phosphorylation or internalization; this effect is independent of PTPN13 or ROCK.\",\n      \"method\": \"siRNA knockdown of Necl-4, phosphorylation assays for PLCγ, c-Raf, MEK, ERK and VEGFR2, VEGFR2 internalization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple downstream phosphorylation readouts; single lab, single method type\",\n      \"pmids\": [\"28601637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cadm4/Necl-4 expressed by oligodendrocytes promotes formation of axoglial contact sites, but excessive adhesion via a membrane-bound extracellular domain (Cadm4dCT) prevents myelin elongation. Transgenic mice expressing Cadm4dCT in oligodendrocytes are hypomyelinated and show myelination of neuronal somata; these abnormalities require specific neuron-glial interaction and depend on axonal Cadm receptors (Cadm3/Necl-1 and Cadm2/Necl-3).\",\n      \"method\": \"Transgenic mouse overexpression, cultured oligodendrocyte-neuron co-culture, nanofiber culture, knockout of axonal Cadm receptors, electron microscopy, immunostaining\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (transgenic OE, axonal receptor KO), in vitro and in vivo readouts, orthogonal experiments distinguishing cell-autonomous vs. contact-dependent effects\",\n      \"pmids\": [\"30551998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The cytoplasmic terminal region (CTR) of Necl-4/Cadm4 contains a PDZ-binding motif that directly binds the first PDZ domain of Par-3. Necl-4 and Par-3 colocalize along the inner (adaxonal) Schwann cell membrane and co-precipitate from Schwann cell lysates. Knockdown of Necl-4 perturbs Par-3 localization to the inner Schwann cell membrane in myelinating co-cultures, implicating Necl-1/Necl-4 interaction in recruiting Par-3 to establish Schwann cell radial polarity.\",\n      \"method\": \"Unbiased proteomic PDZ-domain screen with Necl-4 CTR, co-immunoprecipitation from Schwann cell lysates, immunofluorescence colocalization, siRNA knockdown in myelinating co-cultures\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic screen plus reciprocal co-IP plus functional KD with localization readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"30585357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cadm4 forms a complex with Mpp6 (Pals2), protein band 4.1G (Epb41l2), and Lin7 in Schmidt-Lanterman incisures (SLIs) of peripheral nerve myelin, as identified by mass spectrometry-based proteomics of purified myelin. This complex is increased in aged FA2H-deficient mouse sciatic nerves alongside increased SLI frequency.\",\n      \"method\": \"Mass spectrometry-based proteomics of purified myelin, quantitative protein analysis, SLI counting by electron/light microscopy\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS proteomics of purified myelin fractions identifies complex members; indirect evidence of complex enrichment; single study\",\n      \"pmids\": [\"35445918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cadm4 undergoes palmitoylation at cysteine-347 (C347), catalyzed by ZDHHC3, which is required for stable Cadm4 localization at the plasma membrane. Mutation C347A blocks palmitoylation, causes Cadm4 internalization and degradation. Cadm4-KI (C347A knock-in) mice show severe CNS myelin abnormalities (loss, demyelination, hypermyelination), impaired neuronal transmission, and cognitive deficits. Genetic deletion of ZDHHC3 reduces Cadm4 palmitoylation and causes CNS myelination defects phenocopying Cadm4-KI. Cadm4 may regulate oligodendrocyte differentiation via the WNT-β-Catenin pathway.\",\n      \"method\": \"Site-directed mutagenesis (C347A), palmitoylation assay, knock-in mouse model, ZDHHC3 knockout mice, plasma membrane fractionation, electron microscopy, electrophysiology, behavioral assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis identifies specific palmitoylation site, enzymatic writer (ZDHHC3) identified, two independent in vivo genetic models phenocopy each other, multiple orthogonal readouts\",\n      \"pmids\": [\"39327467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Necl-4/CADM4 is expressed in GABAergic inhibitory neurons and localizes at GABAergic synapses on inhibitory neurons in the hippocampus. Genetic ablation of Necl-4 increases GABAergic synapse density on inhibitory neurons and enhances GABAergic synaptic currents, effects mediated through ErbB4 activation. This leads to high-frequency firing, excitotoxicity-mediated neuronal death, and hippocampal neuronal loss with synaptic degeneration.\",\n      \"method\": \"Necl-4 KO mouse, immunofluorescence of hippocampal neurons and cultured neurons, electrophysiology (mIPSC recording), ErbB4 activation assays, cell death assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with electrophysiological readout and ErbB4 pathway activation identified; single lab, multiple methods\",\n      \"pmids\": [\"40728771\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CADM4 (Necl-4/SynCAM4) is a transmembrane immunoglobulin superfamily cell adhesion molecule that mediates heterophilic trans-interaction with axonal CADM3/Necl-1 to govern Schwann cell–axon contact and PNS myelination, with its cytoplasmic domain recruiting the polarity protein Par-3 to the adaxonal membrane; in the CNS, tightly regulated Cadm4-mediated axoglial adhesion is required for proper myelin targeting and wrapping by oligodendrocytes; Cadm4 plasma membrane stability is maintained by ZDHHC3-catalyzed palmitoylation at C347, loss of which causes severe CNS demyelination; additionally, Cadm4 cis-interacts with VEGFR2, ErbB3, and integrin α6β4 to modulate growth factor signaling and contact inhibition via PTPN13, and at GABAergic synapses on inhibitory neurons it restrains ErbB4-dependent synaptic strengthening to prevent excitotoxic neuronal death.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CADM4 (Necl-4/SynCAM4/TSLL2) is a transmembrane immunoglobulin-superfamily cell adhesion molecule that governs glia–axon contact during myelination and modulates contact-dependent growth factor signaling [#0, #5]. In the peripheral nervous system, CADM4 expressed by myelinating Schwann cells mediates heterophilic trans-adhesion to axonal CADM3/Necl-1, and disruption of this interaction inhibits myelination [#0]; its cytoplasmic domain is required for normal myelin growth and axonal membrane organization, with loss producing focal hypermyelination, disordered ion channel distribution, and slowed nerve conduction [#1]. This cytoplasmic domain carries a PDZ-binding motif that directly engages the first PDZ domain of Par-3, recruiting it to the adaxonal Schwann cell membrane to establish radial glial polarity [#11]. In the CNS, oligodendroglial CADM4 promotes axoglial contact, and the balance of adhesion must be tightly regulated, as excessive adhesion blocks myelin elongation and mistargets myelin onto neuronal somata in a manner dependent on axonal Cadm receptors [#10]. CADM4 plasma membrane stability requires ZDHHC3-catalyzed palmitoylation at cysteine-347; abolishing this modification triggers internalization and degradation and causes severe CNS demyelination, impaired transmission, and cognitive deficits [#13]. Beyond myelination, CADM4 acts in cis with ErbB3, integrin α6β4, and VEGFR2 to restrain or shape growth factor signaling, in several cases by recruiting the phosphatase PTPN13 [#5, #8], and at hippocampal GABAergic synapses it restrains ErbB4-dependent synaptic strengthening to prevent excitotoxic neuronal death [#14]. Reintroduction of CADM4 suppresses tumor formation in prostate and renal carcinoma xenografts, consistent with a tumor-suppressor role [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that CADM4 is a functional adhesion molecule with homophilic trans-interaction capacity and an in vivo tumor-suppressing activity, moving it beyond a cloned sequence to a candidate functional protein.\",\n      \"evidence\": \"Polarized MDCK localization, cell aggregation assay, homodimerization pulldown, and prostate cancer xenograft suppression\",\n      \"pmids\": [\"16261159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homophilic adhesion later contrasts with heterophilic axon-glia adhesion; cis vs trans contexts not unified\", \"Molecular basis of tumor suppression not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined CADM4's primary physiological role by showing it is the Schwann cell partner for axonal CADM3, mediating the adhesion required for PNS myelination.\",\n      \"evidence\": \"Soluble extracellular domain competition, dominant-negative overexpression, and co-culture myelination assay\",\n      \"pmids\": [\"17558405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic signaling downstream of adhesion not yet defined\", \"Whether adhesion is purely structural or instructive unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CADM4 to the actin cytoskeleton and reinforced tumor suppression, showing a cis association with protein 4.1B in native kidney tissue.\",\n      \"evidence\": \"Co-immunoprecipitation from human kidney lysates and renal carcinoma xenograft suppression\",\n      \"pmids\": [\"21544807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of 4.1B binding not tested\", \"Single lab, no reciprocal validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that the CADM4 cytoplasmic domain is required for normal myelin unit growth and axonal membrane organization, distinguishing adhesion from intracellular signaling functions.\",\n      \"evidence\": \"Schwann cell-specific conditional knockout and cytoplasmic-domain-deleted dominant-negative transgenic mice with EM, ion channel immunostaining, and nerve conduction measurements\",\n      \"pmids\": [\"23825401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic effector mediating the phenotype not yet identified\", \"Mechanism of ion channel redistribution unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CADM4 as a cis-acting brake on receptor signaling, binding ErbB3 and integrin α6β4 and recruiting PTPN13 to dampen heregulin signaling and stabilize hemidesmosomes.\",\n      \"evidence\": \"Reciprocal co-IP, pulldown, ErbB2/ErbB3 phosphorylation assays, and hemidesmosome disassembly assay\",\n      \"pmids\": [\"23611113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without in vivo confirmation\", \"Relevance to myelinating cells not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Raised a discrepancy regarding CADM4 requirement, with one knockout reporting it dispensable for both CNS and PNS myelination.\",\n      \"evidence\": \"Necl4 knockout mouse with myelin marker immunostaining and EM of PNS and CNS\",\n      \"pmids\": [\"23700466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result conflicts with PNS phenotypes from other groups\", \"Knockout strategy and developmental window differences unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CADM4 function to organogenesis, showing it limits second heart field progenitor deployment to the cardiac outflow tract.\",\n      \"evidence\": \"Morpholino knockdown and mRNA overexpression with progenitor quantification and live imaging in zebrafish\",\n      \"pmids\": [\"24813897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners in heart field unknown\", \"Conservation in mammalian heart development not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CADM4 signaling is context-dependent, acting through VEGFR2 and PTPN13 to inhibit endothelial movement at confluence but promote it at sparse leading edges.\",\n      \"evidence\": \"Co-IP, knockdown, VEGFR2 phosphorylation, Rac1/ROCK activity, and migration/proliferation assays\",\n      \"pmids\": [\"25893857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch mechanism between confluent and sparse states unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the VEGF signaling model by showing a PTPN13/ROCK-independent CADM4 enhancement of the PLCγ–c-Raf–MEK–ERK cascade.\",\n      \"evidence\": \"siRNA knockdown with PLCγ, c-Raf, MEK, ERK, and VEGFR2 phosphorylation and internalization assays\",\n      \"pmids\": [\"28601637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link to PLCγ pathway not defined\", \"Single method type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that CNS myelination requires tightly tuned CADM4 adhesion, with excessive oligodendroglial adhesion blocking myelin elongation and mistargeting myelin to somata via axonal Cadm receptors.\",\n      \"evidence\": \"Cadm4dCT transgenic mice, oligodendrocyte-neuron and nanofiber co-cultures, axonal Cadm receptor knockouts, EM and immunostaining\",\n      \"pmids\": [\"30551998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signal controlling elongation not identified\", \"Reconciliation with the earlier dispensable-CNS result incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the cytoplasmic effector linking CADM4 adhesion to polarity, showing its PDZ-binding motif directly recruits Par-3 to the adaxonal membrane.\",\n      \"evidence\": \"Unbiased PDZ-domain proteomic screen, co-IP from Schwann cell lysates, colocalization, and siRNA knockdown with Par-3 localization readout\",\n      \"pmids\": [\"30585357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream polarity machinery beyond Par-3 not mapped\", \"Link to ion channel phenotypes not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CADM4 in a defined membrane scaffold complex at Schmidt-Lanterman incisures with Mpp6, band 4.1G, and Lin7.\",\n      \"evidence\": \"Mass spectrometry proteomics of purified myelin with quantitative analysis and SLI counting\",\n      \"pmids\": [\"35445918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the complex not tested\", \"Co-enrichment is indirect evidence of a stable complex\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a post-translational mechanism stabilizing CADM4, showing ZDHHC3-catalyzed palmitoylation at C347 maintains plasma membrane localization and is required for CNS myelin integrity.\",\n      \"evidence\": \"C347A mutagenesis, palmitoylation assays, knock-in and ZDHHC3-knockout mice that phenocopy, membrane fractionation, EM, electrophysiology, and behavioral assays\",\n      \"pmids\": [\"39327467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link to WNT-β-catenin in oligodendrocyte differentiation not fully resolved\", \"Regulation of palmitoylation dynamics unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CADM4 to synaptic regulation, showing it restrains ErbB4-dependent GABAergic synapse strengthening on inhibitory neurons to prevent excitotoxic death.\",\n      \"evidence\": \"Necl-4 knockout mice, mIPSC recording, ErbB4 activation assays, and cell death assays in hippocampal neurons\",\n      \"pmids\": [\"40728771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CADM4–ErbB4 interaction not biochemically demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CADM4's adhesion, cytoplasmic scaffolding (Par-3, 4.1 proteins), palmitoylation-dependent stability, and diverse cis-receptor signaling roles are integrated into a single regulatory logic across glia, endothelium, heart, and neurons remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of cis vs trans interactions\", \"Discrepancy between dispensable and required myelination phenotypes not fully reconciled\", \"Direct synaptic ErbB4 interaction unverified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 9]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 10, 14]}\n    ],\n    \"complexes\": [\n      \"Cadm4-Mpp6(Pals2)-band 4.1G(Epb41l2)-Lin7 complex (Schmidt-Lanterman incisures)\"\n    ],\n    \"partners\": [\n      \"CADM3\",\n      \"CADM2\",\n      \"PARD3\",\n      \"ERBB3\",\n      \"ITGB4\",\n      \"KDR\",\n      \"PTPN13\",\n      \"ZDHHC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}