{"gene":"CLSTN1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2014,"finding":"Calsyntenin-1 (CLSTN1) acts as a kinesin adaptor required for axon branching and neuronal compartmentalization in vivo. Morpholino knockdown and genetic mutants in zebrafish showed that CLSTN1 is required for peripheral (but not central) sensory axon formation and branching. Live imaging demonstrated that CLSTN1 regulates transport of Rab5-containing endosomes from the cell body to specific locations of developing axons, defining separate axonal compartments and their ability to branch.","method":"Morpholino knockdown, genetic mutant analysis, live in vivo imaging of endosomal trafficking in zebrafish","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (morpholino + mutant) combined with live imaging of endosomal trafficking, multiple orthogonal methods in vivo","pmids":["25009257"],"is_preprint":false},{"year":2020,"finding":"CLSTN1 (ALCα) forms a tripartite complex with APP and the adaptor protein X11L (MINT2), suppressing amyloidogenic β-site cleavage of APP. ALCα-deficient mice showed attenuated X11L–APP association, significantly enhanced amyloidogenic processing of APP in endosomes, increased endogenous Aβ generation in the brain, and amyloid plaque formation in human APP-transgenic/ALCα-deficient mice.","method":"ALCα-deficient mouse generation, immunohistochemistry, immunoblotting, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo with multiple orthogonal methods (co-IP, IHC, immunoblot) and clear cellular phenotype (enhanced APP β-cleavage in endosomes, Aβ increase, plaque formation)","pmids":["32467230"],"is_preprint":false},{"year":2019,"finding":"CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. shRNA-mediated knockdown of CLSTN1 increases ICAM5 surface abundance at synaptic membranes, impairing dendritic spine maturation. Restoring CLSTN1 levels in Fmr1 KO neurons reduces synaptic ICAM5 and rescues filopodia-like spine phenotypes, placing CLSTN1 as a negative regulator of ICAM5 redistribution to postsynaptic membranes.","method":"shRNA knockdown, immunofluorescence co-localization, surface abundance assays, rescue experiments in Fmr1 KO neurons and mice","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with clear cellular phenotype and rescue experiments, single lab with multiple methods","pmids":["31680833"],"is_preprint":false},{"year":2020,"finding":"AKAP8 regulates alternative splicing of CLSTN1; experimental isoform switching of CLSTN1 (exon inclusion/exclusion) is causally required for epithelial-to-mesenchymal transition (EMT) and promotes breast cancer metastasis. Manipulation of CLSTN1 splice isoforms in cells demonstrated that the specific isoform switch is functionally sufficient to drive EMT features.","method":"Genome-wide splicing analysis, experimental isoform manipulation, EMT and metastasis assays in breast cancer cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional manipulation of CLSTN1 isoforms with defined EMT phenotype, single lab with multiple methods","pmids":["31980632"],"is_preprint":false},{"year":2023,"finding":"ESRP1 promotes exon 11 inclusion in CLSTN1 pre-mRNA by alternative splicing. The resulting short CLSTN1 isoform stabilizes the E-cadherin/β-catenin binding structure and promotes β-catenin ubiquitination and degradation, thereby inhibiting migration and invasion of gastric cancer cells in vitro and in vivo.","method":"RNA splicing assays, Western blotting, co-immunoprecipitation, ubiquitination assays, migration/invasion assays, in vivo experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with multiple methods (splicing assay, co-IP, ubiquitination assay, in vivo), single lab","pmids":["38114495"],"is_preprint":false},{"year":2026,"finding":"TIA1 is a key suppressor of CLSTN1 exon 11 inclusion. During EMT, the kinase DAPK3 is upregulated and phosphorylates TIA1, antagonizing its function and enabling exon 11 inclusion. This DAPK3-TIA1-CLSTN1 splicing axis drives EMT, breast cancer cell migration, invasion, and generation of circulating tumor cells in vivo. Splice-switching antisense oligonucleotides that reverse exon 11 inclusion suppress cancer cell migration.","method":"RNA-binding protein screening, splicing reporter assays, ASO splice-switching, kinase assay, in vivo circulating tumor cell assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RBP screening plus functional validation with ASOs and in vivo models, single lab","pmids":["42225952"],"is_preprint":false},{"year":2022,"finding":"CLSTN1 overexpression in rat heart promotes doxorubicin-induced dilated cardiomyopathy; mechanistically, CLSTN1 overexpression downregulates SERCA2 expression and increases phosphorylation of PI3K-Akt and CaMK2. Knockdown of CLSTN1 reduces doxorubicin-induced cardiomyocyte toxicity in vitro.","method":"Cardiac-specific overexpression rat model, proteomics, Western blotting, echocardiography, shRNA knockdown in H9c2 cells","journal":"Cardiovascular drugs and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vivo and in vitro with pathway-level mechanistic readouts, single lab","pmids":["36350487"],"is_preprint":false},{"year":2014,"finding":"Zebrafish calsyntenin-1 (clstn1) ectodomain mediates homophilic cell-cell adhesion through two amino-terminal cadherin repeats, as demonstrated by bead-sorting assays. The ectodomains do not show homophilic preferences in bead-sorting, suggesting they can act as adhesion molecules or diffusible homophilic/heterophilic ligands.","method":"Cloning of zebrafish calsyntenins, bead-sorting adhesion assays, expression analysis in developing nervous system","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct adhesion assay with defined structural domain, single lab, single method","pmids":["25463516"],"is_preprint":false},{"year":2024,"finding":"STRBP (spermatid perinuclear RNA-binding protein) loss or dsHSATII overexpression drives isoform switching of CLSTN1, which is sufficient to induce EMT-like morphological changes in pancreatic cancer cells, linking CLSTN1 splicing to cancer cell invasiveness downstream of dsRNA/STRBP signaling.","method":"dsRNA overexpression, STRBP knockdown/overexpression, CLSTN1 isoform analysis, morphological and invasion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic epistasis via RNA-binding protein manipulation with CLSTN1 isoform readout and functional EMT phenotype, single lab","pmids":["38346537"],"is_preprint":false},{"year":2025,"finding":"MAP4 kinases (MAP4K4) repress CLSTN1 recruitment to cell-cell contacts and reduce its surface expression. Pharmacological inhibition of MAP4 kinases increases CLSTN1 expression and its accumulation at cell-cell contacts. Reduction of CLSTN1 expression increases growth factor-driven invasiveness in medulloblastoma cells, establishing CLSTN1 as a repressor of invasiveness downstream of MAP4K signaling.","method":"MAP4K pharmacological inhibition, CLSTN1 knockdown, invasion assays, immunofluorescence localization in MB cell lines and co-culture with astrocytes","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and kinase inhibition with defined invasiveness phenotype and localization readout, single lab","pmids":["39762313"],"is_preprint":false},{"year":2024,"finding":"Knockdown of CLSTN1 in hippocampus of lithium-pilocarpine rat seizure models (via lentiviral RNAi) delayed the latency to spontaneous seizures and reduced their frequency, indicating CLSTN1 promotes epileptogenesis. CLSTN1 was found upregulated in the cortex and hippocampus of epileptic rats and co-localized primarily with neurons in the cytoplasm.","method":"Lentiviral RNAi knockdown in rat hippocampus (stereotactic injection), Western blotting, immunohistochemistry, immunofluorescence co-localization, seizure behavioral monitoring","journal":"Synapse","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with behavioral phenotype and localization data, single lab","pmids":["39171546"],"is_preprint":false},{"year":2013,"finding":"CLSTN1 alternative splicing is part of a conserved program controlled by MBNL1 and RBFOX2 splicing regulators that is involved in late mesoderm differentiation and fixed across at least 10 genes in vertebrate evolution, suggesting vertebrates require this alternative splicing to implement differentiation transcriptional programs.","method":"High-throughput RT-PCR during iPSC reprogramming and redifferentiation, splicing factor knockdown","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CLSTN1 splicing identified in a broader program; MBNL1/RBFOX2 regulators established at program level, not directly demonstrated for CLSTN1 in isolation","pmids":["24048253"],"is_preprint":false}],"current_model":"CLSTN1 (calsyntenin-1/alcadein-α) is a neuronal type I transmembrane protein that functions as a kinesin adaptor for axonal transport of Rab5-containing endosomes, controls axon branching and compartmentalization, suppresses amyloidogenic APP processing by forming a tripartite complex with APP and X11L/MINT2, negatively regulates ICAM5 surface accumulation to promote dendritic spine maturation, and undergoes regulated alternative splicing of exon 11 (controlled by ESRP1, AKAP8, TIA1/DAPK3, and STRBP) whose isoform switching is causally required for epithelial-to-mesenchymal transition and cancer metastasis; additionally, MAP4 kinases repress CLSTN1 recruitment to cell-cell contacts and CLSTN1 loss promotes invasiveness, while cardiac CLSTN1 overexpression drives cardiomyopathy through SERCA2 downregulation and PI3K-Akt/CaMK2 hyperphosphorylation."},"narrative":{"mechanistic_narrative":"CLSTN1 (calsyntenin-1/alcadein-α) is a neuronal type I transmembrane protein that operates as a kinesin adaptor coupling intracellular cargo transport to axonal and synaptic development [PMID:25009257]. In developing sensory neurons it directs transport of Rab5-containing endosomes from the cell body to defined axonal compartments, an activity required for peripheral axon formation and branching [PMID:25009257]. At the synapse it co-transports with the adhesion molecule ICAM5 and acts as a negative regulator of ICAM5 surface accumulation, thereby promoting dendritic spine maturation [PMID:31680833]. CLSTN1 also forms a tripartite complex with APP and the adaptor X11L/MINT2 that restrains amyloidogenic β-site cleavage of APP in endosomes, so that its loss enhances Aβ generation and amyloid plaque formation [PMID:32467230]. Its ectodomain mediates homophilic cell-cell adhesion through amino-terminal cadherin repeats [PMID:25463516]. A distinct and well-developed theme is the regulated alternative splicing of CLSTN1 exon 11: isoform switching is causally sufficient to drive epithelial-to-mesenchymal transition and cancer cell invasion across breast, gastric, and pancreatic models, and is controlled by a network of splicing regulators including ESRP1, AKAP8, the DAPK3-TIA1 axis, and STRBP [PMID:31980632, PMID:38114495, PMID:42225952, PMID:38346537]. In epithelial and tumor cells the short isoform stabilizes E-cadherin/β-catenin and promotes β-catenin degradation, while CLSTN1 recruitment to cell-cell contacts is repressed by MAP4K signaling, and loss of CLSTN1 increases invasiveness [PMID:38114495, PMID:39762313].","teleology":[{"year":2014,"claim":"Established CLSTN1's core cellular function as a kinesin adaptor that routes Rab5 endosomes to specific axonal compartments, answering how a transmembrane protein controls axon branching.","evidence":"Morpholino knockdown, genetic mutants, and live in vivo imaging of endosomal trafficking in zebrafish","pmids":["25009257"],"confidence":"High","gaps":["Identity of the kinesin motor and the linkage between cargo selection and branch site is not resolved in the corpus","Whether the same transport role operates in mammalian central neurons not addressed here"]},{"year":2014,"claim":"Showed the CLSTN1 ectodomain can mediate homophilic adhesion via cadherin repeats, framing it as a candidate cell-surface adhesion/ligand molecule beyond its intracellular adaptor role.","evidence":"Cloning of zebrafish calsyntenins and bead-sorting adhesion assays","pmids":["25463516"],"confidence":"Medium","gaps":["No homophilic binding preference detected, leaving the in vivo adhesive partner undefined","Single assay (bead-sorting) without cell-based or structural validation"]},{"year":2019,"claim":"Defined a synaptic role for CLSTN1 as a negative regulator of ICAM5 surface delivery, connecting its transport activity to dendritic spine maturation and a Fragile X disease context.","evidence":"shRNA knockdown, surface abundance assays, and rescue in Fmr1 KO neurons and mice","pmids":["31680833"],"confidence":"Medium","gaps":["Molecular basis of CLSTN1-ICAM5 co-transport not mapped","Whether ICAM5 regulation depends on the kinesin-adaptor activity is untested"]},{"year":2020,"claim":"Demonstrated that CLSTN1 forms an APP/X11L complex that suppresses amyloidogenic APP processing, establishing a protective role against Aβ generation.","evidence":"ALCα-deficient and APP-transgenic mice with co-IP, IHC, and immunoblotting","pmids":["32467230"],"confidence":"High","gaps":["How CLSTN1 loss shifts APP cleavage to the endosomal β-site mechanistically is not detailed","Stoichiometry and direct binding interfaces of the tripartite complex not resolved"]},{"year":2020,"claim":"Opened a non-neuronal theme by showing CLSTN1 exon 11 isoform switching, controlled by AKAP8, is causally sufficient to drive EMT and breast cancer metastasis.","evidence":"Genome-wide splicing analysis, isoform manipulation, and EMT/metastasis assays in breast cancer cells","pmids":["31980632"],"confidence":"Medium","gaps":["Functional difference between the long and short protein isoforms at the molecular level not defined here","Single lab and single cancer type"]},{"year":2023,"claim":"Provided a downstream mechanism for the splice isoforms by showing the ESRP1-promoted short isoform stabilizes E-cadherin/β-catenin and drives β-catenin degradation to suppress invasion.","evidence":"Splicing assays, co-IP, ubiquitination assays, and migration/invasion assays in gastric cancer in vitro and in vivo","pmids":["38114495"],"confidence":"Medium","gaps":["Direct biochemical interaction of the CLSTN1 isoform with the E-cadherin/β-catenin complex not structurally resolved","Reconciliation with opposite splicing directionality in other cancers not addressed"]},{"year":2024,"claim":"Extended the splicing-regulator network by showing STRBP/dsHSATII signaling controls CLSTN1 isoform switching sufficient to induce EMT in pancreatic cancer.","evidence":"dsRNA and STRBP manipulation with CLSTN1 isoform and invasion readouts","pmids":["38346537"],"confidence":"Medium","gaps":["Whether STRBP acts directly on CLSTN1 pre-mRNA or through intermediaries is unresolved","Single lab, single cancer model"]},{"year":2024,"claim":"Linked CLSTN1 to epileptogenesis, showing hippocampal knockdown delays and reduces spontaneous seizures in a rat model.","evidence":"Lentiviral RNAi knockdown in rat hippocampus with seizure behavioral monitoring and localization","pmids":["39171546"],"confidence":"Medium","gaps":["Molecular pathway by which CLSTN1 promotes epileptogenesis not defined","Single model and single lab"]},{"year":2025,"claim":"Identified MAP4K signaling as an upstream repressor of CLSTN1 localization to cell-cell contacts, with CLSTN1 loss promoting growth-factor-driven invasiveness in medulloblastoma.","evidence":"MAP4K pharmacological inhibition, knockdown, invasion assays, and immunofluorescence in MB cells","pmids":["39762313"],"confidence":"Medium","gaps":["Whether MAP4K acts on CLSTN1 protein, trafficking, or splicing is not distinguished","Direct substrate relationship not established"]},{"year":2026,"claim":"Resolved an upstream splicing axis by showing DAPK3 phosphorylates and inactivates the exon-11 suppressor TIA1 to enable EMT, and that splice-switching ASOs can reverse the invasive phenotype.","evidence":"RBP screening, splicing reporters, kinase assays, ASO splice-switching, and in vivo circulating tumor cell assays","pmids":["42225952"],"confidence":"Medium","gaps":["Direct binding of TIA1 to the CLSTN1 exon 11 region not structurally mapped","Therapeutic ASO efficacy beyond migration readouts not established"]},{"year":2022,"claim":"Implicated cardiac CLSTN1 in doxorubicin-induced cardiomyopathy through SERCA2 downregulation and PI3K-Akt/CaMK2 hyperphosphorylation.","evidence":"Cardiac-specific overexpression rat model, proteomics, echocardiography, and shRNA knockdown in H9c2 cells","pmids":["36350487"],"confidence":"Medium","gaps":["Mechanistic link between CLSTN1 and SERCA2/PI3K-Akt signaling not established","Physiological relevance of CLSTN1 in normal cardiac tissue not addressed"]},{"year":null,"claim":"It remains unknown how CLSTN1's intracellular kinesin-adaptor/cargo-transport activity mechanistically connects to its protein-isoform-dependent control of cell adhesion and EMT, and whether these are one integrated function or separable activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of CLSTN1 or its complexes in the corpus","The biochemical difference between exon-11 included vs excluded protein isoforms is not defined","No unified model linking the neuronal transport role and the epithelial adhesion/EMT role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[],"complexes":[],"partners":["APP","APBA2","ICAM5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94985","full_name":"Calsyntenin-1","aliases":["Alcadein-alpha","Alc-alpha","Alzheimer-related cadherin-like protein","Non-classical cadherin XB31alpha"],"length_aa":981,"mass_kda":109.8,"function":"Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation (By similarity). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with neurexin-alpha at the presynaptic membrane (By similarity). Also functions as a cargo in axonal anterograde transport by acting as a molecular adapter that promotes KLC1 association with vesicles (PubMed:21385839). Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (PubMed:12972431) As intracellular fragment AlcICD, suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding (PubMed:15037614) In complex with APBA2 and C99, a C-terminal APP fragment, abolishes C99 interaction with PSEN1 and thus APP C99 cleavage by gamma-secretase, most probably through stabilization of the direct interaction between APBA2 and APP (PubMed:15037614)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O94985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLSTN1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CLSTN1","total_profiled":1310},"omim":[{"mim_id":"611324","title":"CALSYNTENIN 3; CLSTN3","url":"https://www.omim.org/entry/611324"},{"mim_id":"611323","title":"CALSYNTENIN 2; CLSTN2","url":"https://www.omim.org/entry/611323"},{"mim_id":"611321","title":"CALSYNTENIN 1; CLSTN1","url":"https://www.omim.org/entry/611321"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CLSTN1"},"hgnc":{"alias_symbol":["CSTN1","KIAA0911","CDHR12"],"prev_symbol":[]},"alphafold":{"accession":"O94985","domains":[{"cath_id":"2.60.40.60","chopping":"42-156","consensus_level":"high","plddt":83.8823,"start":42,"end":156},{"cath_id":"2.60.40.60","chopping":"164-259","consensus_level":"high","plddt":95.4822,"start":164,"end":259},{"cath_id":"2.60.40.10","chopping":"265-308_564-648","consensus_level":"high","plddt":88.235,"start":265,"end":648},{"cath_id":"2.60.120.200","chopping":"322-509_530-560","consensus_level":"high","plddt":85.699,"start":322,"end":560},{"cath_id":"2.60.40","chopping":"655-691_709-814","consensus_level":"high","plddt":88.6176,"start":655,"end":814}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94985","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94985-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLSTN1","jax_strain_url":"https://www.jax.org/strain/search?query=CLSTN1"},"sequence":{"accession":"O94985","fasta_url":"https://rest.uniprot.org/uniprotkb/O94985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94985"}},"corpus_meta":[{"pmid":"17606710","id":"PMC_17606710","title":"Age-related 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Morpholino knockdown and genetic mutants in zebrafish showed that CLSTN1 is required for peripheral (but not central) sensory axon formation and branching. Live imaging demonstrated that CLSTN1 regulates transport of Rab5-containing endosomes from the cell body to specific locations of developing axons, defining separate axonal compartments and their ability to branch.\",\n      \"method\": \"Morpholino knockdown, genetic mutant analysis, live in vivo imaging of endosomal trafficking in zebrafish\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (morpholino + mutant) combined with live imaging of endosomal trafficking, multiple orthogonal methods in vivo\",\n      \"pmids\": [\"25009257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CLSTN1 (ALCα) forms a tripartite complex with APP and the adaptor protein X11L (MINT2), suppressing amyloidogenic β-site cleavage of APP. ALCα-deficient mice showed attenuated X11L–APP association, significantly enhanced amyloidogenic processing of APP in endosomes, increased endogenous Aβ generation in the brain, and amyloid plaque formation in human APP-transgenic/ALCα-deficient mice.\",\n      \"method\": \"ALCα-deficient mouse generation, immunohistochemistry, immunoblotting, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo with multiple orthogonal methods (co-IP, IHC, immunoblot) and clear cellular phenotype (enhanced APP β-cleavage in endosomes, Aβ increase, plaque formation)\",\n      \"pmids\": [\"32467230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. shRNA-mediated knockdown of CLSTN1 increases ICAM5 surface abundance at synaptic membranes, impairing dendritic spine maturation. Restoring CLSTN1 levels in Fmr1 KO neurons reduces synaptic ICAM5 and rescues filopodia-like spine phenotypes, placing CLSTN1 as a negative regulator of ICAM5 redistribution to postsynaptic membranes.\",\n      \"method\": \"shRNA knockdown, immunofluorescence co-localization, surface abundance assays, rescue experiments in Fmr1 KO neurons and mice\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with clear cellular phenotype and rescue experiments, single lab with multiple methods\",\n      \"pmids\": [\"31680833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKAP8 regulates alternative splicing of CLSTN1; experimental isoform switching of CLSTN1 (exon inclusion/exclusion) is causally required for epithelial-to-mesenchymal transition (EMT) and promotes breast cancer metastasis. Manipulation of CLSTN1 splice isoforms in cells demonstrated that the specific isoform switch is functionally sufficient to drive EMT features.\",\n      \"method\": \"Genome-wide splicing analysis, experimental isoform manipulation, EMT and metastasis assays in breast cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional manipulation of CLSTN1 isoforms with defined EMT phenotype, single lab with multiple methods\",\n      \"pmids\": [\"31980632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ESRP1 promotes exon 11 inclusion in CLSTN1 pre-mRNA by alternative splicing. The resulting short CLSTN1 isoform stabilizes the E-cadherin/β-catenin binding structure and promotes β-catenin ubiquitination and degradation, thereby inhibiting migration and invasion of gastric cancer cells in vitro and in vivo.\",\n      \"method\": \"RNA splicing assays, Western blotting, co-immunoprecipitation, ubiquitination assays, migration/invasion assays, in vivo experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with multiple methods (splicing assay, co-IP, ubiquitination assay, in vivo), single lab\",\n      \"pmids\": [\"38114495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TIA1 is a key suppressor of CLSTN1 exon 11 inclusion. During EMT, the kinase DAPK3 is upregulated and phosphorylates TIA1, antagonizing its function and enabling exon 11 inclusion. This DAPK3-TIA1-CLSTN1 splicing axis drives EMT, breast cancer cell migration, invasion, and generation of circulating tumor cells in vivo. Splice-switching antisense oligonucleotides that reverse exon 11 inclusion suppress cancer cell migration.\",\n      \"method\": \"RNA-binding protein screening, splicing reporter assays, ASO splice-switching, kinase assay, in vivo circulating tumor cell assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RBP screening plus functional validation with ASOs and in vivo models, single lab\",\n      \"pmids\": [\"42225952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CLSTN1 overexpression in rat heart promotes doxorubicin-induced dilated cardiomyopathy; mechanistically, CLSTN1 overexpression downregulates SERCA2 expression and increases phosphorylation of PI3K-Akt and CaMK2. Knockdown of CLSTN1 reduces doxorubicin-induced cardiomyocyte toxicity in vitro.\",\n      \"method\": \"Cardiac-specific overexpression rat model, proteomics, Western blotting, echocardiography, shRNA knockdown in H9c2 cells\",\n      \"journal\": \"Cardiovascular drugs and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vivo and in vitro with pathway-level mechanistic readouts, single lab\",\n      \"pmids\": [\"36350487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zebrafish calsyntenin-1 (clstn1) ectodomain mediates homophilic cell-cell adhesion through two amino-terminal cadherin repeats, as demonstrated by bead-sorting assays. The ectodomains do not show homophilic preferences in bead-sorting, suggesting they can act as adhesion molecules or diffusible homophilic/heterophilic ligands.\",\n      \"method\": \"Cloning of zebrafish calsyntenins, bead-sorting adhesion assays, expression analysis in developing nervous system\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct adhesion assay with defined structural domain, single lab, single method\",\n      \"pmids\": [\"25463516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STRBP (spermatid perinuclear RNA-binding protein) loss or dsHSATII overexpression drives isoform switching of CLSTN1, which is sufficient to induce EMT-like morphological changes in pancreatic cancer cells, linking CLSTN1 splicing to cancer cell invasiveness downstream of dsRNA/STRBP signaling.\",\n      \"method\": \"dsRNA overexpression, STRBP knockdown/overexpression, CLSTN1 isoform analysis, morphological and invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic epistasis via RNA-binding protein manipulation with CLSTN1 isoform readout and functional EMT phenotype, single lab\",\n      \"pmids\": [\"38346537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP4 kinases (MAP4K4) repress CLSTN1 recruitment to cell-cell contacts and reduce its surface expression. Pharmacological inhibition of MAP4 kinases increases CLSTN1 expression and its accumulation at cell-cell contacts. Reduction of CLSTN1 expression increases growth factor-driven invasiveness in medulloblastoma cells, establishing CLSTN1 as a repressor of invasiveness downstream of MAP4K signaling.\",\n      \"method\": \"MAP4K pharmacological inhibition, CLSTN1 knockdown, invasion assays, immunofluorescence localization in MB cell lines and co-culture with astrocytes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and kinase inhibition with defined invasiveness phenotype and localization readout, single lab\",\n      \"pmids\": [\"39762313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of CLSTN1 in hippocampus of lithium-pilocarpine rat seizure models (via lentiviral RNAi) delayed the latency to spontaneous seizures and reduced their frequency, indicating CLSTN1 promotes epileptogenesis. CLSTN1 was found upregulated in the cortex and hippocampus of epileptic rats and co-localized primarily with neurons in the cytoplasm.\",\n      \"method\": \"Lentiviral RNAi knockdown in rat hippocampus (stereotactic injection), Western blotting, immunohistochemistry, immunofluorescence co-localization, seizure behavioral monitoring\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with behavioral phenotype and localization data, single lab\",\n      \"pmids\": [\"39171546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLSTN1 alternative splicing is part of a conserved program controlled by MBNL1 and RBFOX2 splicing regulators that is involved in late mesoderm differentiation and fixed across at least 10 genes in vertebrate evolution, suggesting vertebrates require this alternative splicing to implement differentiation transcriptional programs.\",\n      \"method\": \"High-throughput RT-PCR during iPSC reprogramming and redifferentiation, splicing factor knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CLSTN1 splicing identified in a broader program; MBNL1/RBFOX2 regulators established at program level, not directly demonstrated for CLSTN1 in isolation\",\n      \"pmids\": [\"24048253\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLSTN1 (calsyntenin-1/alcadein-α) is a neuronal type I transmembrane protein that functions as a kinesin adaptor for axonal transport of Rab5-containing endosomes, controls axon branching and compartmentalization, suppresses amyloidogenic APP processing by forming a tripartite complex with APP and X11L/MINT2, negatively regulates ICAM5 surface accumulation to promote dendritic spine maturation, and undergoes regulated alternative splicing of exon 11 (controlled by ESRP1, AKAP8, TIA1/DAPK3, and STRBP) whose isoform switching is causally required for epithelial-to-mesenchymal transition and cancer metastasis; additionally, MAP4 kinases repress CLSTN1 recruitment to cell-cell contacts and CLSTN1 loss promotes invasiveness, while cardiac CLSTN1 overexpression drives cardiomyopathy through SERCA2 downregulation and PI3K-Akt/CaMK2 hyperphosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLSTN1 (calsyntenin-1/alcadein-\\u03b1) is a neuronal type I transmembrane protein that operates as a kinesin adaptor coupling intracellular cargo transport to axonal and synaptic development [#0]. In developing sensory neurons it directs transport of Rab5-containing endosomes from the cell body to defined axonal compartments, an activity required for peripheral axon formation and branching [#0]. At the synapse it co-transports with the adhesion molecule ICAM5 and acts as a negative regulator of ICAM5 surface accumulation, thereby promoting dendritic spine maturation [#2]. CLSTN1 also forms a tripartite complex with APP and the adaptor X11L/MINT2 that restrains amyloidogenic \\u03b2-site cleavage of APP in endosomes, so that its loss enhances A\\u03b2 generation and amyloid plaque formation [#1]. Its ectodomain mediates homophilic cell-cell adhesion through amino-terminal cadherin repeats [#7]. A distinct and well-developed theme is the regulated alternative splicing of CLSTN1 exon 11: isoform switching is causally sufficient to drive epithelial-to-mesenchymal transition and cancer cell invasion across breast, gastric, and pancreatic models, and is controlled by a network of splicing regulators including ESRP1, AKAP8, the DAPK3-TIA1 axis, and STRBP [#3, #4, #5, #8]. In epithelial and tumor cells the short isoform stabilizes E-cadherin/\\u03b2-catenin and promotes \\u03b2-catenin degradation, while CLSTN1 recruitment to cell-cell contacts is repressed by MAP4K signaling, and loss of CLSTN1 increases invasiveness [#4, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CLSTN1's core cellular function as a kinesin adaptor that routes Rab5 endosomes to specific axonal compartments, answering how a transmembrane protein controls axon branching.\",\n      \"evidence\": \"Morpholino knockdown, genetic mutants, and live in vivo imaging of endosomal trafficking in zebrafish\",\n      \"pmids\": [\"25009257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the kinesin motor and the linkage between cargo selection and branch site is not resolved in the corpus\",\n        \"Whether the same transport role operates in mammalian central neurons not addressed here\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed the CLSTN1 ectodomain can mediate homophilic adhesion via cadherin repeats, framing it as a candidate cell-surface adhesion/ligand molecule beyond its intracellular adaptor role.\",\n      \"evidence\": \"Cloning of zebrafish calsyntenins and bead-sorting adhesion assays\",\n      \"pmids\": [\"25463516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No homophilic binding preference detected, leaving the in vivo adhesive partner undefined\",\n        \"Single assay (bead-sorting) without cell-based or structural validation\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a synaptic role for CLSTN1 as a negative regulator of ICAM5 surface delivery, connecting its transport activity to dendritic spine maturation and a Fragile X disease context.\",\n      \"evidence\": \"shRNA knockdown, surface abundance assays, and rescue in Fmr1 KO neurons and mice\",\n      \"pmids\": [\"31680833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of CLSTN1-ICAM5 co-transport not mapped\",\n        \"Whether ICAM5 regulation depends on the kinesin-adaptor activity is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that CLSTN1 forms an APP/X11L complex that suppresses amyloidogenic APP processing, establishing a protective role against A\\u03b2 generation.\",\n      \"evidence\": \"ALC\\u03b1-deficient and APP-transgenic mice with co-IP, IHC, and immunoblotting\",\n      \"pmids\": [\"32467230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CLSTN1 loss shifts APP cleavage to the endosomal \\u03b2-site mechanistically is not detailed\",\n        \"Stoichiometry and direct binding interfaces of the tripartite complex not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Opened a non-neuronal theme by showing CLSTN1 exon 11 isoform switching, controlled by AKAP8, is causally sufficient to drive EMT and breast cancer metastasis.\",\n      \"evidence\": \"Genome-wide splicing analysis, isoform manipulation, and EMT/metastasis assays in breast cancer cells\",\n      \"pmids\": [\"31980632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional difference between the long and short protein isoforms at the molecular level not defined here\",\n        \"Single lab and single cancer type\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a downstream mechanism for the splice isoforms by showing the ESRP1-promoted short isoform stabilizes E-cadherin/\\u03b2-catenin and drives \\u03b2-catenin degradation to suppress invasion.\",\n      \"evidence\": \"Splicing assays, co-IP, ubiquitination assays, and migration/invasion assays in gastric cancer in vitro and in vivo\",\n      \"pmids\": [\"38114495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical interaction of the CLSTN1 isoform with the E-cadherin/\\u03b2-catenin complex not structurally resolved\",\n        \"Reconciliation with opposite splicing directionality in other cancers not addressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the splicing-regulator network by showing STRBP/dsHSATII signaling controls CLSTN1 isoform switching sufficient to induce EMT in pancreatic cancer.\",\n      \"evidence\": \"dsRNA and STRBP manipulation with CLSTN1 isoform and invasion readouts\",\n      \"pmids\": [\"38346537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether STRBP acts directly on CLSTN1 pre-mRNA or through intermediaries is unresolved\",\n        \"Single lab, single cancer model\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked CLSTN1 to epileptogenesis, showing hippocampal knockdown delays and reduces spontaneous seizures in a rat model.\",\n      \"evidence\": \"Lentiviral RNAi knockdown in rat hippocampus with seizure behavioral monitoring and localization\",\n      \"pmids\": [\"39171546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular pathway by which CLSTN1 promotes epileptogenesis not defined\",\n        \"Single model and single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified MAP4K signaling as an upstream repressor of CLSTN1 localization to cell-cell contacts, with CLSTN1 loss promoting growth-factor-driven invasiveness in medulloblastoma.\",\n      \"evidence\": \"MAP4K pharmacological inhibition, knockdown, invasion assays, and immunofluorescence in MB cells\",\n      \"pmids\": [\"39762313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MAP4K acts on CLSTN1 protein, trafficking, or splicing is not distinguished\",\n        \"Direct substrate relationship not established\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved an upstream splicing axis by showing DAPK3 phosphorylates and inactivates the exon-11 suppressor TIA1 to enable EMT, and that splice-switching ASOs can reverse the invasive phenotype.\",\n      \"evidence\": \"RBP screening, splicing reporters, kinase assays, ASO splice-switching, and in vivo circulating tumor cell assays\",\n      \"pmids\": [\"42225952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of TIA1 to the CLSTN1 exon 11 region not structurally mapped\",\n        \"Therapeutic ASO efficacy beyond migration readouts not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated cardiac CLSTN1 in doxorubicin-induced cardiomyopathy through SERCA2 downregulation and PI3K-Akt/CaMK2 hyperphosphorylation.\",\n      \"evidence\": \"Cardiac-specific overexpression rat model, proteomics, echocardiography, and shRNA knockdown in H9c2 cells\",\n      \"pmids\": [\"36350487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between CLSTN1 and SERCA2/PI3K-Akt signaling not established\",\n        \"Physiological relevance of CLSTN1 in normal cardiac tissue not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CLSTN1's intracellular kinesin-adaptor/cargo-transport activity mechanistically connects to its protein-isoform-dependent control of cell adhesion and EMT, and whether these are one integrated function or separable activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of CLSTN1 or its complexes in the corpus\",\n        \"The biochemical difference between exon-11 included vs excluded protein isoforms is not defined\",\n        \"No unified model linking the neuronal transport role and the epithelial adhesion/EMT role\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"APP\",\n      \"APBA2\",\n      \"ICAM5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}