{"gene":"SEZ6","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1995,"finding":"SEZ-6 encodes a brain-specific type I transmembrane protein containing five short consensus repeats (SCRs/sushi domains, complement C3b/C4b binding sites) and two CUB domain-like sequences, plus a signal sequence, threonine-rich domain, transmembrane domain, and short cytoplasmic tail. The protein is post-translationally modified and expressed in cerebrum and cerebellum.","method":"cDNA cloning, sequence analysis, in vitro translation, immunoblot with anti-SEZ6 peptide antibody","journal":"Brain research. Molecular brain research / Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary sequence characterization confirmed by in vitro translation and immunoblot, replicated across two independent papers from same group","pmids":["7723619","7488116"],"is_preprint":false},{"year":1995,"finding":"SEZ-6 exists in at least three isoforms generated by alternative splicing: one encoding a membrane protein with the full complement of SCRs/CUB domains, one encoding a membrane protein with a different C-terminal region, and one encoding a secreted protein with two SCRs and one CUB-like domain.","method":"PCR-based cDNA cloning and sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct sequence characterization from cDNA cloning, single lab","pmids":["7488116"],"is_preprint":false},{"year":2007,"finding":"Sez-6 is required for normal dendritic arborization of cortical pyramidal neurons: sez-6 null mice exhibit excess short dendrites and excessive neurite branching in cultured cortical neurons. Membrane-bound and secreted Sez-6 isoforms exert opposing effects on dendritic branching, with membrane-bound Sez-6 exerting an anti-branching effect under basal and depolarizing conditions. Loss of Sez-6 also reduces dendritic spine density and PSD-95 punctate staining, and reduces excitatory postsynaptic responses in layer V pyramidal neurons.","method":"Sez-6 null mouse analysis, isoform overexpression rescue in knockout neurons, slice electrophysiology, immunostaining for PSD-95","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, isoform rescue experiment, electrophysiology, replicated with multiple orthogonal methods in single rigorous study","pmids":["18031681"],"is_preprint":false},{"year":2021,"finding":"Sez6 family members (Sez6, Sez6L, Sez6L2) inhibit complement activation: they inhibit C3b/iC3b opsonization by classical and alternative pathways. Using Sez6L2 as representative, the mechanism involves (1) accelerating dissociation of C3 convertases (decay-accelerating activity) and (2) functioning as a cofactor for Factor I to facilitate cleavage of C3b (but not C4b). Sez6 is the strongest classical pathway inhibitor among family members.","method":"In vitro complement opsonization assay, C3 convertase decay assay, Factor I cofactor assay with purified proteins","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro biochemical assays with purified components, two mechanistic activities demonstrated with orthogonal assays in single study","pmids":["33936031"],"is_preprint":false},{"year":2015,"finding":"N-glycosylation of Sez-6 regulates its cell surface distribution and function. Sez-6 has 11 N-glycosylation sites in three clusters (SC1-3, SC4-7, SC8-11) in the extracellular domain. Mutants lacking the SC4-7 cluster fail to induce filopodia-like protrusions, indicating SC4-7 is required for this activity. The unglycosylated mutant and mutants with only one cluster showed altered localization on the cell membrane compared to wild-type even distribution.","method":"Site-directed mutagenesis of N-glycosylation sites, transfection into Neuro2a cells, immunofluorescence, conditioned medium analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct mutagenesis with cellular phenotype readout, single lab, single study","pmids":["25960298"],"is_preprint":false},{"year":2011,"finding":"Sez-6 promotes neurite outgrowth in PC12 cells: shRNA-mediated knockdown of Sez-6 inhibited NGF-induced neurite outgrowth and was associated with increased PKCγ protein levels, suggesting Sez-6 acts through the PKCγ signaling pathway.","method":"shRNA knockdown in PC12 cells, NGF treatment, neurite outgrowth measurement, PKCγ Western blot","journal":"Zeitschrift fur Naturforschung. C, Journal of biosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with indirect pathway inference (PKCγ correlation, not direct interaction)","pmids":["22351987"],"is_preprint":false},{"year":2018,"finding":"BACE1 cleaves Sez6 and Sez6L, shedding their extracellular domains. Enhanced BACE1 cleavage of Sez6 and Sez6L is detected in NPC1-null mouse brains at 4 weeks of age. In NPC1-null primary cortical neurons, Sez6 and Sez6L show increased punctate staining within the endolysosomal pathway, suggesting trafficking defects within the endolysosomal pathway contribute to enhanced BACE1 proteolysis.","method":"Immunoblot quantification of BACE1-cleaved fragments in NPC1-/- vs wild-type mouse brains, immunofluorescence of endolysosomal markers in primary neurons","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (biochemical and imaging), in vivo and in vitro evidence in single study, single lab","pmids":["29979789"],"is_preprint":false},{"year":2019,"finding":"The type I transmembrane isoform of Sez6 is cleaved by BACE1, resulting in shedding of the Sez6 extracellular domain; BACE1-shed Sez6 is detectable in human cerebrospinal fluid by Western blot.","method":"Western blot detection of shed Sez6 ectodomain in human CSF samples","journal":"Pain reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct detection of BACE1-cleaved product in human CSF, single lab, single method","pmids":["31041421"],"is_preprint":false},{"year":2020,"finding":"Triple knockout of all three Sez6 family proteins (Sez6, Sez6L, Sez6L2) reduces dendritic spine density in the hippocampus and shifts spine morphology toward more immature forms in the somatosensory cortex, establishing a collective role for the Sez6 family in dendritic spine structure.","method":"Sez6 triple knockout mice, dendritic spine morphology analysis (imaging)","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic triple knockout with defined structural cellular phenotype, multiple brain regions analyzed, single lab","pmids":["31711114"],"is_preprint":false},{"year":2022,"finding":"In the 5xFAD Alzheimer's disease mouse model, accumulation of BACE1 around amyloid plaques does NOT result in enhanced proteolysis of Sez6 or Sez6L (in contrast to APP). Instead, Sez6 and Sez6L show altered spatial distribution in peri-plaque regions, suggesting their localization but not their BACE1-mediated cleavage is affected in AD pathology.","method":"Immunoblot for BACE1-cleaved Sez6/Sez6L fragments in 5xFAD vs wild-type brains, immunofluorescence co-localization","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative result for BACE1 proteolysis of Sez6 in AD model confirmed by biochemical and imaging methods, single lab","pmids":["35998821"],"is_preprint":false},{"year":2022,"finding":"Alternative splicing of Sez6 produces isoforms with distinct brain region-specific expression patterns; convulsant drug stimulation increases expression of recessive (secreted) isoforms alongside the dominant transmembrane isoform in cultured cortical neurons, indicating neuronal activity modulates isoform balance.","method":"Isoform-specific qPCR on mouse brain area punches and cultured cortical neurons treated with convulsant","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — descriptive expression analysis of splice isoforms without functional rescue, single lab","pmids":["36368155"],"is_preprint":false}],"current_model":"SEZ6 is a brain-enriched type I transmembrane protein that, at the cell surface, inhibits complement activation by accelerating C3 convertase decay and acting as a Factor I cofactor to cleave C3b; membrane-bound SEZ6 suppresses dendritic branching and promotes dendritic spine formation/excitatory connectivity, while BACE1-mediated ectodomain shedding releases a soluble form detectable in CSF, and N-glycosylation of the extracellular domain regulates its membrane distribution and filopodia-inducing activity."},"narrative":{"mechanistic_narrative":"SEZ6 is a brain-enriched type I transmembrane protein whose extracellular region comprises five complement-control short consensus repeats (sushi/SCR domains) and CUB-like domains, and which exists as both membrane-bound and secreted isoforms generated by alternative splicing [PMID:7723619, PMID:7488116]. Through its SCR domains, SEZ6 acts as a negative regulator of complement: it inhibits C3b/iC3b opsonization by accelerating decay of C3 convertases and serving as a Factor I cofactor for cleavage of C3b, with SEZ6 the strongest classical-pathway inhibitor among its family [PMID:33936031]. In the nervous system, SEZ6 shapes neuronal morphology, with membrane-bound and secreted isoforms exerting opposing effects on dendritic branching; loss of SEZ6 produces excess short dendrites and excessive branching while reducing dendritic spine density, PSD-95 puncta, and excitatory postsynaptic responses in cortical pyramidal neurons [PMID:18031681], and combined loss across the SEZ6 family reduces hippocampal spine density and shifts spines toward immature forms [PMID:31711114]. The membrane isoform is processed by BACE1, which sheds the SEZ6 ectodomain into cerebrospinal fluid [PMID:29979789, PMID:31041421]. N-glycosylation of the extracellular domain, particularly the SC4-7 site cluster, governs SEZ6 membrane distribution and its filopodia-inducing activity [PMID:25960298].","teleology":[{"year":1995,"claim":"Established the molecular identity of SEZ6 as a brain-specific type I transmembrane protein built from complement-control sushi/SCR repeats and CUB-like domains, defining the domain architecture that would later predict its complement-regulatory function.","evidence":"cDNA cloning, sequence analysis, in vitro translation, and anti-peptide immunoblot","pmids":["7723619","7488116"],"confidence":"High","gaps":["No functional activity assigned to the SCR/CUB domains at this stage","Tissue expression resolved only to cerebrum/cerebellum"]},{"year":1995,"claim":"Identified alternative splicing yielding membrane-bound and secreted SEZ6 isoforms, raising the possibility that different isoforms carry distinct functions.","evidence":"PCR-based cDNA cloning and sequence analysis","pmids":["7488116"],"confidence":"Medium","gaps":["Functional differences between isoforms not tested","Relative abundance and regulation of isoforms unknown"]},{"year":2007,"claim":"Demonstrated a physiological neuronal role: SEZ6 controls dendritic arborization and excitatory connectivity, with membrane-bound and secreted isoforms acting in opposition.","evidence":"Sez6-null mouse analysis, isoform overexpression rescue in knockout neurons, slice electrophysiology, PSD-95 immunostaining","pmids":["18031681"],"confidence":"High","gaps":["Molecular mediators of the opposing isoform effects not identified","No receptor or binding partner defined for the secreted form"]},{"year":2011,"claim":"Linked SEZ6 to NGF-induced neurite outgrowth via a candidate PKCγ pathway, offering an intracellular signaling correlate.","evidence":"shRNA knockdown in PC12 cells with NGF treatment and PKCγ Western blot","pmids":["22351987"],"confidence":"Low","gaps":["PKCγ link is correlative, not a demonstrated direct interaction","Single cell line and single knockdown approach","Apparent pro-outgrowth role contrasts with anti-branching role of membrane isoform in cortical neurons"]},{"year":2015,"claim":"Showed that extracellular N-glycosylation, specifically the SC4-7 cluster, is required for SEZ6 surface distribution and filopodia induction, identifying a post-translational determinant of its membrane activity.","evidence":"Site-directed mutagenesis of N-glycosylation sites in Neuro2a cells with immunofluorescence and conditioned-medium analysis","pmids":["25960298"],"confidence":"Medium","gaps":["Mechanism connecting glycosylation to filopodia formation unresolved","Single cell line, single study"]},{"year":2018,"claim":"Identified BACE1 as the protease that sheds the SEZ6 ectodomain and showed endolysosomal trafficking defects (in NPC1-null neurons) enhance this cleavage.","evidence":"Immunoblot of BACE1-cleaved fragments in NPC1-/- mouse brain and endolysosomal marker immunofluorescence in primary neurons","pmids":["29979789"],"confidence":"Medium","gaps":["Functional consequence of shedding for neuronal SEZ6 activity not established","Cleavage site not mapped"]},{"year":2019,"claim":"Confirmed that BACE1-shed SEZ6 ectodomain reaches human cerebrospinal fluid, establishing it as an accessible product of SEZ6 processing.","evidence":"Western blot detection of shed SEZ6 ectodomain in human CSF","pmids":["31041421"],"confidence":"Medium","gaps":["No quantitative or disease-state correlation established","Single method, single lab"]},{"year":2020,"claim":"Demonstrated a collective SEZ6-family requirement for dendritic spine structure, extending the single-gene synaptic phenotype to functional redundancy across SEZ6/SEZ6L/SEZ6L2.","evidence":"Sez6 triple-knockout mice with dendritic spine morphology imaging across brain regions","pmids":["31711114"],"confidence":"Medium","gaps":["Relative contribution of each family member not dissected","Downstream synaptic mechanism unresolved"]},{"year":2021,"claim":"Defined the biochemical mechanism of SEZ6 complement regulation: accelerated C3 convertase decay plus Factor I cofactor activity for C3b cleavage, assigning function to the sushi-domain architecture identified in 1995.","evidence":"Reconstituted in vitro complement opsonization, convertase decay, and Factor I cofactor assays with purified proteins","pmids":["33936031"],"confidence":"High","gaps":["In vivo relevance of complement regulation in brain not demonstrated","Mechanism uses SEZ6L2 as the representative for detailed assays"]},{"year":2022,"claim":"Distinguished SEZ6 from APP in Alzheimer pathology: peri-plaque BACE1 accumulation alters SEZ6 spatial distribution without enhancing its proteolysis.","evidence":"Immunoblot for BACE1-cleaved fragments and immunofluorescence co-localization in 5xFAD versus wild-type brains","pmids":["35998821"],"confidence":"Medium","gaps":["Cause of the localization shift unexplained","Functional consequence for synapses near plaques untested"]},{"year":2022,"claim":"Showed that neuronal activity modulates the balance of SEZ6 splice isoforms in a region-specific manner, connecting isoform choice to neuronal state.","evidence":"Isoform-specific qPCR on mouse brain punches and convulsant-treated cultured cortical neurons","pmids":["36368155"],"confidence":"Low","gaps":["Descriptive expression analysis without functional rescue","Mechanism coupling activity to splicing unknown"]},{"year":null,"claim":"How SEZ6 integrates its surface complement-regulatory activity with its control of dendritic morphology and spines remains unresolved, and no neuronal receptor or binding partner for the secreted isoform has been identified.","evidence":"No direct evidence in the available corpus links the complement and synaptic functions mechanistically","pmids":[],"confidence":"Low","gaps":["No identified neuronal binding partner or receptor","Unclear whether complement regulation operates in the CNS in vivo","Functional role of the shed ectodomain unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,8]}],"complexes":[],"partners":["BACE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53EL9","full_name":"Seizure protein 6 homolog","aliases":[],"length_aa":994,"mass_kda":107.4,"function":"May play a role in cell-cell recognition and in neuronal membrane signaling. Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. Involved in the development of appropriate excitatory synaptic connectivity (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q53EL9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEZ6","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEZ6","total_profiled":1310},"omim":[{"mim_id":"616667","title":"SEZ6-LIKE PROTEIN 2; SEZ6L2","url":"https://www.omim.org/entry/616667"},{"mim_id":"616666","title":"SEIZURE-RELATED 6, MOUSE, HOMOLOG OF; SEZ6","url":"https://www.omim.org/entry/616666"},{"mim_id":"607021","title":"SEZ6-LIKE PROTEIN; SEZ6L","url":"https://www.omim.org/entry/607021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":109.8}],"url":"https://www.proteinatlas.org/search/SEZ6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q53EL9","domains":[{"cath_id":"2.60.120.290","chopping":"246-258_268-355","consensus_level":"high","plddt":84.6592,"start":246,"end":355},{"cath_id":"2.60.120.290","chopping":"412-590","consensus_level":"medium","plddt":90.0067,"start":412,"end":590},{"cath_id":"2.60.120.290","chopping":"592-706","consensus_level":"medium","plddt":88.0519,"start":592,"end":706},{"cath_id":"2.10.70.10","chopping":"720-768","consensus_level":"medium","plddt":85.9539,"start":720,"end":768},{"cath_id":"2.10.70.10","chopping":"781-833","consensus_level":"high","plddt":86.1313,"start":781,"end":833},{"cath_id":"2.10.70.10","chopping":"839-898","consensus_level":"high","plddt":81.0738,"start":839,"end":898}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EL9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EL9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EL9-F1-predicted_aligned_error_v6.png","plddt_mean":69.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEZ6","jax_strain_url":"https://www.jax.org/strain/search?query=SEZ6"},"sequence":{"accession":"Q53EL9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EL9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EL9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EL9"}},"corpus_meta":[{"pmid":"18031681","id":"PMC_18031681","title":"Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/18031681","citation_count":123,"is_preprint":false},{"pmid":"35642431","id":"PMC_35642431","title":"ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.","date":"2022","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35642431","citation_count":52,"is_preprint":false},{"pmid":"31711114","id":"PMC_31711114","title":"Lack of Sez6 Family Proteins Impairs Motor Functions, Short-Term Memory, and Cognitive Flexibility and Alters Dendritic Spine Properties.","date":"2020","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/31711114","citation_count":47,"is_preprint":false},{"pmid":"7723619","id":"PMC_7723619","title":"Cloning and expression of SEZ-6, a brain-specific and seizure-related cDNA.","date":"1995","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7723619","citation_count":41,"is_preprint":false},{"pmid":"33936031","id":"PMC_33936031","title":"The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33936031","citation_count":34,"is_preprint":false},{"pmid":"7488116","id":"PMC_7488116","title":"Cloning and characterization of seizure-related gene, SEZ-6.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7488116","citation_count":32,"is_preprint":false},{"pmid":"12351182","id":"PMC_12351182","title":"Localized expression of the seizure-related gene SEZ-6 in developing and adult forebrains.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12351182","citation_count":25,"is_preprint":false},{"pmid":"21334315","id":"PMC_21334315","title":"The distribution of the seizure-related gene 6 (Sez-6) protein during postnatal development of the mouse forebrain suggests multiple functions for this protein: an analysis using a new antibody.","date":"2011","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/21334315","citation_count":22,"is_preprint":false},{"pmid":"21785725","id":"PMC_21785725","title":"The Role of Seizure-Related SEZ6 as a Susceptibility Gene in Febrile Seizures.","date":"2011","source":"Neurology research international","url":"https://pubmed.ncbi.nlm.nih.gov/21785725","citation_count":21,"is_preprint":false},{"pmid":"9073173","id":"PMC_9073173","title":"SEZ-6: promoter selectivity, genomic structure and localized expression in the brain.","date":"1997","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9073173","citation_count":19,"is_preprint":false},{"pmid":"29979789","id":"PMC_29979789","title":"BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29979789","citation_count":14,"is_preprint":false},{"pmid":"30309378","id":"PMC_30309378","title":"Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H.","date":"2018","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30309378","citation_count":13,"is_preprint":false},{"pmid":"34135477","id":"PMC_34135477","title":"ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment.","date":"2021","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/34135477","citation_count":12,"is_preprint":false},{"pmid":"31041421","id":"PMC_31041421","title":"Sez6 levels are elevated in cerebrospinal fluid of patients with inflammatory pain-associated conditions.","date":"2019","source":"Pain reports","url":"https://pubmed.ncbi.nlm.nih.gov/31041421","citation_count":10,"is_preprint":false},{"pmid":"19662096","id":"PMC_19662096","title":"Seizure-related gene 6 (Sez-6) in amacrine cells of the rodent retina and the consequence of gene deletion.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19662096","citation_count":10,"is_preprint":false},{"pmid":"38050039","id":"PMC_38050039","title":"Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6-Targeting Antibody-Drug Conjugate.","date":"2024","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/38050039","citation_count":5,"is_preprint":false},{"pmid":"40911432","id":"PMC_40911432","title":"Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.","date":"2025","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/40911432","citation_count":4,"is_preprint":false},{"pmid":"39324657","id":"PMC_39324657","title":"Detection of SEZ6, a Therapeutic Target, in Medullary Thyroid Carcinoma.","date":"2025","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39324657","citation_count":4,"is_preprint":false},{"pmid":"40699376","id":"PMC_40699376","title":"Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia.","date":"2025","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40699376","citation_count":3,"is_preprint":false},{"pmid":"25960298","id":"PMC_25960298","title":"N-Glycosylation modulates filopodia-like protrusions induced by sez-6 through regulating the distribution of this protein on the cell surface.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25960298","citation_count":3,"is_preprint":false},{"pmid":"35998821","id":"PMC_35998821","title":"Amyloid-ß plaque formation and BACE1 accumulation in the brains of a 5xFAD Alzheimer's disease mouse model is associated with altered distribution and not proteolysis of BACE1 substrates Sez6 and Sez6L.","date":"2022","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/35998821","citation_count":1,"is_preprint":false},{"pmid":"22351987","id":"PMC_22351987","title":"Sez-6 may play an important role in neurite outgrowth through the PKCgamma signaling pathways.","date":"2011","source":"Zeitschrift fur Naturforschung. C, Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/22351987","citation_count":1,"is_preprint":false},{"pmid":"41534317","id":"PMC_41534317","title":"SEZ6 expression and lineage plasticity in small cell lung cancer and transformed non-small cell lung cancer.","date":"2026","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41534317","citation_count":0,"is_preprint":false},{"pmid":"36368155","id":"PMC_36368155","title":"Differential brain expression pattern of Sez6 alternative splicing isoform with deleted transmembrane domain.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36368155","citation_count":0,"is_preprint":false},{"pmid":"41589586","id":"PMC_41589586","title":"Novel ImmunoPET Probes [64Cu]Cu-NOTA-GGB02-F9 for Small-Cell Lung Cancer Derived from a SEZ6-Targeting Antibody.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41589586","citation_count":0,"is_preprint":false},{"pmid":"42225988","id":"PMC_42225988","title":"SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors: a phase 1 trial.","date":"2026","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42225988","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.21.683746","title":"YAP1 defines an emergent, plastic population of relapsed small cell lung cancer","date":"2025-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.21.683746","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16381,"output_tokens":2841,"usd":0.045879,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10099,"output_tokens":3393,"usd":0.06766,"stage2_stop_reason":"end_turn"},"total_usd":0.113539,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"SEZ-6 encodes a brain-specific type I transmembrane protein containing five short consensus repeats (SCRs/sushi domains, complement C3b/C4b binding sites) and two CUB domain-like sequences, plus a signal sequence, threonine-rich domain, transmembrane domain, and short cytoplasmic tail. The protein is post-translationally modified and expressed in cerebrum and cerebellum.\",\n      \"method\": \"cDNA cloning, sequence analysis, in vitro translation, immunoblot with anti-SEZ6 peptide antibody\",\n      \"journal\": \"Brain research. Molecular brain research / Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary sequence characterization confirmed by in vitro translation and immunoblot, replicated across two independent papers from same group\",\n      \"pmids\": [\"7723619\", \"7488116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SEZ-6 exists in at least three isoforms generated by alternative splicing: one encoding a membrane protein with the full complement of SCRs/CUB domains, one encoding a membrane protein with a different C-terminal region, and one encoding a secreted protein with two SCRs and one CUB-like domain.\",\n      \"method\": \"PCR-based cDNA cloning and sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct sequence characterization from cDNA cloning, single lab\",\n      \"pmids\": [\"7488116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sez-6 is required for normal dendritic arborization of cortical pyramidal neurons: sez-6 null mice exhibit excess short dendrites and excessive neurite branching in cultured cortical neurons. Membrane-bound and secreted Sez-6 isoforms exert opposing effects on dendritic branching, with membrane-bound Sez-6 exerting an anti-branching effect under basal and depolarizing conditions. Loss of Sez-6 also reduces dendritic spine density and PSD-95 punctate staining, and reduces excitatory postsynaptic responses in layer V pyramidal neurons.\",\n      \"method\": \"Sez-6 null mouse analysis, isoform overexpression rescue in knockout neurons, slice electrophysiology, immunostaining for PSD-95\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, isoform rescue experiment, electrophysiology, replicated with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18031681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sez6 family members (Sez6, Sez6L, Sez6L2) inhibit complement activation: they inhibit C3b/iC3b opsonization by classical and alternative pathways. Using Sez6L2 as representative, the mechanism involves (1) accelerating dissociation of C3 convertases (decay-accelerating activity) and (2) functioning as a cofactor for Factor I to facilitate cleavage of C3b (but not C4b). Sez6 is the strongest classical pathway inhibitor among family members.\",\n      \"method\": \"In vitro complement opsonization assay, C3 convertase decay assay, Factor I cofactor assay with purified proteins\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro biochemical assays with purified components, two mechanistic activities demonstrated with orthogonal assays in single study\",\n      \"pmids\": [\"33936031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-glycosylation of Sez-6 regulates its cell surface distribution and function. Sez-6 has 11 N-glycosylation sites in three clusters (SC1-3, SC4-7, SC8-11) in the extracellular domain. Mutants lacking the SC4-7 cluster fail to induce filopodia-like protrusions, indicating SC4-7 is required for this activity. The unglycosylated mutant and mutants with only one cluster showed altered localization on the cell membrane compared to wild-type even distribution.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites, transfection into Neuro2a cells, immunofluorescence, conditioned medium analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct mutagenesis with cellular phenotype readout, single lab, single study\",\n      \"pmids\": [\"25960298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sez-6 promotes neurite outgrowth in PC12 cells: shRNA-mediated knockdown of Sez-6 inhibited NGF-induced neurite outgrowth and was associated with increased PKCγ protein levels, suggesting Sez-6 acts through the PKCγ signaling pathway.\",\n      \"method\": \"shRNA knockdown in PC12 cells, NGF treatment, neurite outgrowth measurement, PKCγ Western blot\",\n      \"journal\": \"Zeitschrift fur Naturforschung. C, Journal of biosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with indirect pathway inference (PKCγ correlation, not direct interaction)\",\n      \"pmids\": [\"22351987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BACE1 cleaves Sez6 and Sez6L, shedding their extracellular domains. Enhanced BACE1 cleavage of Sez6 and Sez6L is detected in NPC1-null mouse brains at 4 weeks of age. In NPC1-null primary cortical neurons, Sez6 and Sez6L show increased punctate staining within the endolysosomal pathway, suggesting trafficking defects within the endolysosomal pathway contribute to enhanced BACE1 proteolysis.\",\n      \"method\": \"Immunoblot quantification of BACE1-cleaved fragments in NPC1-/- vs wild-type mouse brains, immunofluorescence of endolysosomal markers in primary neurons\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (biochemical and imaging), in vivo and in vitro evidence in single study, single lab\",\n      \"pmids\": [\"29979789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The type I transmembrane isoform of Sez6 is cleaved by BACE1, resulting in shedding of the Sez6 extracellular domain; BACE1-shed Sez6 is detectable in human cerebrospinal fluid by Western blot.\",\n      \"method\": \"Western blot detection of shed Sez6 ectodomain in human CSF samples\",\n      \"journal\": \"Pain reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct detection of BACE1-cleaved product in human CSF, single lab, single method\",\n      \"pmids\": [\"31041421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Triple knockout of all three Sez6 family proteins (Sez6, Sez6L, Sez6L2) reduces dendritic spine density in the hippocampus and shifts spine morphology toward more immature forms in the somatosensory cortex, establishing a collective role for the Sez6 family in dendritic spine structure.\",\n      \"method\": \"Sez6 triple knockout mice, dendritic spine morphology analysis (imaging)\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic triple knockout with defined structural cellular phenotype, multiple brain regions analyzed, single lab\",\n      \"pmids\": [\"31711114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the 5xFAD Alzheimer's disease mouse model, accumulation of BACE1 around amyloid plaques does NOT result in enhanced proteolysis of Sez6 or Sez6L (in contrast to APP). Instead, Sez6 and Sez6L show altered spatial distribution in peri-plaque regions, suggesting their localization but not their BACE1-mediated cleavage is affected in AD pathology.\",\n      \"method\": \"Immunoblot for BACE1-cleaved Sez6/Sez6L fragments in 5xFAD vs wild-type brains, immunofluorescence co-localization\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative result for BACE1 proteolysis of Sez6 in AD model confirmed by biochemical and imaging methods, single lab\",\n      \"pmids\": [\"35998821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alternative splicing of Sez6 produces isoforms with distinct brain region-specific expression patterns; convulsant drug stimulation increases expression of recessive (secreted) isoforms alongside the dominant transmembrane isoform in cultured cortical neurons, indicating neuronal activity modulates isoform balance.\",\n      \"method\": \"Isoform-specific qPCR on mouse brain area punches and cultured cortical neurons treated with convulsant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — descriptive expression analysis of splice isoforms without functional rescue, single lab\",\n      \"pmids\": [\"36368155\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEZ6 is a brain-enriched type I transmembrane protein that, at the cell surface, inhibits complement activation by accelerating C3 convertase decay and acting as a Factor I cofactor to cleave C3b; membrane-bound SEZ6 suppresses dendritic branching and promotes dendritic spine formation/excitatory connectivity, while BACE1-mediated ectodomain shedding releases a soluble form detectable in CSF, and N-glycosylation of the extracellular domain regulates its membrane distribution and filopodia-inducing activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEZ6 is a brain-enriched type I transmembrane protein whose extracellular region comprises five complement-control short consensus repeats (sushi/SCR domains) and CUB-like domains, and which exists as both membrane-bound and secreted isoforms generated by alternative splicing [#0, #1]. Through its SCR domains, SEZ6 acts as a negative regulator of complement: it inhibits C3b/iC3b opsonization by accelerating decay of C3 convertases and serving as a Factor I cofactor for cleavage of C3b, with SEZ6 the strongest classical-pathway inhibitor among its family [#3]. In the nervous system, SEZ6 shapes neuronal morphology, with membrane-bound and secreted isoforms exerting opposing effects on dendritic branching; loss of SEZ6 produces excess short dendrites and excessive branching while reducing dendritic spine density, PSD-95 puncta, and excitatory postsynaptic responses in cortical pyramidal neurons [#2], and combined loss across the SEZ6 family reduces hippocampal spine density and shifts spines toward immature forms [#8]. The membrane isoform is processed by BACE1, which sheds the SEZ6 ectodomain into cerebrospinal fluid [#6, #7]. N-glycosylation of the extracellular domain, particularly the SC4-7 site cluster, governs SEZ6 membrane distribution and its filopodia-inducing activity [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of SEZ6 as a brain-specific type I transmembrane protein built from complement-control sushi/SCR repeats and CUB-like domains, defining the domain architecture that would later predict its complement-regulatory function.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, in vitro translation, and anti-peptide immunoblot\",\n      \"pmids\": [\"7723619\", \"7488116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional activity assigned to the SCR/CUB domains at this stage\", \"Tissue expression resolved only to cerebrum/cerebellum\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified alternative splicing yielding membrane-bound and secreted SEZ6 isoforms, raising the possibility that different isoforms carry distinct functions.\",\n      \"evidence\": \"PCR-based cDNA cloning and sequence analysis\",\n      \"pmids\": [\"7488116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences between isoforms not tested\", \"Relative abundance and regulation of isoforms unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a physiological neuronal role: SEZ6 controls dendritic arborization and excitatory connectivity, with membrane-bound and secreted isoforms acting in opposition.\",\n      \"evidence\": \"Sez6-null mouse analysis, isoform overexpression rescue in knockout neurons, slice electrophysiology, PSD-95 immunostaining\",\n      \"pmids\": [\"18031681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediators of the opposing isoform effects not identified\", \"No receptor or binding partner defined for the secreted form\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked SEZ6 to NGF-induced neurite outgrowth via a candidate PKCγ pathway, offering an intracellular signaling correlate.\",\n      \"evidence\": \"shRNA knockdown in PC12 cells with NGF treatment and PKCγ Western blot\",\n      \"pmids\": [\"22351987\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PKCγ link is correlative, not a demonstrated direct interaction\", \"Single cell line and single knockdown approach\", \"Apparent pro-outgrowth role contrasts with anti-branching role of membrane isoform in cortical neurons\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that extracellular N-glycosylation, specifically the SC4-7 cluster, is required for SEZ6 surface distribution and filopodia induction, identifying a post-translational determinant of its membrane activity.\",\n      \"evidence\": \"Site-directed mutagenesis of N-glycosylation sites in Neuro2a cells with immunofluorescence and conditioned-medium analysis\",\n      \"pmids\": [\"25960298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting glycosylation to filopodia formation unresolved\", \"Single cell line, single study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified BACE1 as the protease that sheds the SEZ6 ectodomain and showed endolysosomal trafficking defects (in NPC1-null neurons) enhance this cleavage.\",\n      \"evidence\": \"Immunoblot of BACE1-cleaved fragments in NPC1-/- mouse brain and endolysosomal marker immunofluorescence in primary neurons\",\n      \"pmids\": [\"29979789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of shedding for neuronal SEZ6 activity not established\", \"Cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed that BACE1-shed SEZ6 ectodomain reaches human cerebrospinal fluid, establishing it as an accessible product of SEZ6 processing.\",\n      \"evidence\": \"Western blot detection of shed SEZ6 ectodomain in human CSF\",\n      \"pmids\": [\"31041421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative or disease-state correlation established\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a collective SEZ6-family requirement for dendritic spine structure, extending the single-gene synaptic phenotype to functional redundancy across SEZ6/SEZ6L/SEZ6L2.\",\n      \"evidence\": \"Sez6 triple-knockout mice with dendritic spine morphology imaging across brain regions\",\n      \"pmids\": [\"31711114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each family member not dissected\", \"Downstream synaptic mechanism unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the biochemical mechanism of SEZ6 complement regulation: accelerated C3 convertase decay plus Factor I cofactor activity for C3b cleavage, assigning function to the sushi-domain architecture identified in 1995.\",\n      \"evidence\": \"Reconstituted in vitro complement opsonization, convertase decay, and Factor I cofactor assays with purified proteins\",\n      \"pmids\": [\"33936031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of complement regulation in brain not demonstrated\", \"Mechanism uses SEZ6L2 as the representative for detailed assays\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished SEZ6 from APP in Alzheimer pathology: peri-plaque BACE1 accumulation alters SEZ6 spatial distribution without enhancing its proteolysis.\",\n      \"evidence\": \"Immunoblot for BACE1-cleaved fragments and immunofluorescence co-localization in 5xFAD versus wild-type brains\",\n      \"pmids\": [\"35998821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of the localization shift unexplained\", \"Functional consequence for synapses near plaques untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that neuronal activity modulates the balance of SEZ6 splice isoforms in a region-specific manner, connecting isoform choice to neuronal state.\",\n      \"evidence\": \"Isoform-specific qPCR on mouse brain punches and convulsant-treated cultured cortical neurons\",\n      \"pmids\": [\"36368155\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Descriptive expression analysis without functional rescue\", \"Mechanism coupling activity to splicing unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEZ6 integrates its surface complement-regulatory activity with its control of dendritic morphology and spines remains unresolved, and no neuronal receptor or binding partner for the secreted isoform has been identified.\",\n      \"evidence\": \"No direct evidence in the available corpus links the complement and synaptic functions mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified neuronal binding partner or receptor\", \"Unclear whether complement regulation operates in the CNS in vivo\", \"Functional role of the shed ectodomain unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BACE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}