{"gene":"KCTD12","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2013,"finding":"KCTD12 associates with GABAB receptors while they reside in the endoplasmic reticulum (before plasma membrane trafficking), remains associated during receptor activity and internalization, and reduces constitutive receptor internalization, thereby increasing the magnitude of GABAB receptor signaling at the cell surface. Knockdown or knockout of KCTD12 in cultured hippocampal neurons reduces the magnitude of GABAB receptor-mediated K+ current response.","method":"Bimolecular fluorescence complementation, metabolic labeling, glycosylation experiments, immunoprecipitation, bioluminescence resonance energy transfer, hippocampal neuron electrophysiology with KO/knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (BiFC, BRET, Co-IP, electrophysiology in KO neurons) in a single rigorous study establishing mechanism","pmids":["23843457"],"is_preprint":false},{"year":2013,"finding":"The N-terminal BTB/POZ domain of KCTD12 (KCTD12BTB) binds the C-terminal region of GABAB2 with low-micromolar affinity; both the BTB and C-terminal H1 domains independently form tetramers; the two domains bind each other, suggesting a compact structure with interacting structured domains joined by a disordered region.","method":"CD spectroscopy, binding assays, size-exclusion chromatography, computational secondary structure prediction","journal":"Journal of molecular recognition : JMR","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — biophysical characterization with multiple methods in a single lab; no mutagenesis or cell-based functional validation","pmids":["23996491"],"is_preprint":false},{"year":2014,"finding":"KCTD12-induced fast desensitization of GABAB receptor-activated K+ currents is regulated by PKA-dependent phosphorylation of serine-892 on GABAB2: serine-892 phosphorylation rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. PKA activation in hippocampal neurons slows fast desensitization, and this regulation is absent in KCTD12 knockout mice or S892A knock-in mice. Tonic S892 phosphorylation is itself promoted by assembly of receptors with KCTD12, creating a cross-regulatory loop.","method":"Heterologous cell electrophysiology, hippocampal neuron recordings, KCTD12 KO mice, S892A knock-in mice, PKA pharmacology","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic knockouts, phospho-site knock-in mice, and pharmacological manipulation with electrophysiology provide multiple orthogonal lines of evidence","pmids":["25065880"],"is_preprint":false},{"year":2015,"finding":"Loss of KCTD12 (Kctd12−/− mice) increases intrinsic excitability of hippocampal pyramidal neurons and alters emotionality and fear learning, establishing a direct role for KCTD12 in modulating neuronal excitability.","method":"Electrophysiological recordings from hippocampal slices of Kctd12−/− and Kctd12+/− mice, behavioral assays","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO model with defined electrophysiological and behavioral phenotypes, single lab","pmids":["25689571"],"is_preprint":false},{"year":2017,"finding":"KCTD12 interacts with CDK1 (identified by co-immunoprecipitation and mass spectrometry), activates CDK1 and Aurora kinase A to facilitate G2/M transition. CDC25B silencing abrogates the effects of KCTD12 on CDK1 phosphorylation and cell proliferation. Aurora A phosphorylates KCTD12 at serine 243, creating a positive feedback loop.","method":"Co-immunoprecipitation, mass spectrometry, CDC25B siRNA knockdown, phosphorylation assays, cell cycle analysis, xenograft tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS interaction plus epistasis (CDC25B silencing) and phospho-site identification, single lab","pmids":["28869606"],"is_preprint":false},{"year":2017,"finding":"KCTD12 desensitization of GABAB receptor-mediated K+ currents is absent in KCTD12-deficient mice in cholecystokinin-expressing interneurons (CCK-INs) in the rat/mouse hippocampus, demonstrating that KCTD12 is required for the desensitization of GABABR-mediated currents in these interneurons.","method":"Whole-cell recordings from CCK-INs in KCTD12-deficient mice, immunoelectron microscopy","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with direct electrophysiological recordings plus anatomical localization data, replicates known KCTD12 desensitization function in a specific cell type","pmids":["27073217"],"is_preprint":false},{"year":2017,"finding":"Human KCTD12 co-expression accelerates both activation and desensitization kinetics of GABAB receptor-mediated GIRK currents, and enhances the potentiating effects of the positive allosteric modulator CGP7930 on GABAB receptor activation and desensitization.","method":"Automated whole-cell electrophysiology in heterologous expression system with human KCTD12, KCTD12 KO mice (in vivo pharmacology)","journal":"Pharmacology research & perspectives","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology with human construct plus KO validation, single lab","pmids":["28713569"],"is_preprint":false},{"year":2016,"finding":"KCTD12 suppresses colorectal cancer cell stemness markers (CD44, CD133, CD29) by inhibiting the ERK pathway; ERK1/2 inhibitor U0126 abolishes the increase in stemness markers induced by KCTD12 downregulation, placing KCTD12 upstream of ERK in this pathway.","method":"siRNA knockdown, ectopic overexpression, colony/spheroid formation, xenograft model, ERK inhibitor epistasis (U0126)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with pharmacological ERK inhibitor plus KD/OE functional assays, single lab","pmids":["26847701"],"is_preprint":false},{"year":2019,"finding":"Disruption of the KCTD12-CDK1 protein interaction by adefovir dipivoxil induces G2 phase cell cycle arrest and inhibits colon cancer cell proliferation, demonstrating that the KCTD12-CDK1 interaction is functionally necessary for CDK1 activation in this context.","method":"Drug screening of FDA-approved library, co-immunoprecipitation to measure interaction disruption, cell cycle analysis, in vitro and xenograft proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological disruption of a defined PPI with functional readouts, corroborates prior CDK1 interaction data, single lab","pmids":["30872078"],"is_preprint":false},{"year":2019,"finding":"Lithium increases KCTD12 expression via inhibition of GSK-3, which leads to CREB-mediated KCTD12 promoter activation. Conversely, GADL1 overexpression enhances GSK-3 activation and inhibits KCTD12 expression, identifying GSK-3 as a regulator of KCTD12 transcription.","method":"GSK-3 inhibition in SH-SY5Y cells, KCTD12 promoter reporter assays, GADL1 overexpression, lithium treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter activity assay plus pharmacological and genetic manipulation of GSK-3, single lab","pmids":["31311980"],"is_preprint":false},{"year":2019,"finding":"KCTD12 interacts with CD271 (p75NTR), and loss of KCTD12 enhances melanoma cell stemness transformation via this interaction.","method":"KCTD12 knockout cell lines, in vitro stemness assays, in vivo metastasis model","journal":"Cancer biology & medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction inferred from knockout phenotype; direct biochemical demonstration of KCTD12-CD271 binding not described in abstract","pmids":["31565480"],"is_preprint":false},{"year":2018,"finding":"KIT knockdown in GIST T1 cells upregulates KCTD12 (pfetin) at both mRNA and protein levels, and KCTD12 knockdown accelerates GIST cell growth, establishing that KIT negatively regulates KCTD12 expression and that KCTD12 functions as a tumor suppressor in GISTs.","method":"siRNA KIT knockdown, KCTD12 knockdown, cell proliferation assays in GIST T1 cells, qPCR and Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal knockdown experiments with defined growth phenotype, single lab","pmids":["29930747"],"is_preprint":false},{"year":2022,"finding":"KCTD8 and KCTD12 facilitate expression of GABAB receptors specifically in axonal terminals (but not somata) of habenula cholinergic neurons, contributing to presynaptic GABAB-mediated excitation (potentiation of glutamate release and Ca2+ entry). Overexpression of either KCTD8 or KCTD12 in KCTD8/12/16 triple KO mice rescued axonal GABAB expression and presynaptic excitation.","method":"Multiple KCTD KO mouse lines (single, double, triple), axonal/somatic GABAB immunostaining, presynaptic Ca2+ imaging, glutamate release measurement, KCTD rescue overexpression","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal KO combinations with defined anatomical and physiological phenotypes plus rescue experiment in a single rigorous study","pmids":["35017224"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, Kctd12 negatively regulates the kinase Ulk2 via a proline-serine rich domain interaction; Ulk2 positively regulates habenular dendritogenesis, and loss of Kctd12 results in increased dendritic branching/elaboration and decreased anxiety-like behavior.","method":"Zebrafish loss-of-function, protein interaction domain mapping (Ulk2 proline-serine rich domain), morphological dendritic analysis, behavioral assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis with domain mapping and behavioral phenotype in zebrafish, single lab","pmids":["25329151"],"is_preprint":false},{"year":2020,"finding":"Overexpression of Kctd12 in the dentate gyrus (DG) increases vulnerability to social stress and reduces granule cell excitability, while knockdown of Kctd12 in DG prevents social avoidance and stimulates neuronal activity that contributes to antidepressant-like effects of fluoxetine. GABAB receptor antagonist CGP35348 suppresses stress-induced KCTD12 upregulation and improves behavioral responses.","method":"Viral-mediated overexpression and knockdown in mouse DG, chronic social defeat stress model, electrophysiology of DG granule cells, pharmacology with GABABR antagonist","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — region-specific KD/OE with defined electrophysiological and behavioral phenotypes plus pharmacological validation, single lab","pmids":["33285230"],"is_preprint":false},{"year":2025,"finding":"MSL1 negatively regulates KCTD12 expression, and KCTD12 in turn regulates SLC7A11 (xCT). In colon cancer cells, Erastin-induced ferroptosis suppresses MSL1, leading to KCTD12 upregulation and consequent modulation of SLC7A11-dependent ROS, GSH, and MDA levels.","method":"Biochemical assays, knockdown and overexpression studies in HCT116 and SW480 cells, ferroptosis induction with Erastin","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, largely KD/OE with pathway marker readouts; direct molecular mechanism of MSL1-KCTD12 regulation not biochemically characterized in abstract","pmids":["40221412"],"is_preprint":false}],"current_model":"KCTD12 is an auxiliary subunit of GABAB receptors that assembles with the GABAB1/GABAB2 heterodimer in the ER, reduces constitutive receptor internalization to increase surface GABAB signaling, accelerates activation and desensitization kinetics of GABAB-mediated GIRK/K+ currents via binding to Gβγ subunits, and facilitates axonal trafficking of GABAB receptors in specific neuron types; additionally, PKA-mediated phosphorylation of GABAB2-S892 cross-regulates KCTD12-induced desensitization, Aurora A phosphorylates KCTD12 at S243 to potentiate a CDK1/CDC25B/Aurora A cell-cycle feedback loop, and KCTD12 suppresses ERK-dependent stemness signaling in cancer cells."},"narrative":{"mechanistic_narrative":"KCTD12 is an auxiliary subunit of GABAB receptors that shapes inhibitory neurotransmission by tuning receptor surface abundance and signaling kinetics [PMID:23843457, PMID:28713569]. It associates with the GABAB1/GABAB2 heterodimer already in the endoplasmic reticulum through its N-terminal BTB/POZ domain, which binds the C-terminal region of GABAB2; both the BTB and C-terminal H1 domains independently tetramerize, giving the protein a compact multidomain architecture [PMID:23996491]. By reducing constitutive receptor internalization, KCTD12 increases the magnitude of GABAB-mediated K+ (GIRK) currents, while simultaneously accelerating both activation and desensitization kinetics of these currents [PMID:23843457, PMID:28713569]. This desensitization is cross-regulated by PKA-dependent phosphorylation of GABAB2 serine-892, which rearranges KCTD12 at the receptor to slow desensitization, and the receptor-KCTD12 assembly itself promotes tonic S892 phosphorylation, forming a feedback loop [PMID:25065880]. KCTD12 is required for GABAB current desensitization in specific neuron types such as cholecystokinin-expressing hippocampal interneurons, and together with KCTD8 it facilitates axonal-terminal GABAB expression and presynaptic excitation in habenular cholinergic neurons [PMID:27073217, PMID:35017224]. Through these actions KCTD12 controls intrinsic neuronal excitability and influences emotionality, fear learning, and stress-related behavior [PMID:25689571, PMID:33285230]. Beyond the nervous system, KCTD12 acts in cell-cycle and cancer contexts: it interacts with CDK1 and activates CDK1 and Aurora kinase A to drive the G2/M transition through a CDC25B-dependent step, with Aurora A phosphorylating KCTD12 at serine-243 to establish a positive feedback loop [PMID:28869606, PMID:30872078]. In colorectal cancer cells it suppresses stemness markers by inhibiting the ERK pathway, functioning upstream of ERK [PMID:26847701].","teleology":[{"year":2013,"claim":"Established that KCTD12 is a GABAB receptor-associated subunit acting at the ER to limit receptor internalization and thereby amplify surface GABAB signaling, answering how an accessory protein controls receptor abundance.","evidence":"BiFC, metabolic labeling/glycosylation, Co-IP, BRET, and electrophysiology in KCTD12 KO/knockdown hippocampal neurons","pmids":["23843457"],"confidence":"High","gaps":["Structural basis of the ER association not resolved","Mechanism by which internalization is reduced not defined at molecular detail"]},{"year":2013,"claim":"Defined the structural basis of the KCTD12-GABAB2 interaction, showing the N-terminal BTB/POZ domain binds GABAB2 and that BTB and H1 domains tetramerize independently.","evidence":"CD spectroscopy, binding assays, size-exclusion chromatography, secondary structure prediction","pmids":["23996491"],"confidence":"Medium","gaps":["No mutagenesis to validate binding interface","No cell-based functional confirmation of the domain model","No high-resolution structure"]},{"year":2014,"claim":"Revealed cross-regulation between KCTD12-induced desensitization and PKA phosphorylation of GABAB2-S892, showing how receptor phosphorylation reciprocally tunes the auxiliary subunit's kinetic effect.","evidence":"Heterologous and neuronal electrophysiology with KCTD12 KO and S892A knock-in mice plus PKA pharmacology","pmids":["25065880"],"confidence":"High","gaps":["Molecular conformational change of KCTD12 upon S892 phosphorylation not directly visualized","Kinase recruitment mechanism unresolved"]},{"year":2014,"claim":"Identified a non-receptor signaling role in zebrafish whereby Kctd12 negatively regulates the kinase Ulk2 to restrain habenular dendritogenesis and anxiety-like behavior.","evidence":"Zebrafish loss-of-function, Ulk2 proline-serine rich domain interaction mapping, dendritic morphometry, behavioral assays","pmids":["25329151"],"confidence":"Medium","gaps":["Conservation of the Ulk2 interaction in mammals not shown","Direct biochemical binding not validated beyond domain mapping"]},{"year":2015,"claim":"Connected KCTD12 loss to elevated intrinsic excitability of hippocampal pyramidal neurons and altered emotional behavior, linking the molecular function to circuit-level and behavioral output.","evidence":"Slice electrophysiology in Kctd12-/- and Kctd12+/- mice with behavioral assays","pmids":["25689571"],"confidence":"Medium","gaps":["Single lab","Causal chain from excitability change to behavior not dissected"]},{"year":2016,"claim":"Placed KCTD12 upstream of ERK as a suppressor of colorectal cancer cell stemness, extending its function beyond neuronal GABAB signaling.","evidence":"siRNA/overexpression, colony/spheroid assays, xenografts, ERK inhibitor (U0126) epistasis","pmids":["26847701"],"confidence":"Medium","gaps":["Mechanism linking KCTD12 to ERK not biochemically defined","Direct ERK-pathway partner not identified"]},{"year":2017,"claim":"Demonstrated cell-type specificity of KCTD12-dependent GABAB current desensitization, showing it is required in CCK-expressing hippocampal interneurons.","evidence":"Whole-cell recordings in KCTD12-deficient mice with immunoelectron microscopy","pmids":["27073217"],"confidence":"High","gaps":["Why some interneuron types depend on KCTD12 and others differ not explained"]},{"year":2017,"claim":"Showed human KCTD12 accelerates both activation and desensitization of GABAB-GIRK currents and enhances positive allosteric modulation, confirming kinetic control across species.","evidence":"Automated heterologous electrophysiology with human KCTD12 and KCTD12 KO mouse pharmacology","pmids":["28713569"],"confidence":"Medium","gaps":["Single lab","Structural basis of kinetic acceleration not resolved"]},{"year":2017,"claim":"Uncovered a cell-cycle role in which KCTD12 binds and activates CDK1 and Aurora A via CDC25B to promote G2/M, with Aurora A phosphorylating KCTD12-S243 in a feedback loop.","evidence":"Co-IP/mass spectrometry, CDC25B siRNA epistasis, phosphorylation assays, cell-cycle analysis, xenografts","pmids":["28869606"],"confidence":"Medium","gaps":["Direct CDK1 binding interface not mapped","Functional consequence of S243 phosphorylation not isolated","Single lab"]},{"year":2018,"claim":"Positioned KCTD12 as a tumor suppressor downstream of KIT in GISTs, where KIT negatively regulates its expression.","evidence":"Reciprocal KIT and KCTD12 siRNA knockdown with proliferation assays, qPCR, Western blot in GIST T1 cells","pmids":["29930747"],"confidence":"Medium","gaps":["Mechanism of KIT-dependent KCTD12 repression unknown","Downstream effectors of KCTD12 in GIST not defined"]},{"year":2019,"claim":"Validated the KCTD12-CDK1 interaction as functionally required by showing its pharmacological disruption arrests cells in G2 and blocks colon cancer proliferation.","evidence":"FDA library drug screen, Co-IP-based interaction disruption (adefovir dipivoxil), cell-cycle and xenograft proliferation assays","pmids":["30872078"],"confidence":"Medium","gaps":["Drug specificity for the interaction not fully excluded","Structural binding site not defined"]},{"year":2019,"claim":"Identified transcriptional control of KCTD12 via GSK-3/CREB, with lithium increasing and GADL1 decreasing its expression.","evidence":"GSK-3 inhibition, KCTD12 promoter reporter assays, GADL1 overexpression, lithium treatment in SH-SY5Y cells","pmids":["31311980"],"confidence":"Medium","gaps":["In vivo relevance of this regulatory axis not established","Direct CREB occupancy on the promoter not shown"]},{"year":2019,"claim":"Linked KCTD12 loss to enhanced melanoma stemness via a proposed CD271 (p75NTR) interaction.","evidence":"KCTD12 knockout cell lines, in vitro stemness assays, in vivo metastasis model","pmids":["31565480"],"confidence":"Low","gaps":["Direct biochemical KCTD12-CD271 binding not demonstrated","Interaction inferred from phenotype only"]},{"year":2020,"claim":"Established a region-specific behavioral role whereby dentate gyrus KCTD12 levels bidirectionally control stress vulnerability and granule cell excitability, linked to GABAB signaling.","evidence":"Viral KD/OE in mouse DG, social defeat stress, granule cell electrophysiology, GABAB antagonist pharmacology","pmids":["33285230"],"confidence":"Medium","gaps":["Single lab","Molecular link between KCTD12 level and stress circuitry not fully resolved"]},{"year":2022,"claim":"Showed KCTD12, with KCTD8, selectively promotes axonal-terminal GABAB receptor expression and presynaptic excitation in habenular cholinergic neurons, confirmed by rescue in triple-KO mice.","evidence":"Multiple KCTD KO combinations, compartment-specific GABAB immunostaining, presynaptic Ca2+ imaging, glutamate release, rescue overexpression","pmids":["35017224"],"confidence":"High","gaps":["Mechanism of compartment-specific (axonal vs somatic) trafficking not defined","Functional redundancy partition between KCTD8 and KCTD12 unresolved"]},{"year":2025,"claim":"Proposed a ferroptosis-related axis in which MSL1 represses KCTD12, which in turn regulates SLC7A11-dependent redox balance in colon cancer.","evidence":"Knockdown/overexpression in HCT116 and SW480 cells with Erastin-induced ferroptosis and redox marker readouts","pmids":["40221412"],"confidence":"Low","gaps":["Direct molecular mechanism of MSL1-KCTD12 regulation not biochemically characterized","How KCTD12 regulates SLC7A11 not defined","Single lab"]},{"year":null,"claim":"How KCTD12's two functional domains structurally couple GABAB2 binding to Gβγ-dependent kinetic control, and whether its neuronal auxiliary-subunit role and its cytoplasmic cell-cycle/cancer functions involve distinct conformations or partners, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the KCTD12-GABAB receptor complex","Mechanistic unification of neuronal and oncogenic roles lacking","Direct partner interfaces (CDK1, CD271) unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,5,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,8]}],"complexes":["GABAB receptor complex"],"partners":["GABBR2","CDK1","AURKA","CDC25B","ULK2","KCTD8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CX2","full_name":"BTB/POZ domain-containing protein KCTD12","aliases":["Pfetin","Predominantly fetal expressed T1 domain"],"length_aa":325,"mass_kda":35.7,"function":"Auxiliary subunit of GABA-B receptors that determine the pharmacology and kinetics of the receptor response. Increases agonist potency and markedly alter the G-protein signaling of the receptors by accelerating onset and promoting desensitization (By similarity)","subcellular_location":"Presynaptic cell membrane; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96CX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCTD12","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCTD12","total_profiled":1310},"omim":[{"mim_id":"610521","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 12; KCTD12","url":"https://www.omim.org/entry/610521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitochondria","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KCTD12"},"hgnc":{"alias_symbol":["KIAA1778","PFET1"],"prev_symbol":["C13orf2"]},"alphafold":{"accession":"Q96CX2","domains":[{"cath_id":"3.30.710.10","chopping":"34-129","consensus_level":"high","plddt":94.5213,"start":34,"end":129},{"cath_id":"-","chopping":"207-323","consensus_level":"high","plddt":87.059,"start":207,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CX2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CX2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CX2-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCTD12","jax_strain_url":"https://www.jax.org/strain/search?query=KCTD12"},"sequence":{"accession":"Q96CX2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CX2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CX2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CX2"}},"corpus_meta":[{"pmid":"28869606","id":"PMC_28869606","title":"KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28869606","citation_count":57,"is_preprint":false},{"pmid":"25689571","id":"PMC_25689571","title":"Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders.","date":"2015","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25689571","citation_count":43,"is_preprint":false},{"pmid":"23843457","id":"PMC_23843457","title":"Up-regulation of GABA(B) receptor signaling by constitutive assembly with the K+ channel tetramerization domain-containing protein 12 (KCTD12).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23843457","citation_count":36,"is_preprint":false},{"pmid":"26847701","id":"PMC_26847701","title":"KCTD12 Regulates Colorectal Cancer Cell Stemness through the ERK Pathway.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26847701","citation_count":34,"is_preprint":false},{"pmid":"27073217","id":"PMC_27073217","title":"KCTD12 Auxiliary Proteins Modulate Kinetics of GABAB Receptor-Mediated Inhibition in Cholecystokinin-Containing Interneurons.","date":"2017","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/27073217","citation_count":32,"is_preprint":false},{"pmid":"30872078","id":"PMC_30872078","title":"Adefovir dipivoxil sensitizes colon cancer cells to vemurafenib by disrupting the KCTD12-CDK1 interaction.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30872078","citation_count":32,"is_preprint":false},{"pmid":"25065880","id":"PMC_25065880","title":"GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization.","date":"2014","source":"Biochemical 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30157793","citation_count":23,"is_preprint":false},{"pmid":"30886212","id":"PMC_30886212","title":"Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination.","date":"2019","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30886212","citation_count":22,"is_preprint":false},{"pmid":"32207860","id":"PMC_32207860","title":"KCTD12 promotes G1/S transition of breast cancer cell through activating the AKT/FOXO1 signaling.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/32207860","citation_count":18,"is_preprint":false},{"pmid":"28000887","id":"PMC_28000887","title":"Lentiviral-mediated overexpression of KCTD12 inhibits the proliferation of human uveal melanoma OCM-1 cells.","date":"2016","source":"Oncology 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/31311980","citation_count":8,"is_preprint":false},{"pmid":"35426242","id":"PMC_35426242","title":"LINC00365 inhibited lung adenocarcinoma progression and glycolysis via sponging miR-429/KCTD12 axis.","date":"2022","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35426242","citation_count":8,"is_preprint":false},{"pmid":"40221412","id":"PMC_40221412","title":"Male-specific lethal 1 (MSL1) promotes Erastin-induced ferroptosis in colon cancer cells by regulating the KCTD12-SLC7A11 axis.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40221412","citation_count":5,"is_preprint":false},{"pmid":"29930747","id":"PMC_29930747","title":"KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29930747","citation_count":5,"is_preprint":false},{"pmid":"25329151","id":"PMC_25329151","title":"Kctd12 and Ulk2 partner to regulate dendritogenesis and behavior in the habenular nuclei.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25329151","citation_count":4,"is_preprint":false},{"pmid":"41944200","id":"PMC_41944200","title":"RETRACTION: KCTD12 Promotes G1/S Transition of Breast Cancer Cell through Activating the AKT/FOXO1 Signaling.","date":"2026","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/41944200","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14627,"output_tokens":4061,"usd":0.052398,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11868,"output_tokens":4814,"usd":0.089845,"stage2_stop_reason":"end_turn"},"total_usd":0.142243,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"KCTD12 associates with GABAB receptors while they reside in the endoplasmic reticulum (before plasma membrane trafficking), remains associated during receptor activity and internalization, and reduces constitutive receptor internalization, thereby increasing the magnitude of GABAB receptor signaling at the cell surface. Knockdown or knockout of KCTD12 in cultured hippocampal neurons reduces the magnitude of GABAB receptor-mediated K+ current response.\",\n      \"method\": \"Bimolecular fluorescence complementation, metabolic labeling, glycosylation experiments, immunoprecipitation, bioluminescence resonance energy transfer, hippocampal neuron electrophysiology with KO/knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (BiFC, BRET, Co-IP, electrophysiology in KO neurons) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"23843457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal BTB/POZ domain of KCTD12 (KCTD12BTB) binds the C-terminal region of GABAB2 with low-micromolar affinity; both the BTB and C-terminal H1 domains independently form tetramers; the two domains bind each other, suggesting a compact structure with interacting structured domains joined by a disordered region.\",\n      \"method\": \"CD spectroscopy, binding assays, size-exclusion chromatography, computational secondary structure prediction\",\n      \"journal\": \"Journal of molecular recognition : JMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biophysical characterization with multiple methods in a single lab; no mutagenesis or cell-based functional validation\",\n      \"pmids\": [\"23996491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KCTD12-induced fast desensitization of GABAB receptor-activated K+ currents is regulated by PKA-dependent phosphorylation of serine-892 on GABAB2: serine-892 phosphorylation rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. PKA activation in hippocampal neurons slows fast desensitization, and this regulation is absent in KCTD12 knockout mice or S892A knock-in mice. Tonic S892 phosphorylation is itself promoted by assembly of receptors with KCTD12, creating a cross-regulatory loop.\",\n      \"method\": \"Heterologous cell electrophysiology, hippocampal neuron recordings, KCTD12 KO mice, S892A knock-in mice, PKA pharmacology\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic knockouts, phospho-site knock-in mice, and pharmacological manipulation with electrophysiology provide multiple orthogonal lines of evidence\",\n      \"pmids\": [\"25065880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of KCTD12 (Kctd12−/− mice) increases intrinsic excitability of hippocampal pyramidal neurons and alters emotionality and fear learning, establishing a direct role for KCTD12 in modulating neuronal excitability.\",\n      \"method\": \"Electrophysiological recordings from hippocampal slices of Kctd12−/− and Kctd12+/− mice, behavioral assays\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with defined electrophysiological and behavioral phenotypes, single lab\",\n      \"pmids\": [\"25689571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCTD12 interacts with CDK1 (identified by co-immunoprecipitation and mass spectrometry), activates CDK1 and Aurora kinase A to facilitate G2/M transition. CDC25B silencing abrogates the effects of KCTD12 on CDK1 phosphorylation and cell proliferation. Aurora A phosphorylates KCTD12 at serine 243, creating a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, CDC25B siRNA knockdown, phosphorylation assays, cell cycle analysis, xenograft tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS interaction plus epistasis (CDC25B silencing) and phospho-site identification, single lab\",\n      \"pmids\": [\"28869606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCTD12 desensitization of GABAB receptor-mediated K+ currents is absent in KCTD12-deficient mice in cholecystokinin-expressing interneurons (CCK-INs) in the rat/mouse hippocampus, demonstrating that KCTD12 is required for the desensitization of GABABR-mediated currents in these interneurons.\",\n      \"method\": \"Whole-cell recordings from CCK-INs in KCTD12-deficient mice, immunoelectron microscopy\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with direct electrophysiological recordings plus anatomical localization data, replicates known KCTD12 desensitization function in a specific cell type\",\n      \"pmids\": [\"27073217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human KCTD12 co-expression accelerates both activation and desensitization kinetics of GABAB receptor-mediated GIRK currents, and enhances the potentiating effects of the positive allosteric modulator CGP7930 on GABAB receptor activation and desensitization.\",\n      \"method\": \"Automated whole-cell electrophysiology in heterologous expression system with human KCTD12, KCTD12 KO mice (in vivo pharmacology)\",\n      \"journal\": \"Pharmacology research & perspectives\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology with human construct plus KO validation, single lab\",\n      \"pmids\": [\"28713569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KCTD12 suppresses colorectal cancer cell stemness markers (CD44, CD133, CD29) by inhibiting the ERK pathway; ERK1/2 inhibitor U0126 abolishes the increase in stemness markers induced by KCTD12 downregulation, placing KCTD12 upstream of ERK in this pathway.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, colony/spheroid formation, xenograft model, ERK inhibitor epistasis (U0126)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with pharmacological ERK inhibitor plus KD/OE functional assays, single lab\",\n      \"pmids\": [\"26847701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disruption of the KCTD12-CDK1 protein interaction by adefovir dipivoxil induces G2 phase cell cycle arrest and inhibits colon cancer cell proliferation, demonstrating that the KCTD12-CDK1 interaction is functionally necessary for CDK1 activation in this context.\",\n      \"method\": \"Drug screening of FDA-approved library, co-immunoprecipitation to measure interaction disruption, cell cycle analysis, in vitro and xenograft proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological disruption of a defined PPI with functional readouts, corroborates prior CDK1 interaction data, single lab\",\n      \"pmids\": [\"30872078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lithium increases KCTD12 expression via inhibition of GSK-3, which leads to CREB-mediated KCTD12 promoter activation. Conversely, GADL1 overexpression enhances GSK-3 activation and inhibits KCTD12 expression, identifying GSK-3 as a regulator of KCTD12 transcription.\",\n      \"method\": \"GSK-3 inhibition in SH-SY5Y cells, KCTD12 promoter reporter assays, GADL1 overexpression, lithium treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter activity assay plus pharmacological and genetic manipulation of GSK-3, single lab\",\n      \"pmids\": [\"31311980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KCTD12 interacts with CD271 (p75NTR), and loss of KCTD12 enhances melanoma cell stemness transformation via this interaction.\",\n      \"method\": \"KCTD12 knockout cell lines, in vitro stemness assays, in vivo metastasis model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction inferred from knockout phenotype; direct biochemical demonstration of KCTD12-CD271 binding not described in abstract\",\n      \"pmids\": [\"31565480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIT knockdown in GIST T1 cells upregulates KCTD12 (pfetin) at both mRNA and protein levels, and KCTD12 knockdown accelerates GIST cell growth, establishing that KIT negatively regulates KCTD12 expression and that KCTD12 functions as a tumor suppressor in GISTs.\",\n      \"method\": \"siRNA KIT knockdown, KCTD12 knockdown, cell proliferation assays in GIST T1 cells, qPCR and Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal knockdown experiments with defined growth phenotype, single lab\",\n      \"pmids\": [\"29930747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KCTD8 and KCTD12 facilitate expression of GABAB receptors specifically in axonal terminals (but not somata) of habenula cholinergic neurons, contributing to presynaptic GABAB-mediated excitation (potentiation of glutamate release and Ca2+ entry). Overexpression of either KCTD8 or KCTD12 in KCTD8/12/16 triple KO mice rescued axonal GABAB expression and presynaptic excitation.\",\n      \"method\": \"Multiple KCTD KO mouse lines (single, double, triple), axonal/somatic GABAB immunostaining, presynaptic Ca2+ imaging, glutamate release measurement, KCTD rescue overexpression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal KO combinations with defined anatomical and physiological phenotypes plus rescue experiment in a single rigorous study\",\n      \"pmids\": [\"35017224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, Kctd12 negatively regulates the kinase Ulk2 via a proline-serine rich domain interaction; Ulk2 positively regulates habenular dendritogenesis, and loss of Kctd12 results in increased dendritic branching/elaboration and decreased anxiety-like behavior.\",\n      \"method\": \"Zebrafish loss-of-function, protein interaction domain mapping (Ulk2 proline-serine rich domain), morphological dendritic analysis, behavioral assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis with domain mapping and behavioral phenotype in zebrafish, single lab\",\n      \"pmids\": [\"25329151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of Kctd12 in the dentate gyrus (DG) increases vulnerability to social stress and reduces granule cell excitability, while knockdown of Kctd12 in DG prevents social avoidance and stimulates neuronal activity that contributes to antidepressant-like effects of fluoxetine. GABAB receptor antagonist CGP35348 suppresses stress-induced KCTD12 upregulation and improves behavioral responses.\",\n      \"method\": \"Viral-mediated overexpression and knockdown in mouse DG, chronic social defeat stress model, electrophysiology of DG granule cells, pharmacology with GABABR antagonist\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — region-specific KD/OE with defined electrophysiological and behavioral phenotypes plus pharmacological validation, single lab\",\n      \"pmids\": [\"33285230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MSL1 negatively regulates KCTD12 expression, and KCTD12 in turn regulates SLC7A11 (xCT). In colon cancer cells, Erastin-induced ferroptosis suppresses MSL1, leading to KCTD12 upregulation and consequent modulation of SLC7A11-dependent ROS, GSH, and MDA levels.\",\n      \"method\": \"Biochemical assays, knockdown and overexpression studies in HCT116 and SW480 cells, ferroptosis induction with Erastin\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, largely KD/OE with pathway marker readouts; direct molecular mechanism of MSL1-KCTD12 regulation not biochemically characterized in abstract\",\n      \"pmids\": [\"40221412\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCTD12 is an auxiliary subunit of GABAB receptors that assembles with the GABAB1/GABAB2 heterodimer in the ER, reduces constitutive receptor internalization to increase surface GABAB signaling, accelerates activation and desensitization kinetics of GABAB-mediated GIRK/K+ currents via binding to Gβγ subunits, and facilitates axonal trafficking of GABAB receptors in specific neuron types; additionally, PKA-mediated phosphorylation of GABAB2-S892 cross-regulates KCTD12-induced desensitization, Aurora A phosphorylates KCTD12 at S243 to potentiate a CDK1/CDC25B/Aurora A cell-cycle feedback loop, and KCTD12 suppresses ERK-dependent stemness signaling in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCTD12 is an auxiliary subunit of GABAB receptors that shapes inhibitory neurotransmission by tuning receptor surface abundance and signaling kinetics [#0, #6]. It associates with the GABAB1/GABAB2 heterodimer already in the endoplasmic reticulum through its N-terminal BTB/POZ domain, which binds the C-terminal region of GABAB2; both the BTB and C-terminal H1 domains independently tetramerize, giving the protein a compact multidomain architecture [#1]. By reducing constitutive receptor internalization, KCTD12 increases the magnitude of GABAB-mediated K+ (GIRK) currents, while simultaneously accelerating both activation and desensitization kinetics of these currents [#0, #6]. This desensitization is cross-regulated by PKA-dependent phosphorylation of GABAB2 serine-892, which rearranges KCTD12 at the receptor to slow desensitization, and the receptor-KCTD12 assembly itself promotes tonic S892 phosphorylation, forming a feedback loop [#2]. KCTD12 is required for GABAB current desensitization in specific neuron types such as cholecystokinin-expressing hippocampal interneurons, and together with KCTD8 it facilitates axonal-terminal GABAB expression and presynaptic excitation in habenular cholinergic neurons [#5, #12]. Through these actions KCTD12 controls intrinsic neuronal excitability and influences emotionality, fear learning, and stress-related behavior [#3, #14]. Beyond the nervous system, KCTD12 acts in cell-cycle and cancer contexts: it interacts with CDK1 and activates CDK1 and Aurora kinase A to drive the G2/M transition through a CDC25B-dependent step, with Aurora A phosphorylating KCTD12 at serine-243 to establish a positive feedback loop [#4, #8]. In colorectal cancer cells it suppresses stemness markers by inhibiting the ERK pathway, functioning upstream of ERK [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that KCTD12 is a GABAB receptor-associated subunit acting at the ER to limit receptor internalization and thereby amplify surface GABAB signaling, answering how an accessory protein controls receptor abundance.\",\n      \"evidence\": \"BiFC, metabolic labeling/glycosylation, Co-IP, BRET, and electrophysiology in KCTD12 KO/knockdown hippocampal neurons\",\n      \"pmids\": [\"23843457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ER association not resolved\", \"Mechanism by which internalization is reduced not defined at molecular detail\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis of the KCTD12-GABAB2 interaction, showing the N-terminal BTB/POZ domain binds GABAB2 and that BTB and H1 domains tetramerize independently.\",\n      \"evidence\": \"CD spectroscopy, binding assays, size-exclusion chromatography, secondary structure prediction\",\n      \"pmids\": [\"23996491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to validate binding interface\", \"No cell-based functional confirmation of the domain model\", \"No high-resolution structure\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed cross-regulation between KCTD12-induced desensitization and PKA phosphorylation of GABAB2-S892, showing how receptor phosphorylation reciprocally tunes the auxiliary subunit's kinetic effect.\",\n      \"evidence\": \"Heterologous and neuronal electrophysiology with KCTD12 KO and S892A knock-in mice plus PKA pharmacology\",\n      \"pmids\": [\"25065880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular conformational change of KCTD12 upon S892 phosphorylation not directly visualized\", \"Kinase recruitment mechanism unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a non-receptor signaling role in zebrafish whereby Kctd12 negatively regulates the kinase Ulk2 to restrain habenular dendritogenesis and anxiety-like behavior.\",\n      \"evidence\": \"Zebrafish loss-of-function, Ulk2 proline-serine rich domain interaction mapping, dendritic morphometry, behavioral assays\",\n      \"pmids\": [\"25329151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of the Ulk2 interaction in mammals not shown\", \"Direct biochemical binding not validated beyond domain mapping\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected KCTD12 loss to elevated intrinsic excitability of hippocampal pyramidal neurons and altered emotional behavior, linking the molecular function to circuit-level and behavioral output.\",\n      \"evidence\": \"Slice electrophysiology in Kctd12-/- and Kctd12+/- mice with behavioral assays\",\n      \"pmids\": [\"25689571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal chain from excitability change to behavior not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed KCTD12 upstream of ERK as a suppressor of colorectal cancer cell stemness, extending its function beyond neuronal GABAB signaling.\",\n      \"evidence\": \"siRNA/overexpression, colony/spheroid assays, xenografts, ERK inhibitor (U0126) epistasis\",\n      \"pmids\": [\"26847701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking KCTD12 to ERK not biochemically defined\", \"Direct ERK-pathway partner not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated cell-type specificity of KCTD12-dependent GABAB current desensitization, showing it is required in CCK-expressing hippocampal interneurons.\",\n      \"evidence\": \"Whole-cell recordings in KCTD12-deficient mice with immunoelectron microscopy\",\n      \"pmids\": [\"27073217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why some interneuron types depend on KCTD12 and others differ not explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed human KCTD12 accelerates both activation and desensitization of GABAB-GIRK currents and enhances positive allosteric modulation, confirming kinetic control across species.\",\n      \"evidence\": \"Automated heterologous electrophysiology with human KCTD12 and KCTD12 KO mouse pharmacology\",\n      \"pmids\": [\"28713569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of kinetic acceleration not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered a cell-cycle role in which KCTD12 binds and activates CDK1 and Aurora A via CDC25B to promote G2/M, with Aurora A phosphorylating KCTD12-S243 in a feedback loop.\",\n      \"evidence\": \"Co-IP/mass spectrometry, CDC25B siRNA epistasis, phosphorylation assays, cell-cycle analysis, xenografts\",\n      \"pmids\": [\"28869606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDK1 binding interface not mapped\", \"Functional consequence of S243 phosphorylation not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned KCTD12 as a tumor suppressor downstream of KIT in GISTs, where KIT negatively regulates its expression.\",\n      \"evidence\": \"Reciprocal KIT and KCTD12 siRNA knockdown with proliferation assays, qPCR, Western blot in GIST T1 cells\",\n      \"pmids\": [\"29930747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of KIT-dependent KCTD12 repression unknown\", \"Downstream effectors of KCTD12 in GIST not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated the KCTD12-CDK1 interaction as functionally required by showing its pharmacological disruption arrests cells in G2 and blocks colon cancer proliferation.\",\n      \"evidence\": \"FDA library drug screen, Co-IP-based interaction disruption (adefovir dipivoxil), cell-cycle and xenograft proliferation assays\",\n      \"pmids\": [\"30872078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drug specificity for the interaction not fully excluded\", \"Structural binding site not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified transcriptional control of KCTD12 via GSK-3/CREB, with lithium increasing and GADL1 decreasing its expression.\",\n      \"evidence\": \"GSK-3 inhibition, KCTD12 promoter reporter assays, GADL1 overexpression, lithium treatment in SH-SY5Y cells\",\n      \"pmids\": [\"31311980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of this regulatory axis not established\", \"Direct CREB occupancy on the promoter not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked KCTD12 loss to enhanced melanoma stemness via a proposed CD271 (p75NTR) interaction.\",\n      \"evidence\": \"KCTD12 knockout cell lines, in vitro stemness assays, in vivo metastasis model\",\n      \"pmids\": [\"31565480\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct biochemical KCTD12-CD271 binding not demonstrated\", \"Interaction inferred from phenotype only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a region-specific behavioral role whereby dentate gyrus KCTD12 levels bidirectionally control stress vulnerability and granule cell excitability, linked to GABAB signaling.\",\n      \"evidence\": \"Viral KD/OE in mouse DG, social defeat stress, granule cell electrophysiology, GABAB antagonist pharmacology\",\n      \"pmids\": [\"33285230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular link between KCTD12 level and stress circuitry not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed KCTD12, with KCTD8, selectively promotes axonal-terminal GABAB receptor expression and presynaptic excitation in habenular cholinergic neurons, confirmed by rescue in triple-KO mice.\",\n      \"evidence\": \"Multiple KCTD KO combinations, compartment-specific GABAB immunostaining, presynaptic Ca2+ imaging, glutamate release, rescue overexpression\",\n      \"pmids\": [\"35017224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of compartment-specific (axonal vs somatic) trafficking not defined\", \"Functional redundancy partition between KCTD8 and KCTD12 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a ferroptosis-related axis in which MSL1 represses KCTD12, which in turn regulates SLC7A11-dependent redox balance in colon cancer.\",\n      \"evidence\": \"Knockdown/overexpression in HCT116 and SW480 cells with Erastin-induced ferroptosis and redox marker readouts\",\n      \"pmids\": [\"40221412\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct molecular mechanism of MSL1-KCTD12 regulation not biochemically characterized\", \"How KCTD12 regulates SLC7A11 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KCTD12's two functional domains structurally couple GABAB2 binding to Gβγ-dependent kinetic control, and whether its neuronal auxiliary-subunit role and its cytoplasmic cell-cycle/cancer functions involve distinct conformations or partners, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the KCTD12-GABAB receptor complex\", \"Mechanistic unification of neuronal and oncogenic roles lacking\", \"Direct partner interfaces (CDK1, CD271) unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 5, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"complexes\": [\"GABAB receptor complex\"],\n    \"partners\": [\"GABBR2\", \"CDK1\", \"AURKA\", \"CDC25B\", \"ULK2\", \"KCTD8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}