{"gene":"CBY1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"CBY1 (Chibby) was identified as a nuclear protein that directly interacts with the C-terminal region of β-catenin and inhibits β-catenin-mediated transcriptional activation by competing with Lef-1 for binding to β-catenin. Epistasis experiments in Drosophila placed chibby downstream of wingless and upstream of armadillo.","method":"Protein interaction screen, competition binding assay, RNAi in Drosophila, genetic epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — original discovery with direct binding assay, transcriptional competition, and genetic epistasis; highly cited foundational paper","pmids":["12712206"],"is_preprint":false},{"year":2008,"finding":"CBY1 cooperates with 14-3-3ε and 14-3-3ζ to facilitate nuclear export of β-catenin. Akt kinase phosphorylates CBY1 at serine 20, which creates a 14-3-3 binding motif; 14-3-3 binding sequesters CBY1 in the cytoplasm and CBY1, 14-3-3, and β-catenin form a stable tripartite complex causing β-catenin to partition into the cytoplasm.","method":"Affinity purification/mass spectrometry, site-directed mutagenesis (S20), co-immunoprecipitation, subcellular fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including MS identification, mutagenesis, and functional localization studies","pmids":["18573912"],"is_preprint":false},{"year":2009,"finding":"CBY1 harbors bona fide nuclear localization signal (NLS) and nuclear export signal (NES) motifs and constitutively shuttles between nucleus and cytoplasm. Efficient nuclear export requires cooperative action of the intrinsic NES, 14-3-3, and CRM1 nuclear export receptor. 14-3-3 docking promotes CBY1 binding to CRM1 while inhibiting its interaction with importin-α, and NLS/NES-dependent shuttling of CBY1 modulates β-catenin intracellular localization.","method":"NLS/NES mutagenesis, nuclear export inhibitor (leptomycin B), shRNA knockdown, co-immunoprecipitation, live cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of NLS/NES combined with functional import/export assays and epistasis with CRM1","pmids":["19940019"],"is_preprint":false},{"year":2009,"finding":"CBY1 forms a stable homodimer through a heptad repeat of four leucine residues in its C-terminal coiled-coil motif. Alanine substitution of two or more leucine residues abolishes homodimerization. Homodimerization is required for efficient interaction with importin-α and subsequent nuclear translocation, but monomeric CBY1 retains the ability to bind β-catenin and repress its transcriptional activity.","method":"Alanine scanning mutagenesis, co-immunoprecipitation, size exclusion chromatography","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — comprehensive mutagenesis with multiple functional readouts","pmids":["19435523"],"is_preprint":false},{"year":2009,"finding":"CBY1 is localized at the base of cilia in mouse nasal epithelium, and Cby−/− mice exhibit impaired basal body docking to the apical surface of multiciliated cells, resulting in a marked paucity of motile cilia and complete absence of mucociliary transport.","method":"Cby knockout mouse, immunofluorescence localization, electron microscopy of basal body docking, mucociliary transport assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse with direct ultrastructural and functional phenotypic analysis","pmids":["19364920"],"is_preprint":false},{"year":2007,"finding":"CBY1 promotes adipocyte differentiation by inhibiting β-catenin signaling. Ectopic expression of CBY1 induces spontaneous differentiation of 3T3-L1 preadipocytes, while RNAi depletion of CBY1 blocks adipogenesis. Embryonic fibroblasts from Cby-deficient embryos show attenuated adipogenic differentiation.","method":"RNAi knockdown, ectopic overexpression, Cby-deficient mouse embryonic fibroblasts, adipogenic differentiation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — both gain- and loss-of-function in multiple cell types including knockout-derived cells","pmids":["17403895"],"is_preprint":false},{"year":2012,"finding":"CBY1 is a centriolar component specifically located at the distal end of the mother centriole and is essential for assembly of the primary cilium. CBY1 interacts physically with the distal appendage component Cenexin (ODF2), which abrogates CBY1's inhibitory effect on β-catenin-mediated transcription in a dose-dependent manner. Cenexin is required for recruitment of CBY1 to the mother centriole, but CBY1 is dispensable for Cenexin localization.","method":"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, TOPflash reporter assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal localization dependencies established with knockdown and co-IP","pmids":["22911743"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, CBY localizes to the basal body transition zone in sensory neurons and male germ cells, and is required for basal body structure and ciliary function, including proper ciliary protein trafficking and axonemal assembly, but is not required for Wingless signaling in flies.","method":"cby mutant Drosophila, immunofluorescence, electron microscopy, sensory transduction assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — ortholog in Drosophila with clean KO and multiple functional/structural readouts; consistent with mammalian CBY1 function at basal bodies","pmids":["22508513"],"is_preprint":false},{"year":2014,"finding":"CBY1 facilitates basal body docking to the apical cell membrane during airway multiciliated cell differentiation through proper formation of ciliary vesicles at distal appendages. CBY1 is recruited to distal appendages via physical interaction with CEP164, then associates with Rabin8 (a GEF for Rab8) to promote Rab8 recruitment and efficient assembly of ciliary vesicles.","method":"Primary mouse tracheal epithelial cell cultures, co-immunoprecipitation, RNAi knockdown, immunofluorescence, electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct interaction with CEP164 and Rabin8 shown by co-IP, combined with functional vesicle assembly assay in primary cells","pmids":["25313408"],"is_preprint":false},{"year":2014,"finding":"CBY1 localizes to an ~250-nm ring at the distal end of the mature centriole (dependent on ODF1/Ofd1) and promotes the recruitment of Ahi1 to the transition zone. In Cby1-knockout cells, centriole-localized Ahi1 is reduced, impairing ciliogenesis and ciliary recruitment of the Joubert syndrome protein Arl13b. CBY1 deletion causes cystic kidneys in mice.","method":"3D-SIM and STED superresolution microscopy, Cby1 knockout mouse, immunofluorescence, quantitative localization analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — superresolution structural data combined with KO phenotype and quantitative protein recruitment assay","pmids":["25103236"],"is_preprint":false},{"year":2015,"finding":"The crystal structure of the human 14-3-3ζ/CBY1 peptide complex was solved at 2.2 Å, revealing a canonical binding mode where phosphorylation of S20 is essential for 14-3-3 recognition. NMR titration shows that residues outside the conserved 14-3-3 binding cleft (flexible loop residues 203-210) also contribute to the interaction.","method":"X-ray crystallography, NMR spectroscopy, isothermal titration calorimetry, mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus NMR and ITC providing atomic-level mechanism","pmids":["25909186"],"is_preprint":false},{"year":2015,"finding":"CBY1 is required for normal ciliary morphology and proper distribution of IFT-B complex proteins (IFT88, IFT20, IFT57) but not IFT-A or BBS proteins in airway ciliated cells. Loss of CBY1 causes paddle-like cilia with dilated tips and accumulation of IFT-B components within those tips.","method":"Cby knockout mouse, primary MTECs, Cby-/- MEFs, immunofluorescence, electron microscopy","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 — KO combined with specific IFT subcomplex analysis provides pathway placement","pmids":["26266958"],"is_preprint":false},{"year":2016,"finding":"FAM92A and FAM92B (BAR domain-containing proteins) interact with CBY1 and colocalize with it at centrioles/basal bodies. Centriolar localization of FAM92A and FAM92B depends largely on CBY1. FAM92A knockdown impairs ciliogenesis. FAM92A and FAM92B, in cooperation with CBY1, induce Rab8-containing membrane-remodeling structures.","method":"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, immunofluorescence, ciliogenesis assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — MS identification followed by functional validation with multiple orthogonal methods","pmids":["27528616"],"is_preprint":false},{"year":2006,"finding":"TC1 (C8orf4) interacts with CBY1 and antagonizes CBY1's inhibitory function on β-catenin-mediated transcription, thereby acting as a positive regulator of the Wnt/β-catenin pathway. Co-expression of TC1 and CBY1 results in relocalization of TC1 from nucleolus to nuclear speckles where it colocalizes with CBY1.","method":"Co-immunoprecipitation, TOPflash reporter assay, immunofluorescence colocalization","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP with functional reporter assay but no mutagenesis mapping of interaction","pmids":["16424001"],"is_preprint":false},{"year":2007,"finding":"TC-1 (thyroid cancer-1), an intrinsically disordered protein, interacts with CBY1 via three regions with high helical propensity (D44-R53, K58-A64, D73-T88) in its C-terminal portion, as determined by NMR spectroscopy.","method":"NMR spectroscopy (chemical shift analysis, relaxation measurements, resonance broadening)","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 — NMR structural mapping of interaction interface with functional context","pmids":["17905836"],"is_preprint":false},{"year":2011,"finding":"Human CBY1 is a partially disordered protein: its N-terminal portion is predominantly unstructured in solution while the C-terminal half adopts a coiled-coil structure through self-association. CBY1 uses its N-terminal disordered module to bind 14-3-3ζ and its C-terminal coiled-coil for self-association and TC-1 binding.","method":"NMR spectroscopy, ESI-MS, CD, DLS","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical methods characterizing structure-function relationship","pmids":["21182262"],"is_preprint":false},{"year":2004,"finding":"CBY1 (PIGEA-14) was identified as an interacting partner of the C-terminus of polycystin-2 (PC2) via yeast two-hybrid screen. Co-expression of CBY1 and PC2 in LLC-PK1 and HeLa cells caused redistribution of both proteins to the trans-Golgi network, suggesting CBY1 regulates intracellular trafficking of PC2. CBY1 also interacts with GM130, a cis-Golgi component.","method":"Yeast two-hybrid screen, co-expression/immunofluorescence localization, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid and colocalization, limited functional mechanistic follow-up","pmids":["15194699"],"is_preprint":false},{"year":2010,"finding":"CBY1 protein is prominently associated with centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells and at the base of motile cilia in airway ciliated cells. CBY1 is a direct downstream transcriptional target of the master ciliogenesis transcription factor Foxj1. Loss of CBY1 results in alveolar airspace enlargement with reduced proliferation, abnormal epithelial cell differentiation, and failure of basal body docking in airway ciliated cells.","method":"Cby-/- mouse lung analysis, immunofluorescence, Foxj1 promoter analysis, electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple phenotypic readouts plus direct identification of Foxj1 as upstream transcriptional regulator","pmids":["21049041"],"is_preprint":false},{"year":2018,"finding":"Centrosomal protein Dzip1l interacts with CBY1 (shown by co-immunoprecipitation), colocalizes with basal body appendage proteins, and acts upstream of CBY1 in ciliogenesis. Loss of Dzip1l reduces ciliogenesis and prevents removal of the capping protein Cp110 from distal mother centrioles, arresting ciliogenesis at the ciliary bud stage.","method":"Co-immunoprecipitation, Dzip1l knockout mouse, immunofluorescence, epistasis analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus genetic epistasis placing Dzip1l upstream of Cby1, but epistasis with Cby1 not fully dissected","pmids":["29487109"],"is_preprint":false},{"year":2021,"finding":"DZIP1 forms a multimeric complex with CBY1 and β-catenin at the basal body of primary cilia during cardiac valve development. A specific DZIP1 peptide is required for stabilization of this complex and suppression of β-catenin activities. Loss of DZIP1-CBY1 interaction leads to increased nuclear β-catenin, elevated MMP2, altered ECM, and myxomatous valve phenotype.","method":"Co-immunoprecipitation, decoy peptide experiments, immunofluorescence, TOPflash reporter assay, mouse cardiac valve analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — complex characterized biochemically with functional peptide experiments and in vivo phenotype","pmids":["33811421"],"is_preprint":false},{"year":2015,"finding":"In CML cells, CBY1 protein stability is reduced upon binding to 14-3-3σ, a process mediated by BCR-ABL1 tyrosine kinase and AKT phosphorylation of CBY1 at serine 20. JNK phosphorylation of 14-3-3σ at S186 promotes dissociation of CBY1 from 14-3-3σ. The ubiquitin-proteasome system reduces CBY1 stability via enhanced SUMOylation when CBY1 is bound to 14-3-3σ.","method":"Co-immunoprecipitation, site-directed mutagenesis, kinase inhibitor experiments, SUMOylation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — phosphorylation-dependent interaction mechanism with multiple PTM writers identified, though in disease cell context","pmids":["26147002"],"is_preprint":false},{"year":2020,"finding":"Loss-of-function variants in CBY1 cause a ciliopathy with features of Joubert syndrome in humans. Patient fibroblasts show reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B. Depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes.","method":"Human genetics (biallelic LOF variants), patient fibroblast immunofluorescence, zebrafish morpholino knockdown","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — human disease variants with cell-based functional validation and zebrafish model","pmids":["33131181"],"is_preprint":false},{"year":2021,"finding":"Loss of CBY1 in mice causes severe exocrine pancreatic atrophy with dilated ducts, reduction in cilia number and length, inflammatory infiltration, and defective zymogen granule secretion in acinar cells. CBY1-KO acinar cells show altered polarity and accumulate zymogen granules due to defective exocytosis.","method":"Cby1 knockout mouse, immunofluorescence, electron microscopy, ex vivo acini secretion assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with both in vivo and ex vivo functional secretion assays","pmids":["34446743"],"is_preprint":false},{"year":2024,"finding":"The Cby-Fam92 module (near the ciliary membrane) and the Cep131-Cep162 module (near the axoneme) cooperatively maintain Cep290 at the basal body and control the initiation of ciliogenesis. Concurrent deletion of members of both modules leads to complete loss of Cep290 from the basal body and blocks ciliogenesis at its initiation stage.","method":"Drosophila genetics (double mutants), immunofluorescence, epistasis analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with clear pathway placement of Cby in Cep290 maintenance","pmids":["38442096"],"is_preprint":false},{"year":2025,"finding":"The crystal structure (2.2 Å) of mouse FAM92A BAR domain reveals an antiparallel crescent-shaped homodimer. FAM92A BAR directly binds the N-terminal region of CBY1, and their respective dimerizations synergistically enhance binding affinity. Structure-guided mutagenesis identified residues critical for lipid binding on the concave surface and residues essential for dimerization.","method":"X-ray crystallography, structure-guided mutagenesis, co-immunoprecipitation, binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis defining molecular basis of FAM92A-CBY1 interaction","pmids":["40484380"],"is_preprint":false},{"year":2026,"finding":"Rhotekin interacts with CBY1 and competes with β-catenin for binding to CBY1, thereby relieving CBY1's antagonistic effect on β-catenin and activating the canonical Wnt/β-catenin pathway to promote osteoblast differentiation. Rhotekin also activates the FAK/AKT signaling pathway.","method":"Co-immunoprecipitation, competition binding assay, overexpression/knockdown in mesenchymal progenitors, in vivo bone marrow silencing","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP plus functional competition assay, single study","pmids":["42000008"],"is_preprint":false},{"year":2010,"finding":"CBY1 interacts with multiple NBPF proteins via a coiled-coil region in NBPF that binds the coiled-coil domain in the C-terminal region of CBY1. CBY1 also interacts with clusterin. NBPF1, CBY1, and clusterin can be co-immunoprecipitated together, suggesting a tri-molecular complex, though NBPF interaction does not influence CBY1's Wnt repressor function.","method":"Yeast two-hybrid screen, co-immunoprecipitation, TOPflash reporter assay","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid and single co-IP with limited mechanistic follow-up","pmids":["20096688"],"is_preprint":false}],"current_model":"CBY1 (Chibby1) is a conserved, partially disordered coiled-coil protein that functions as a dual antagonist of Wnt/β-catenin signaling and a critical regulator of ciliogenesis: it directly binds the C-terminal activation domain of β-catenin to compete with Tcf/Lef transcription factors, and upon Akt-mediated phosphorylation at S20, recruits 14-3-3 proteins to form a tripartite complex with β-catenin that is exported from the nucleus via CRM1; at centrioles, CBY1 localizes to an ~250 nm ring at the distal appendages of mature mother centrioles (recruited via CEP164 and Cenexin/ODF2), where it promotes ciliary vesicle formation through Rabin8/Rab8 recruitment and efficient basal body docking, facilitates Ahi1 transition zone assembly, and maintains proper IFT-B particle distribution—loss of CBY1 in mice causes primary ciliary dyskinesia-like airway defects, cystic kidneys, exocrine pancreatic degeneration, and lung developmental abnormalities, while human biallelic CBY1 loss-of-function causes Joubert syndrome."},"narrative":{"teleology":[{"year":2003,"claim":"The fundamental question of CBY1's molecular function was answered: it directly binds the C-terminus of β-catenin and competitively inhibits Tcf/Lef-dependent transcription, establishing CBY1 as a nuclear antagonist of canonical Wnt signaling.","evidence":"Protein interaction screen, competition binding assay, and Drosophila genetic epistasis (Nature)","pmids":["12712206"],"confidence":"High","gaps":["Mechanism of CBY1 recruitment to β-catenin unknown","No structural detail of the CBY1–β-catenin interface","Whether CBY1 functions outside Wnt signaling was unexplored"]},{"year":2004,"claim":"An independent screen revealed that CBY1 interacts with polycystin-2 and may regulate its intracellular trafficking to the trans-Golgi network, providing the first hint of a cilia/polycystin-related role for CBY1.","evidence":"Yeast two-hybrid screen and co-expression/immunofluorescence in LLC-PK1 and HeLa cells","pmids":["15194699"],"confidence":"Medium","gaps":["Functional consequence of CBY1–PC2 interaction on ciliary signaling not tested","No in vivo validation","No reciprocal pulldown from endogenous PC2"]},{"year":2006,"claim":"TC-1 (C8orf4) was identified as a binding partner that antagonizes CBY1's repression of β-catenin, establishing that CBY1's Wnt-inhibitory activity is itself subject to regulation by competing interactors.","evidence":"Co-immunoprecipitation and TOPflash reporter assay in cancer cells","pmids":["16424001"],"confidence":"Medium","gaps":["No mutagenesis mapping of the TC-1–CBY1 interface at the time","Physiological context of TC-1 regulation of CBY1 unclear"]},{"year":2007,"claim":"CBY1's role in adipocyte differentiation demonstrated that its β-catenin antagonism has developmental consequences: CBY1 promotes adipogenesis by relieving Wnt/β-catenin-mediated suppression of differentiation.","evidence":"Gain- and loss-of-function in 3T3-L1 cells and Cby-deficient MEFs","pmids":["17403895"],"confidence":"High","gaps":["Whether CBY1 regulates adipogenesis through β-catenin-independent mechanisms not addressed","In vivo adipose phenotype in KO mice not characterized"]},{"year":2008,"claim":"The mechanism by which CBY1 clears β-catenin from the nucleus was resolved: Akt phosphorylation at Ser20 creates a 14-3-3 binding site, and the resulting tripartite CBY1–14-3-3–β-catenin complex partitions β-catenin to the cytoplasm.","evidence":"AP-MS, site-directed mutagenesis of S20, co-IP, subcellular fractionation (J. Cell Biol.)","pmids":["18573912"],"confidence":"High","gaps":["Structural basis of 14-3-3 recognition of phospho-CBY1 not yet determined","Nuclear export route not characterized"]},{"year":2009,"claim":"Three key structural and functional properties were established simultaneously: CBY1 contains functional NLS/NES motifs and shuttles between nucleus and cytoplasm via CRM1; CBY1 homodimerizes through a C-terminal coiled-coil required for nuclear import; and Cby-knockout mice lack motile cilia due to failed basal body docking, revealing CBY1's essential role in ciliogenesis.","evidence":"NLS/NES mutagenesis with leptomycin B and live imaging; coiled-coil alanine scanning and SEC; Cby−/− mouse with EM and mucociliary transport assays","pmids":["19940019","19435523","19364920"],"confidence":"High","gaps":["How CBY1's Wnt and cilia functions are coordinated at the same protein was unclear","Mechanism of basal body docking failure not resolved at the molecular level"]},{"year":2010,"claim":"CBY1 was placed downstream of the master ciliogenesis transcription factor Foxj1 and shown to be essential for lung epithelial development, linking its transcriptional regulation to its basal body/cilia function in vivo.","evidence":"Cby−/− mouse lung analysis, Foxj1 promoter analysis, immunofluorescence, EM","pmids":["21049041"],"confidence":"High","gaps":["Whether Foxj1 is the sole transcriptional regulator of Cby1 not determined","Alveolar enlargement phenotype mechanism not molecularly defined"]},{"year":2011,"claim":"The biophysical architecture of CBY1 was resolved: its N-terminal half is intrinsically disordered (harboring the 14-3-3 binding region), while its C-terminal coiled-coil mediates homodimerization and TC-1 binding, establishing a modular structure-function framework.","evidence":"NMR spectroscopy, ESI-MS, CD, and DLS on full-length CBY1","pmids":["21182262"],"confidence":"High","gaps":["Full-length CBY1 structure in complex with β-catenin not determined","How disorder-to-order transitions regulate partner selectivity unknown"]},{"year":2012,"claim":"CBY1's centriolar location was pinpointed to the distal end of the mother centriole, dependent on Cenexin/ODF2 recruitment, and Drosophila Cby was shown to localize to the basal body transition zone and be required for ciliary structure but dispensable for Wingless signaling—clarifying that the cilia function is the conserved ancestral role.","evidence":"Mammalian co-IP and siRNA with immunofluorescence; Drosophila cby mutant with EM and sensory assays","pmids":["22911743","22508513"],"confidence":"High","gaps":["The precise distal appendage substructure where CBY1 sits was not yet resolved at nanometer resolution","Why Drosophila Cby is dispensable for Wnt but mammalian CBY1 is not was unresolved"]},{"year":2014,"claim":"The molecular pathway by which CBY1 promotes ciliogenesis was elaborated: CBY1 is recruited to distal appendages by CEP164, then engages Rabin8 to activate Rab8 and form ciliary vesicles; superresolution microscopy resolved CBY1 to an ~250-nm ring, and its loss impairs Ahi1 transition zone assembly and causes cystic kidneys.","evidence":"Co-IP of CBY1–CEP164 and CBY1–Rabin8 in primary MTECs; 3D-SIM/STED in Cby1-KO cells; KO mouse kidney phenotype","pmids":["25313408","25103236"],"confidence":"High","gaps":["Whether CBY1 directly activates Rabin8 or serves as a scaffold unknown","Structural basis of the CBY1–CEP164 interaction not determined"]},{"year":2015,"claim":"The atomic basis of 14-3-3 recognition was established (2.2 Å crystal structure of 14-3-3ζ–phospho-CBY1 peptide), and separately, CBY1 was shown to be required for proper IFT-B distribution in cilia—its loss causes paddle-like cilia with IFT-B accumulation at tips.","evidence":"X-ray crystallography, NMR, and ITC for 14-3-3 structure; Cby−/− mouse MTECs and MEFs with IFT subcomplex immunofluorescence","pmids":["25909186","26266958"],"confidence":"High","gaps":["How CBY1 specifically affects IFT-B but not IFT-A turnover is mechanistically unexplained","Whether IFT defects are secondary to basal body docking failure was not fully resolved"]},{"year":2016,"claim":"FAM92A and FAM92B were identified as CBY1 interactors that depend on CBY1 for centriolar localization and cooperate with it in Rab8-dependent membrane remodeling, establishing the CBY1–FAM92 module as a membrane-shaping unit at basal bodies.","evidence":"Tandem affinity purification/MS, co-IP, siRNA, and ciliogenesis assays","pmids":["27528616"],"confidence":"High","gaps":["Structural basis of FAM92–CBY1 interaction unknown at the time","Whether FAM92 BAR domain directly tubulates membranes in a CBY1-dependent manner was not shown"]},{"year":2020,"claim":"The clinical significance of CBY1 was established: biallelic loss-of-function variants cause Joubert syndrome in humans, with patient fibroblasts showing reduced ciliation, elongated cilia, and reduced AHI1/ARL13B—directly linking the mouse cilia phenotype to a human ciliopathy.","evidence":"Human genetic analysis (biallelic LOF), patient fibroblast immunofluorescence, zebrafish morpholino knockdown","pmids":["33131181"],"confidence":"High","gaps":["Genotype-phenotype correlations across different CBY1 mutations not yet characterized","Whether CBY1 loss-of-function contributes to a broader spectrum of ciliopathies unknown"]},{"year":2021,"claim":"CBY1's role was extended to two additional tissues: DZIP1 forms a complex with CBY1 and β-catenin at cardiac valve basal bodies to suppress β-catenin and prevent myxomatous degeneration, and Cby1-KO mice develop severe exocrine pancreatic atrophy with defective zymogen secretion, broadening the phenotypic spectrum.","evidence":"Co-IP and decoy peptide experiments in cardiac valves; Cby1-KO mouse pancreas EM and ex vivo secretion assays","pmids":["33811421","34446743"],"confidence":"High","gaps":["Whether pancreatic defects are purely cilia-dependent or involve CBY1's Wnt function not resolved","DZIP1–CBY1 complex stoichiometry and structure unknown"]},{"year":2024,"claim":"Genetic epistasis in Drosophila established that the Cby–Fam92 module and the Cep131–Cep162 module cooperatively maintain Cep290 at the basal body, and concurrent loss blocks ciliogenesis initiation, placing CBY1 in a defined pathway hierarchy for transition zone assembly.","evidence":"Drosophila double mutants with immunofluorescence and epistasis analysis","pmids":["38442096"],"confidence":"Medium","gaps":["Whether this pathway hierarchy is conserved in mammals not yet tested","Direct physical interaction between Cby–Fam92 module and Cep290 not demonstrated"]},{"year":2025,"claim":"The structural basis of the CBY1–FAM92A interaction was resolved: a 2.2 Å crystal structure of the FAM92A BAR domain revealed an antiparallel crescent homodimer, and FAM92A binds the N-terminal region of CBY1, with dimerization of both proteins synergistically enhancing affinity.","evidence":"X-ray crystallography, structure-guided mutagenesis, co-IP, binding affinity measurements","pmids":["40484380"],"confidence":"High","gaps":["Structure of a full CBY1–FAM92A complex on membranes not determined","How FAM92A lipid binding coordinates with CBY1-mediated Rab8 recruitment is undefined"]},{"year":null,"claim":"Key unresolved questions include: how CBY1's dual Wnt-inhibitory and ciliogenic functions are spatiotemporally coordinated within the same cell; the atomic structure of the CBY1–β-catenin complex; and the full genotype-phenotype spectrum of human CBY1 ciliopathies.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of full-length CBY1 in complex with β-catenin","Mechanism by which CBY1 selectively affects IFT-B versus IFT-A not molecularly explained","How Foxj1-driven transcription of Cby1 is integrated with post-translational regulation (Akt, 14-3-3) is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4,6,8,9]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4,7,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,8,9,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,17,19]}],"complexes":["CBY1–14-3-3–β-catenin tripartite complex","CBY1–FAM92A/B membrane-remodeling module","DZIP1–CBY1–β-catenin basal body complex"],"partners":["CTNNB1","YWHAZ","YWHAE","CEP164","ODF2","FAM92A","FAM92B","RABIN8"],"other_free_text":[]},"mechanistic_narrative":"CBY1 (Chibby1) is a conserved, partially disordered coiled-coil protein that functions both as an antagonist of canonical Wnt/β-catenin signaling and as an essential regulator of ciliogenesis. CBY1 directly binds the C-terminal activation domain of β-catenin, competing with Tcf/Lef transcription factors to repress β-catenin-mediated transcription; Akt phosphorylation of CBY1 at Ser20 creates a 14-3-3 binding motif, enabling formation of a tripartite CBY1–14-3-3–β-catenin complex that is exported from the nucleus via CRM1-dependent transport [PMID:12712206, PMID:18573912, PMID:19940019]. At centrioles, CBY1 localizes to a distal appendage ring on the mother centriole (recruited by CEP164 and Cenexin/ODF2), where it promotes ciliary vesicle formation through Rabin8/Rab8 recruitment, facilitates Ahi1 transition zone assembly, and cooperates with the BAR-domain proteins FAM92A/B to remodel membranes during basal body docking [PMID:25313408, PMID:25103236, PMID:27528616, PMID:40484380]. Biallelic loss-of-function variants in CBY1 cause Joubert syndrome in humans, and Cby1-knockout mice exhibit primary ciliary dyskinesia-like airway defects, cystic kidneys, and exocrine pancreatic degeneration [PMID:33131181, PMID:19364920, PMID:34446743]."},"prefetch_data":{"uniprot":{"accession":"Q9Y3M2","full_name":"Protein chibby homolog 1","aliases":["ARPP-binding protein","Cytosolic leucine-rich protein","PIGEA-14","PKD2 interactor, Golgi and endoplasmic reticulum-associated 1"],"length_aa":126,"mass_kda":14.5,"function":"Inhibits the Wnt/Wingless pathway by binding to CTNNB1/beta-catenin and inhibiting beta-catenin-mediated transcriptional activation through competition with TCF/LEF transcription factors (PubMed:12712206, PubMed:19435523). Has also been shown to play a role in regulating the intracellular trafficking of polycystin-2/PKD2 and possibly of other intracellular proteins (PubMed:15194699). Promotes adipocyte and cardiomyocyte differentiation (By similarity)","subcellular_location":"Nucleus speckle; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Golgi apparatus; Golgi apparatus, trans-Golgi network; Cell projection, cilium, flagellum; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y3M2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBY1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBY1","total_profiled":1310},"omim":[{"mim_id":"620892","title":"CHIBBY FAMILY, MEMBER 3; CBY3","url":"https://www.omim.org/entry/620892"},{"mim_id":"617274","title":"CBY1-INTERACTING BAR DOMAIN-CONTAINING PROTEIN 2; CIBAR2","url":"https://www.omim.org/entry/617274"},{"mim_id":"617273","title":"CBY1-INTERACTING BAR DOMAIN-CONTAINING PROTEIN 1; CIBAR1","url":"https://www.omim.org/entry/617273"},{"mim_id":"607757","title":"CHIBBY FAMILY, MEMBER 1, BETA-CATENIN ANTAGONIST; CBY1","url":"https://www.omim.org/entry/607757"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CBY1"},"hgnc":{"alias_symbol":["PIGEA14","PIGEA-14","Chibby","Cby","Chibby1"],"prev_symbol":["C22orf2","PGEA1"]},"alphafold":{"accession":"Q9Y3M2","domains":[{"cath_id":"-","chopping":"30-62","consensus_level":"medium","plddt":84.2648,"start":30,"end":62},{"cath_id":"1.10.287","chopping":"77-126","consensus_level":"medium","plddt":95.9764,"start":77,"end":126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3M2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3M2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3M2-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBY1","jax_strain_url":"https://www.jax.org/strain/search?query=CBY1"},"sequence":{"accession":"Q9Y3M2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3M2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3M2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3M2"}},"corpus_meta":[{"pmid":"12712206","id":"PMC_12712206","title":"Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12712206","citation_count":231,"is_preprint":false},{"pmid":"6573537","id":"PMC_6573537","title":"Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice.","date":"1983","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/6573537","citation_count":118,"is_preprint":false},{"pmid":"18573912","id":"PMC_18573912","title":"Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18573912","citation_count":116,"is_preprint":false},{"pmid":"10340409","id":"PMC_10340409","title":"Development and aging of primitive hematopoietic stem cells in BALB/cBy mice.","date":"1999","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10340409","citation_count":88,"is_preprint":false},{"pmid":"25313408","id":"PMC_25313408","title":"Chibby promotes ciliary vesicle formation and basal body docking during airway cell differentiation.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25313408","citation_count":80,"is_preprint":false},{"pmid":"19364920","id":"PMC_19364920","title":"Inactivation of Chibby affects function of motile airway cilia.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19364920","citation_count":79,"is_preprint":false},{"pmid":"10846099","id":"PMC_10846099","title":"Differences between C57BL/6 and BALB/cBy mice in mortality and virus replication after intranasal infection with neuroadapted Sindbis virus.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10846099","citation_count":65,"is_preprint":false},{"pmid":"22508513","id":"PMC_22508513","title":"Drosophila chibby is required for basal body formation and ciliogenesis but not for Wg signaling.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22508513","citation_count":54,"is_preprint":false},{"pmid":"15194699","id":"PMC_15194699","title":"PIGEA-14, a novel coiled-coil protein affecting the intracellular distribution of polycystin-2.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15194699","citation_count":52,"is_preprint":false},{"pmid":"17261658","id":"PMC_17261658","title":"Chibby, an antagonist of the Wnt/beta-catenin pathway, facilitates cardiomyocyte differentiation of murine embryonic stem cells.","date":"2007","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/17261658","citation_count":52,"is_preprint":false},{"pmid":"25103236","id":"PMC_25103236","title":"Cby1 promotes Ahi1 recruitment to a ring-shaped domain at the centriole-cilium interface and facilitates proper cilium formation and function.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25103236","citation_count":52,"is_preprint":false},{"pmid":"16424001","id":"PMC_16424001","title":"TC1 (C8orf4) enhances the Wnt/beta-catenin pathway by relieving antagonistic activity of Chibby.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16424001","citation_count":52,"is_preprint":false},{"pmid":"17403895","id":"PMC_17403895","title":"Chibby promotes adipocyte differentiation through inhibition of beta-catenin signaling.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17403895","citation_count":48,"is_preprint":false},{"pmid":"29764469","id":"PMC_29764469","title":"Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/β-catenin-Lin28/let7-PDK1 cascade.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29764469","citation_count":47,"is_preprint":false},{"pmid":"19940019","id":"PMC_19940019","title":"Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19940019","citation_count":47,"is_preprint":false},{"pmid":"27528616","id":"PMC_27528616","title":"BAR Domain-Containing FAM92 Proteins Interact with Chibby1 To Facilitate Ciliogenesis.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27528616","citation_count":43,"is_preprint":false},{"pmid":"19158508","id":"PMC_19158508","title":"Fine-tuning of nuclear-catenin by Chibby and 14-3-3.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19158508","citation_count":37,"is_preprint":false},{"pmid":"2326831","id":"PMC_2326831","title":"Effects of social isolation and the time of day on testosterone levels in plasma of C57BL/6By and BALB/cBy mice.","date":"1990","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/2326831","citation_count":35,"is_preprint":false},{"pmid":"22911743","id":"PMC_22911743","title":"A Wnt/beta-catenin pathway antagonist Chibby binds Cenexin at the distal end of mother centrioles and functions in primary cilia formation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22911743","citation_count":34,"is_preprint":false},{"pmid":"18663750","id":"PMC_18663750","title":"Real-time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12-q13.","date":"2008","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18663750","citation_count":31,"is_preprint":false},{"pmid":"21049041","id":"PMC_21049041","title":"Altered lung morphogenesis, epithelial cell differentiation and mechanics in mice deficient in the Wnt/β-catenin antagonist Chibby.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21049041","citation_count":30,"is_preprint":false},{"pmid":"25909186","id":"PMC_25909186","title":"Structural Analysis of the 14-3-3ζ/Chibby Interaction Involved in Wnt/β-Catenin Signaling.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25909186","citation_count":26,"is_preprint":false},{"pmid":"10066341","id":"PMC_10066341","title":"Multidose streptozotocin induction of diabetes in BALB/cBy mice induces a T cell proliferation defect in thymocytes which is reversible by interleukin-4.","date":"1999","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10066341","citation_count":26,"is_preprint":false},{"pmid":"20096688","id":"PMC_20096688","title":"Chibby interacts with NBPF1 and clusterin, two candidate tumor suppressors linked to neuroblastoma.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20096688","citation_count":24,"is_preprint":false},{"pmid":"17905836","id":"PMC_17905836","title":"The intrinsically disordered TC-1 interacts with Chibby via regions with high helical propensity.","date":"2007","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/17905836","citation_count":24,"is_preprint":false},{"pmid":"29487109","id":"PMC_29487109","title":"Centrosomal protein Dzip1l binds Cby, promotes ciliary bud formation, and acts redundantly with Bromi to regulate ciliogenesis in the mouse.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29487109","citation_count":22,"is_preprint":false},{"pmid":"16570344","id":"PMC_16570344","title":"Reduced expression of beta-catenin inhibitor Chibby in colon carcinoma cell lines.","date":"2006","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16570344","citation_count":21,"is_preprint":false},{"pmid":"21182262","id":"PMC_21182262","title":"Structural characterization of partially disordered human Chibby: insights into its function in the Wnt-signaling pathway.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21182262","citation_count":20,"is_preprint":false},{"pmid":"33131181","id":"PMC_33131181","title":"Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome.","date":"2020","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/33131181","citation_count":20,"is_preprint":false},{"pmid":"26266958","id":"PMC_26266958","title":"Chibby functions to preserve normal ciliary morphology through the regulation of intraflagellar transport in airway ciliated cells.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26266958","citation_count":20,"is_preprint":false},{"pmid":"6179860","id":"PMC_6179860","title":"Molecular heterogeneity of D-end products detected by anti-H-2.28 sera. I. A. molecule similar to Qa-2, detected in the BALB/cBy but not in the BALB/c-H-2dm2 mutant.","date":"1982","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/6179860","citation_count":18,"is_preprint":false},{"pmid":"33934099","id":"PMC_33934099","title":"A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33934099","citation_count":16,"is_preprint":false},{"pmid":"19435523","id":"PMC_19435523","title":"Chibby forms a homodimer through a heptad repeat of leucine residues in its C-terminal coiled-coil motif.","date":"2009","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19435523","citation_count":16,"is_preprint":false},{"pmid":"23707389","id":"PMC_23707389","title":"Chibby drives β catenin cytoplasmic accumulation leading to activation of the unfolded protein response in BCR-ABL1+ cells.","date":"2013","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/23707389","citation_count":15,"is_preprint":false},{"pmid":"21995627","id":"PMC_21995627","title":"The expression patterns and correlations of chibby, β-catenin, and DNA methyltransferase-1 and their clinicopathological significance in lung cancers.","date":"2011","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/21995627","citation_count":14,"is_preprint":false},{"pmid":"24339928","id":"PMC_24339928","title":"BCR-ABL1-associated reduction of beta catenin antagonist Chibby1 in chronic myeloid leukemia.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24339928","citation_count":13,"is_preprint":false},{"pmid":"15737694","id":"PMC_15737694","title":"Chibby, a novel antagonist of the Wnt pathway, is not involved in Wilms tumor development.","date":"2005","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/15737694","citation_count":13,"is_preprint":false},{"pmid":"22651859","id":"PMC_22651859","title":"Chibby suppresses growth of human SW480 colon adenocarcinoma cells through inhibition of β-catenin signaling.","date":"2012","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22651859","citation_count":12,"is_preprint":false},{"pmid":"15245581","id":"PMC_15245581","title":"Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?","date":"2004","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15245581","citation_count":11,"is_preprint":false},{"pmid":"16889488","id":"PMC_16889488","title":"Differential Susceptibility of BALB/c and BALB/cBy mice to Graves' hyperthyroidism.","date":"2006","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/16889488","citation_count":9,"is_preprint":false},{"pmid":"32491167","id":"PMC_32491167","title":"Role of DZIP1-CBY-FAM92 transition zone complex in the basal body to membrane attachment and ciliary budding.","date":"2020","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/32491167","citation_count":8,"is_preprint":false},{"pmid":"33811421","id":"PMC_33811421","title":"DZIP1 regulates mammalian cardiac valve development through a Cby1-β-catenin mechanism.","date":"2021","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/33811421","citation_count":8,"is_preprint":false},{"pmid":"26147002","id":"PMC_26147002","title":"14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist chibby 1 in Chronic Myeloid Leukemia.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26147002","citation_count":8,"is_preprint":false},{"pmid":"38442096","id":"PMC_38442096","title":"Cep131-Cep162 and Cby-Fam92 complexes cooperatively maintain Cep290 at the basal body and contribute to ciliogenesis initiation.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/38442096","citation_count":7,"is_preprint":false},{"pmid":"25389112","id":"PMC_25389112","title":"DNA methyltransferase 1 drives transcriptional down-modulation of β catenin antagonist Chibby1 associated with the BCR-ABL1 gene of chronic myeloid leukemia.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25389112","citation_count":7,"is_preprint":false},{"pmid":"23838289","id":"PMC_23838289","title":"Phosphorylation of C-terminal polycystin-2 influences the interaction with PIGEA14: a QCM study based on solid supported membranes.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23838289","citation_count":7,"is_preprint":false},{"pmid":"34446743","id":"PMC_34446743","title":"Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34446743","citation_count":6,"is_preprint":false},{"pmid":"21529289","id":"PMC_21529289","title":"Generation and characterization of monoclonal antibodies against human Chibby protein.","date":"2011","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/21529289","citation_count":6,"is_preprint":false},{"pmid":"29689303","id":"PMC_29689303","title":"Cloning, identification and function analysis of a Chibby homolog from Litopenaeus vannamei.","date":"2018","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29689303","citation_count":6,"is_preprint":false},{"pmid":"29152155","id":"PMC_29152155","title":"Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29152155","citation_count":6,"is_preprint":false},{"pmid":"32192213","id":"PMC_32192213","title":"Combined Chibby and β-Catenin Predicts Clinical Outcomes in Patients with Hepatocellular Carcinoma.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32192213","citation_count":5,"is_preprint":false},{"pmid":"27082063","id":"PMC_27082063","title":"Conformational characterization of the intrinsically disordered protein Chibby: Interplay between structural elements in target recognition.","date":"2016","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/27082063","citation_count":5,"is_preprint":false},{"pmid":"28107095","id":"PMC_28107095","title":"Chibby1 knockdown promotes mesenchymal-to-epithelial transition-like changes.","date":"2017","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28107095","citation_count":5,"is_preprint":false},{"pmid":"25838250","id":"PMC_25838250","title":"Expression of CBY and methylation of CBY at promoter region in human laryngeal squamous cell carcinoma.","date":"2015","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/25838250","citation_count":4,"is_preprint":false},{"pmid":"25175341","id":"PMC_25175341","title":"Downregulated Chibby in laryngeal squamous cell carcinoma with increased expression in laryngeal carcinoma Hep-2 cells.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25175341","citation_count":3,"is_preprint":false},{"pmid":"29552214","id":"PMC_29552214","title":"Anti-oncogenic activity of Chibby in the development of human nasopharyngeal carcinoma.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29552214","citation_count":3,"is_preprint":false},{"pmid":"38733656","id":"PMC_38733656","title":"Identification of a novel mutation in chibby family member 2 in a non-obstructive azoospermic patient.","date":"2024","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/38733656","citation_count":3,"is_preprint":false},{"pmid":"10369925","id":"PMC_10369925","title":"The H-mshi antigen is conserved among standard BALB/cBy, C57BL/6J, and wild-derived CAST/Ei and SPRET/Ei inbred strains of mice.","date":"1999","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10369925","citation_count":2,"is_preprint":false},{"pmid":"23645032","id":"PMC_23645032","title":"No important role for genetic variation in the Chibby gene in monogenic and complex obesity.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23645032","citation_count":2,"is_preprint":false},{"pmid":"30063079","id":"PMC_30063079","title":"Chibby is a weak regulator of β-catenin activity in gastric epithelium.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30063079","citation_count":2,"is_preprint":false},{"pmid":"29181101","id":"PMC_29181101","title":"Downregulation of nuclear and cytoplasmic Chibby is associated with advanced cervical cancer.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29181101","citation_count":1,"is_preprint":false},{"pmid":"35947191","id":"PMC_35947191","title":"Defective bone repletion in aged Balb/cBy mice was caused by impaired osteoblastic differentiation.","date":"2022","source":"Journal of bone and mineral metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35947191","citation_count":1,"is_preprint":false},{"pmid":"36637515","id":"PMC_36637515","title":"Elimination of 4T1 Mammary Tumor Cells by BALB/cBy UBC-GFP Transgenics following Stable Inheritance of the H-2b MHC Allele.","date":"2023","source":"ImmunoHorizons","url":"https://pubmed.ncbi.nlm.nih.gov/36637515","citation_count":1,"is_preprint":false},{"pmid":"37986347","id":"PMC_37986347","title":"Upregulated TC1 and downregulated Chibby were correlated with the aberrant β-catenin expression in laryngeal squamous cell carcinoma.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37986347","citation_count":1,"is_preprint":false},{"pmid":"40484380","id":"PMC_40484380","title":"Dimerization of the BAR domain-containing protein FAM92A modulates lipid binding and interaction with CBY1.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40484380","citation_count":0,"is_preprint":false},{"pmid":"42000008","id":"PMC_42000008","title":"Rhotekin contributes to osteoblast differentiation and bone homeostasis by interacting with Chibby 1.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/42000008","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33135,"output_tokens":6547,"usd":0.098805},"stage2":{"model":"claude-opus-4-6","input_tokens":10293,"output_tokens":4372,"usd":0.241147},"total_usd":0.339952,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"CBY1 (Chibby) was identified as a nuclear protein that directly interacts with the C-terminal region of β-catenin and inhibits β-catenin-mediated transcriptional activation by competing with Lef-1 for binding to β-catenin. Epistasis experiments in Drosophila placed chibby downstream of wingless and upstream of armadillo.\",\n      \"method\": \"Protein interaction screen, competition binding assay, RNAi in Drosophila, genetic epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original discovery with direct binding assay, transcriptional competition, and genetic epistasis; highly cited foundational paper\",\n      \"pmids\": [\"12712206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CBY1 cooperates with 14-3-3ε and 14-3-3ζ to facilitate nuclear export of β-catenin. Akt kinase phosphorylates CBY1 at serine 20, which creates a 14-3-3 binding motif; 14-3-3 binding sequesters CBY1 in the cytoplasm and CBY1, 14-3-3, and β-catenin form a stable tripartite complex causing β-catenin to partition into the cytoplasm.\",\n      \"method\": \"Affinity purification/mass spectrometry, site-directed mutagenesis (S20), co-immunoprecipitation, subcellular fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including MS identification, mutagenesis, and functional localization studies\",\n      \"pmids\": [\"18573912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CBY1 harbors bona fide nuclear localization signal (NLS) and nuclear export signal (NES) motifs and constitutively shuttles between nucleus and cytoplasm. Efficient nuclear export requires cooperative action of the intrinsic NES, 14-3-3, and CRM1 nuclear export receptor. 14-3-3 docking promotes CBY1 binding to CRM1 while inhibiting its interaction with importin-α, and NLS/NES-dependent shuttling of CBY1 modulates β-catenin intracellular localization.\",\n      \"method\": \"NLS/NES mutagenesis, nuclear export inhibitor (leptomycin B), shRNA knockdown, co-immunoprecipitation, live cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of NLS/NES combined with functional import/export assays and epistasis with CRM1\",\n      \"pmids\": [\"19940019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CBY1 forms a stable homodimer through a heptad repeat of four leucine residues in its C-terminal coiled-coil motif. Alanine substitution of two or more leucine residues abolishes homodimerization. Homodimerization is required for efficient interaction with importin-α and subsequent nuclear translocation, but monomeric CBY1 retains the ability to bind β-catenin and repress its transcriptional activity.\",\n      \"method\": \"Alanine scanning mutagenesis, co-immunoprecipitation, size exclusion chromatography\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — comprehensive mutagenesis with multiple functional readouts\",\n      \"pmids\": [\"19435523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CBY1 is localized at the base of cilia in mouse nasal epithelium, and Cby−/− mice exhibit impaired basal body docking to the apical surface of multiciliated cells, resulting in a marked paucity of motile cilia and complete absence of mucociliary transport.\",\n      \"method\": \"Cby knockout mouse, immunofluorescence localization, electron microscopy of basal body docking, mucociliary transport assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse with direct ultrastructural and functional phenotypic analysis\",\n      \"pmids\": [\"19364920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CBY1 promotes adipocyte differentiation by inhibiting β-catenin signaling. Ectopic expression of CBY1 induces spontaneous differentiation of 3T3-L1 preadipocytes, while RNAi depletion of CBY1 blocks adipogenesis. Embryonic fibroblasts from Cby-deficient embryos show attenuated adipogenic differentiation.\",\n      \"method\": \"RNAi knockdown, ectopic overexpression, Cby-deficient mouse embryonic fibroblasts, adipogenic differentiation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both gain- and loss-of-function in multiple cell types including knockout-derived cells\",\n      \"pmids\": [\"17403895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CBY1 is a centriolar component specifically located at the distal end of the mother centriole and is essential for assembly of the primary cilium. CBY1 interacts physically with the distal appendage component Cenexin (ODF2), which abrogates CBY1's inhibitory effect on β-catenin-mediated transcription in a dose-dependent manner. Cenexin is required for recruitment of CBY1 to the mother centriole, but CBY1 is dispensable for Cenexin localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, TOPflash reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal localization dependencies established with knockdown and co-IP\",\n      \"pmids\": [\"22911743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, CBY localizes to the basal body transition zone in sensory neurons and male germ cells, and is required for basal body structure and ciliary function, including proper ciliary protein trafficking and axonemal assembly, but is not required for Wingless signaling in flies.\",\n      \"method\": \"cby mutant Drosophila, immunofluorescence, electron microscopy, sensory transduction assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ortholog in Drosophila with clean KO and multiple functional/structural readouts; consistent with mammalian CBY1 function at basal bodies\",\n      \"pmids\": [\"22508513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CBY1 facilitates basal body docking to the apical cell membrane during airway multiciliated cell differentiation through proper formation of ciliary vesicles at distal appendages. CBY1 is recruited to distal appendages via physical interaction with CEP164, then associates with Rabin8 (a GEF for Rab8) to promote Rab8 recruitment and efficient assembly of ciliary vesicles.\",\n      \"method\": \"Primary mouse tracheal epithelial cell cultures, co-immunoprecipitation, RNAi knockdown, immunofluorescence, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction with CEP164 and Rabin8 shown by co-IP, combined with functional vesicle assembly assay in primary cells\",\n      \"pmids\": [\"25313408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CBY1 localizes to an ~250-nm ring at the distal end of the mature centriole (dependent on ODF1/Ofd1) and promotes the recruitment of Ahi1 to the transition zone. In Cby1-knockout cells, centriole-localized Ahi1 is reduced, impairing ciliogenesis and ciliary recruitment of the Joubert syndrome protein Arl13b. CBY1 deletion causes cystic kidneys in mice.\",\n      \"method\": \"3D-SIM and STED superresolution microscopy, Cby1 knockout mouse, immunofluorescence, quantitative localization analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — superresolution structural data combined with KO phenotype and quantitative protein recruitment assay\",\n      \"pmids\": [\"25103236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The crystal structure of the human 14-3-3ζ/CBY1 peptide complex was solved at 2.2 Å, revealing a canonical binding mode where phosphorylation of S20 is essential for 14-3-3 recognition. NMR titration shows that residues outside the conserved 14-3-3 binding cleft (flexible loop residues 203-210) also contribute to the interaction.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, isothermal titration calorimetry, mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus NMR and ITC providing atomic-level mechanism\",\n      \"pmids\": [\"25909186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CBY1 is required for normal ciliary morphology and proper distribution of IFT-B complex proteins (IFT88, IFT20, IFT57) but not IFT-A or BBS proteins in airway ciliated cells. Loss of CBY1 causes paddle-like cilia with dilated tips and accumulation of IFT-B components within those tips.\",\n      \"method\": \"Cby knockout mouse, primary MTECs, Cby-/- MEFs, immunofluorescence, electron microscopy\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO combined with specific IFT subcomplex analysis provides pathway placement\",\n      \"pmids\": [\"26266958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM92A and FAM92B (BAR domain-containing proteins) interact with CBY1 and colocalize with it at centrioles/basal bodies. Centriolar localization of FAM92A and FAM92B depends largely on CBY1. FAM92A knockdown impairs ciliogenesis. FAM92A and FAM92B, in cooperation with CBY1, induce Rab8-containing membrane-remodeling structures.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, immunofluorescence, ciliogenesis assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS identification followed by functional validation with multiple orthogonal methods\",\n      \"pmids\": [\"27528616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TC1 (C8orf4) interacts with CBY1 and antagonizes CBY1's inhibitory function on β-catenin-mediated transcription, thereby acting as a positive regulator of the Wnt/β-catenin pathway. Co-expression of TC1 and CBY1 results in relocalization of TC1 from nucleolus to nuclear speckles where it colocalizes with CBY1.\",\n      \"method\": \"Co-immunoprecipitation, TOPflash reporter assay, immunofluorescence colocalization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with functional reporter assay but no mutagenesis mapping of interaction\",\n      \"pmids\": [\"16424001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TC-1 (thyroid cancer-1), an intrinsically disordered protein, interacts with CBY1 via three regions with high helical propensity (D44-R53, K58-A64, D73-T88) in its C-terminal portion, as determined by NMR spectroscopy.\",\n      \"method\": \"NMR spectroscopy (chemical shift analysis, relaxation measurements, resonance broadening)\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural mapping of interaction interface with functional context\",\n      \"pmids\": [\"17905836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human CBY1 is a partially disordered protein: its N-terminal portion is predominantly unstructured in solution while the C-terminal half adopts a coiled-coil structure through self-association. CBY1 uses its N-terminal disordered module to bind 14-3-3ζ and its C-terminal coiled-coil for self-association and TC-1 binding.\",\n      \"method\": \"NMR spectroscopy, ESI-MS, CD, DLS\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods characterizing structure-function relationship\",\n      \"pmids\": [\"21182262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CBY1 (PIGEA-14) was identified as an interacting partner of the C-terminus of polycystin-2 (PC2) via yeast two-hybrid screen. Co-expression of CBY1 and PC2 in LLC-PK1 and HeLa cells caused redistribution of both proteins to the trans-Golgi network, suggesting CBY1 regulates intracellular trafficking of PC2. CBY1 also interacts with GM130, a cis-Golgi component.\",\n      \"method\": \"Yeast two-hybrid screen, co-expression/immunofluorescence localization, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and colocalization, limited functional mechanistic follow-up\",\n      \"pmids\": [\"15194699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CBY1 protein is prominently associated with centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells and at the base of motile cilia in airway ciliated cells. CBY1 is a direct downstream transcriptional target of the master ciliogenesis transcription factor Foxj1. Loss of CBY1 results in alveolar airspace enlargement with reduced proliferation, abnormal epithelial cell differentiation, and failure of basal body docking in airway ciliated cells.\",\n      \"method\": \"Cby-/- mouse lung analysis, immunofluorescence, Foxj1 promoter analysis, electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple phenotypic readouts plus direct identification of Foxj1 as upstream transcriptional regulator\",\n      \"pmids\": [\"21049041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Centrosomal protein Dzip1l interacts with CBY1 (shown by co-immunoprecipitation), colocalizes with basal body appendage proteins, and acts upstream of CBY1 in ciliogenesis. Loss of Dzip1l reduces ciliogenesis and prevents removal of the capping protein Cp110 from distal mother centrioles, arresting ciliogenesis at the ciliary bud stage.\",\n      \"method\": \"Co-immunoprecipitation, Dzip1l knockout mouse, immunofluorescence, epistasis analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus genetic epistasis placing Dzip1l upstream of Cby1, but epistasis with Cby1 not fully dissected\",\n      \"pmids\": [\"29487109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DZIP1 forms a multimeric complex with CBY1 and β-catenin at the basal body of primary cilia during cardiac valve development. A specific DZIP1 peptide is required for stabilization of this complex and suppression of β-catenin activities. Loss of DZIP1-CBY1 interaction leads to increased nuclear β-catenin, elevated MMP2, altered ECM, and myxomatous valve phenotype.\",\n      \"method\": \"Co-immunoprecipitation, decoy peptide experiments, immunofluorescence, TOPflash reporter assay, mouse cardiac valve analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — complex characterized biochemically with functional peptide experiments and in vivo phenotype\",\n      \"pmids\": [\"33811421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In CML cells, CBY1 protein stability is reduced upon binding to 14-3-3σ, a process mediated by BCR-ABL1 tyrosine kinase and AKT phosphorylation of CBY1 at serine 20. JNK phosphorylation of 14-3-3σ at S186 promotes dissociation of CBY1 from 14-3-3σ. The ubiquitin-proteasome system reduces CBY1 stability via enhanced SUMOylation when CBY1 is bound to 14-3-3σ.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, kinase inhibitor experiments, SUMOylation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation-dependent interaction mechanism with multiple PTM writers identified, though in disease cell context\",\n      \"pmids\": [\"26147002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss-of-function variants in CBY1 cause a ciliopathy with features of Joubert syndrome in humans. Patient fibroblasts show reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B. Depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes.\",\n      \"method\": \"Human genetics (biallelic LOF variants), patient fibroblast immunofluorescence, zebrafish morpholino knockdown\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human disease variants with cell-based functional validation and zebrafish model\",\n      \"pmids\": [\"33131181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of CBY1 in mice causes severe exocrine pancreatic atrophy with dilated ducts, reduction in cilia number and length, inflammatory infiltration, and defective zymogen granule secretion in acinar cells. CBY1-KO acinar cells show altered polarity and accumulate zymogen granules due to defective exocytosis.\",\n      \"method\": \"Cby1 knockout mouse, immunofluorescence, electron microscopy, ex vivo acini secretion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with both in vivo and ex vivo functional secretion assays\",\n      \"pmids\": [\"34446743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Cby-Fam92 module (near the ciliary membrane) and the Cep131-Cep162 module (near the axoneme) cooperatively maintain Cep290 at the basal body and control the initiation of ciliogenesis. Concurrent deletion of members of both modules leads to complete loss of Cep290 from the basal body and blocks ciliogenesis at its initiation stage.\",\n      \"method\": \"Drosophila genetics (double mutants), immunofluorescence, epistasis analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with clear pathway placement of Cby in Cep290 maintenance\",\n      \"pmids\": [\"38442096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The crystal structure (2.2 Å) of mouse FAM92A BAR domain reveals an antiparallel crescent-shaped homodimer. FAM92A BAR directly binds the N-terminal region of CBY1, and their respective dimerizations synergistically enhance binding affinity. Structure-guided mutagenesis identified residues critical for lipid binding on the concave surface and residues essential for dimerization.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, co-immunoprecipitation, binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis defining molecular basis of FAM92A-CBY1 interaction\",\n      \"pmids\": [\"40484380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rhotekin interacts with CBY1 and competes with β-catenin for binding to CBY1, thereby relieving CBY1's antagonistic effect on β-catenin and activating the canonical Wnt/β-catenin pathway to promote osteoblast differentiation. Rhotekin also activates the FAK/AKT signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, overexpression/knockdown in mesenchymal progenitors, in vivo bone marrow silencing\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP plus functional competition assay, single study\",\n      \"pmids\": [\"42000008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CBY1 interacts with multiple NBPF proteins via a coiled-coil region in NBPF that binds the coiled-coil domain in the C-terminal region of CBY1. CBY1 also interacts with clusterin. NBPF1, CBY1, and clusterin can be co-immunoprecipitated together, suggesting a tri-molecular complex, though NBPF interaction does not influence CBY1's Wnt repressor function.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, TOPflash reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and single co-IP with limited mechanistic follow-up\",\n      \"pmids\": [\"20096688\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBY1 (Chibby1) is a conserved, partially disordered coiled-coil protein that functions as a dual antagonist of Wnt/β-catenin signaling and a critical regulator of ciliogenesis: it directly binds the C-terminal activation domain of β-catenin to compete with Tcf/Lef transcription factors, and upon Akt-mediated phosphorylation at S20, recruits 14-3-3 proteins to form a tripartite complex with β-catenin that is exported from the nucleus via CRM1; at centrioles, CBY1 localizes to an ~250 nm ring at the distal appendages of mature mother centrioles (recruited via CEP164 and Cenexin/ODF2), where it promotes ciliary vesicle formation through Rabin8/Rab8 recruitment and efficient basal body docking, facilitates Ahi1 transition zone assembly, and maintains proper IFT-B particle distribution—loss of CBY1 in mice causes primary ciliary dyskinesia-like airway defects, cystic kidneys, exocrine pancreatic degeneration, and lung developmental abnormalities, while human biallelic CBY1 loss-of-function causes Joubert syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CBY1 (Chibby1) is a conserved, partially disordered coiled-coil protein that functions both as an antagonist of canonical Wnt/β-catenin signaling and as an essential regulator of ciliogenesis. CBY1 directly binds the C-terminal activation domain of β-catenin, competing with Tcf/Lef transcription factors to repress β-catenin-mediated transcription; Akt phosphorylation of CBY1 at Ser20 creates a 14-3-3 binding motif, enabling formation of a tripartite CBY1–14-3-3–β-catenin complex that is exported from the nucleus via CRM1-dependent transport [PMID:12712206, PMID:18573912, PMID:19940019]. At centrioles, CBY1 localizes to a distal appendage ring on the mother centriole (recruited by CEP164 and Cenexin/ODF2), where it promotes ciliary vesicle formation through Rabin8/Rab8 recruitment, facilitates Ahi1 transition zone assembly, and cooperates with the BAR-domain proteins FAM92A/B to remodel membranes during basal body docking [PMID:25313408, PMID:25103236, PMID:27528616, PMID:40484380]. Biallelic loss-of-function variants in CBY1 cause Joubert syndrome in humans, and Cby1-knockout mice exhibit primary ciliary dyskinesia-like airway defects, cystic kidneys, and exocrine pancreatic degeneration [PMID:33131181, PMID:19364920, PMID:34446743].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The fundamental question of CBY1's molecular function was answered: it directly binds the C-terminus of β-catenin and competitively inhibits Tcf/Lef-dependent transcription, establishing CBY1 as a nuclear antagonist of canonical Wnt signaling.\",\n      \"evidence\": \"Protein interaction screen, competition binding assay, and Drosophila genetic epistasis (Nature)\",\n      \"pmids\": [\"12712206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CBY1 recruitment to β-catenin unknown\", \"No structural detail of the CBY1–β-catenin interface\", \"Whether CBY1 functions outside Wnt signaling was unexplored\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"An independent screen revealed that CBY1 interacts with polycystin-2 and may regulate its intracellular trafficking to the trans-Golgi network, providing the first hint of a cilia/polycystin-related role for CBY1.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-expression/immunofluorescence in LLC-PK1 and HeLa cells\",\n      \"pmids\": [\"15194699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CBY1–PC2 interaction on ciliary signaling not tested\", \"No in vivo validation\", \"No reciprocal pulldown from endogenous PC2\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"TC-1 (C8orf4) was identified as a binding partner that antagonizes CBY1's repression of β-catenin, establishing that CBY1's Wnt-inhibitory activity is itself subject to regulation by competing interactors.\",\n      \"evidence\": \"Co-immunoprecipitation and TOPflash reporter assay in cancer cells\",\n      \"pmids\": [\"16424001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis mapping of the TC-1–CBY1 interface at the time\", \"Physiological context of TC-1 regulation of CBY1 unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CBY1's role in adipocyte differentiation demonstrated that its β-catenin antagonism has developmental consequences: CBY1 promotes adipogenesis by relieving Wnt/β-catenin-mediated suppression of differentiation.\",\n      \"evidence\": \"Gain- and loss-of-function in 3T3-L1 cells and Cby-deficient MEFs\",\n      \"pmids\": [\"17403895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CBY1 regulates adipogenesis through β-catenin-independent mechanisms not addressed\", \"In vivo adipose phenotype in KO mice not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The mechanism by which CBY1 clears β-catenin from the nucleus was resolved: Akt phosphorylation at Ser20 creates a 14-3-3 binding site, and the resulting tripartite CBY1–14-3-3–β-catenin complex partitions β-catenin to the cytoplasm.\",\n      \"evidence\": \"AP-MS, site-directed mutagenesis of S20, co-IP, subcellular fractionation (J. Cell Biol.)\",\n      \"pmids\": [\"18573912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of 14-3-3 recognition of phospho-CBY1 not yet determined\", \"Nuclear export route not characterized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Three key structural and functional properties were established simultaneously: CBY1 contains functional NLS/NES motifs and shuttles between nucleus and cytoplasm via CRM1; CBY1 homodimerizes through a C-terminal coiled-coil required for nuclear import; and Cby-knockout mice lack motile cilia due to failed basal body docking, revealing CBY1's essential role in ciliogenesis.\",\n      \"evidence\": \"NLS/NES mutagenesis with leptomycin B and live imaging; coiled-coil alanine scanning and SEC; Cby−/− mouse with EM and mucociliary transport assays\",\n      \"pmids\": [\"19940019\", \"19435523\", \"19364920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CBY1's Wnt and cilia functions are coordinated at the same protein was unclear\", \"Mechanism of basal body docking failure not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"CBY1 was placed downstream of the master ciliogenesis transcription factor Foxj1 and shown to be essential for lung epithelial development, linking its transcriptional regulation to its basal body/cilia function in vivo.\",\n      \"evidence\": \"Cby−/− mouse lung analysis, Foxj1 promoter analysis, immunofluorescence, EM\",\n      \"pmids\": [\"21049041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Foxj1 is the sole transcriptional regulator of Cby1 not determined\", \"Alveolar enlargement phenotype mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The biophysical architecture of CBY1 was resolved: its N-terminal half is intrinsically disordered (harboring the 14-3-3 binding region), while its C-terminal coiled-coil mediates homodimerization and TC-1 binding, establishing a modular structure-function framework.\",\n      \"evidence\": \"NMR spectroscopy, ESI-MS, CD, and DLS on full-length CBY1\",\n      \"pmids\": [\"21182262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length CBY1 structure in complex with β-catenin not determined\", \"How disorder-to-order transitions regulate partner selectivity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CBY1's centriolar location was pinpointed to the distal end of the mother centriole, dependent on Cenexin/ODF2 recruitment, and Drosophila Cby was shown to localize to the basal body transition zone and be required for ciliary structure but dispensable for Wingless signaling—clarifying that the cilia function is the conserved ancestral role.\",\n      \"evidence\": \"Mammalian co-IP and siRNA with immunofluorescence; Drosophila cby mutant with EM and sensory assays\",\n      \"pmids\": [\"22911743\", \"22508513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The precise distal appendage substructure where CBY1 sits was not yet resolved at nanometer resolution\", \"Why Drosophila Cby is dispensable for Wnt but mammalian CBY1 is not was unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The molecular pathway by which CBY1 promotes ciliogenesis was elaborated: CBY1 is recruited to distal appendages by CEP164, then engages Rabin8 to activate Rab8 and form ciliary vesicles; superresolution microscopy resolved CBY1 to an ~250-nm ring, and its loss impairs Ahi1 transition zone assembly and causes cystic kidneys.\",\n      \"evidence\": \"Co-IP of CBY1–CEP164 and CBY1–Rabin8 in primary MTECs; 3D-SIM/STED in Cby1-KO cells; KO mouse kidney phenotype\",\n      \"pmids\": [\"25313408\", \"25103236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CBY1 directly activates Rabin8 or serves as a scaffold unknown\", \"Structural basis of the CBY1–CEP164 interaction not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The atomic basis of 14-3-3 recognition was established (2.2 Å crystal structure of 14-3-3ζ–phospho-CBY1 peptide), and separately, CBY1 was shown to be required for proper IFT-B distribution in cilia—its loss causes paddle-like cilia with IFT-B accumulation at tips.\",\n      \"evidence\": \"X-ray crystallography, NMR, and ITC for 14-3-3 structure; Cby−/− mouse MTECs and MEFs with IFT subcomplex immunofluorescence\",\n      \"pmids\": [\"25909186\", \"26266958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CBY1 specifically affects IFT-B but not IFT-A turnover is mechanistically unexplained\", \"Whether IFT defects are secondary to basal body docking failure was not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"FAM92A and FAM92B were identified as CBY1 interactors that depend on CBY1 for centriolar localization and cooperate with it in Rab8-dependent membrane remodeling, establishing the CBY1–FAM92 module as a membrane-shaping unit at basal bodies.\",\n      \"evidence\": \"Tandem affinity purification/MS, co-IP, siRNA, and ciliogenesis assays\",\n      \"pmids\": [\"27528616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FAM92–CBY1 interaction unknown at the time\", \"Whether FAM92 BAR domain directly tubulates membranes in a CBY1-dependent manner was not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The clinical significance of CBY1 was established: biallelic loss-of-function variants cause Joubert syndrome in humans, with patient fibroblasts showing reduced ciliation, elongated cilia, and reduced AHI1/ARL13B—directly linking the mouse cilia phenotype to a human ciliopathy.\",\n      \"evidence\": \"Human genetic analysis (biallelic LOF), patient fibroblast immunofluorescence, zebrafish morpholino knockdown\",\n      \"pmids\": [\"33131181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlations across different CBY1 mutations not yet characterized\", \"Whether CBY1 loss-of-function contributes to a broader spectrum of ciliopathies unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CBY1's role was extended to two additional tissues: DZIP1 forms a complex with CBY1 and β-catenin at cardiac valve basal bodies to suppress β-catenin and prevent myxomatous degeneration, and Cby1-KO mice develop severe exocrine pancreatic atrophy with defective zymogen secretion, broadening the phenotypic spectrum.\",\n      \"evidence\": \"Co-IP and decoy peptide experiments in cardiac valves; Cby1-KO mouse pancreas EM and ex vivo secretion assays\",\n      \"pmids\": [\"33811421\", \"34446743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pancreatic defects are purely cilia-dependent or involve CBY1's Wnt function not resolved\", \"DZIP1–CBY1 complex stoichiometry and structure unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic epistasis in Drosophila established that the Cby–Fam92 module and the Cep131–Cep162 module cooperatively maintain Cep290 at the basal body, and concurrent loss blocks ciliogenesis initiation, placing CBY1 in a defined pathway hierarchy for transition zone assembly.\",\n      \"evidence\": \"Drosophila double mutants with immunofluorescence and epistasis analysis\",\n      \"pmids\": [\"38442096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this pathway hierarchy is conserved in mammals not yet tested\", \"Direct physical interaction between Cby–Fam92 module and Cep290 not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The structural basis of the CBY1–FAM92A interaction was resolved: a 2.2 Å crystal structure of the FAM92A BAR domain revealed an antiparallel crescent homodimer, and FAM92A binds the N-terminal region of CBY1, with dimerization of both proteins synergistically enhancing affinity.\",\n      \"evidence\": \"X-ray crystallography, structure-guided mutagenesis, co-IP, binding affinity measurements\",\n      \"pmids\": [\"40484380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of a full CBY1–FAM92A complex on membranes not determined\", \"How FAM92A lipid binding coordinates with CBY1-mediated Rab8 recruitment is undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how CBY1's dual Wnt-inhibitory and ciliogenic functions are spatiotemporally coordinated within the same cell; the atomic structure of the CBY1–β-catenin complex; and the full genotype-phenotype spectrum of human CBY1 ciliopathies.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full-length CBY1 in complex with β-catenin\", \"Mechanism by which CBY1 selectively affects IFT-B versus IFT-A not molecularly explained\", \"How Foxj1-driven transcription of Cby1 is integrated with post-translational regulation (Akt, 14-3-3) is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4, 6, 8, 9]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 17, 19]}\n    ],\n    \"complexes\": [\n      \"CBY1–14-3-3–β-catenin tripartite complex\",\n      \"CBY1–FAM92A/B membrane-remodeling module\",\n      \"DZIP1–CBY1–β-catenin basal body complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"YWHAZ\",\n      \"YWHAE\",\n      \"CEP164\",\n      \"ODF2\",\n      \"FAM92A\",\n      \"FAM92B\",\n      \"RABIN8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}