{"gene":"BICC1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2008,"finding":"Mouse Bicc1 KH domains bind RNA in vitro; specifically, the third KH domain is necessary and sufficient for homoribopolymer binding in vitro. The jcpk PKD-causing mutation abolishes this RNA-binding activity.","method":"In vitro RNA-binding assays with deletion constructs of mBicc1 protein","journal":"Nephron. Experimental nephrology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay with domain-deletion constructs, single lab, single method","pmids":["18182784"],"is_preprint":false},{"year":2009,"finding":"Bicc1 physically interacts with SamCystin (ANKS6) in kidney cells; SamCystin self-associates and Bicc1–SamCystin interact by co-immunoprecipitation. The Han:SPRD-Cy rat PKD mutation disrupts SamCystin self-association but not the Bicc1–SamCystin interaction. RNA may be a component of the Bicc1–SamCystin complex.","method":"Co-immunoprecipitation of epitope-tagged recombinant proteins transiently transfected in IMCD cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP in cell-based system, replicated with mutant variant, single lab","pmids":["19324013"],"is_preprint":false},{"year":2010,"finding":"Bicc1 knockdown (shRNA) in IMCD cells disrupts normal tubulomorphogenesis, induces cystogenesis in 3D culture, and causes defects in E-cadherin-based cell–cell adhesion, actin cytoskeleton organization, cell–matrix interactions, proliferation, and apoptosis.","method":"Stable shRNA knockdown of Bicc1 in IMCD cells; 3D culture morphogenesis assay, immunofluorescence for E-cadherin and actin","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal readouts, single lab","pmids":["20219263"],"is_preprint":false},{"year":2011,"finding":"Human BICC1 blocks canonical Wnt signaling, largely through its SAM domain. A nonsense mutation in the first KH domain abolishes Wnt inhibitory activity; a missense mutation in the SAM domain (equivalent to full SAM deletion) reduces activity by ~22%.","method":"Wnt reporter assays in cell lines with wild-type and mutant BICC1 constructs; patient mutation analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with domain-specific mutants, single lab, consistent with mouse data","pmids":["21922595"],"is_preprint":false},{"year":2012,"finding":"Bicc1 KH domains bind AC6 mRNA and recruit miR-125a from Dicer; the SAM domain enables silencing through Argonaute and TNRC6A/GW182. Bicc1 similarly recruits miR-27a to silence PKIα mRNA. Loss of Bicc1 leads to upregulation of AC6 and elevated cAMP in cystic kidneys.","method":"RNA immunoprecipitation, reporter silencing assays, Bicc1 knockout mouse kidney analysis (cAMP measurement, AC6 expression), co-immunoprecipitation with Dicer/Argonaute/GW182","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, reporter assays, co-IP with silencing machinery, KO mouse biochemistry), single lab with comprehensive mechanistic dissection","pmids":["22641646"],"is_preprint":false},{"year":2014,"finding":"Bicc1 regulates Pkd2 transcript levels in osteoblasts; Bicc1 knockdown and Pkd2 knockdown each impair osteoblastogenesis, and Pkd2 overexpression rescues Bicc1-deficiency-dependent osteoblast defects, placing Pkd2 downstream of Bicc1 in osteoblast differentiation.","method":"Bicc1 heterozygous null mice (low BMD phenotype), siRNA knockdown of Bicc1 and Pkd2 in osteoblast cultures, rescue by Pkd2 overexpression, co-expression network analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via KD/OE rescue, in vivo mouse model, single lab","pmids":["24789909"],"is_preprint":false},{"year":2014,"finding":"Loss of polycystin-1 (PC1/Pkd1) downregulates Bicc1 expression in vitro and in vivo, revealing a molecular link between PKD1 and BICC1 in kidney development.","method":"Immunohistochemistry and western blot in Pkd1 knockout mice and Pkd1-depleted cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein expression analysis in KO mouse and cell lines, two orthogonal detection methods, single lab","pmids":["24594709"],"is_preprint":false},{"year":2015,"finding":"Bicc1 SAM domain self-polymerizes in vitro in a left-handed helix; this polymerization concentrates Bicc1 in cytoplasmic clusters that localize and silence bound mRNA (e.g., AC6). SAM polymerization also stabilizes Bicc1 protein and is required for inhibition of Dishevelled 2 in the Wnt/β-catenin pathway. The bpk mutation (C-terminal SAM extension) phenocopies polymerization-deficient mutants.","method":"Structure modeling of SAM domain; SAM interface mutagenesis; subcellular localization by fluorescence microscopy; mRNA silencing reporter assays; Wnt reporter assay; protein stability measurement","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure modeling validated by mutagenesis, multiple functional readouts (localization, silencing, Wnt pathway), single lab with orthogonal methods","pmids":["26217012"],"is_preprint":false},{"year":2015,"finding":"BICC1 knockdown in the rat hippocampus protects against CUS-induced anhedonia, establishing a functional role for elevated BICC1 in depressive behavior. Neuronal activity downregulates BICC1 in vitro; acute ketamine rapidly decreases BICC1 mRNA in vivo.","method":"In vivo hippocampal knockdown via viral vector, sucrose preference test (CUS model); in vitro neuronal stimulation with BICC1 mRNA measurement","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined behavioral phenotype plus in vitro mechanistic follow-up, single lab","pmids":["25178406"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of Bicc1 SAM polymer determined at high resolution, revealing a canonical head-to-tail SAM polymer with flexibility in subunit interface orientations. ANKS3 recruits ANKS6 to Bicc1, and together the three proteins cooperatively generate giant macromolecular complexes through SAM domain interactions and flanking sequences.","method":"X-ray crystallography of Bicc1 SAM domain; co-immunoprecipitation and domain-mapping of full-length and truncated Bicc1, ANKS3, ANKS6 proteins","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical interaction mapping, multiple domain constructs, single rigorous study","pmids":["29290488"],"is_preprint":false},{"year":2021,"finding":"Bicc1 preferentially recognizes GACR and YGAC sequences and specifically binds a conserved GACGUGAC motif in the proximal Dand5 3'-UTR. Bicc1 interacts with Cnot3 of the Ccr4-Not deadenylase complex, and this interaction is required for leftward Dand5 mRNA decay at the mouse embryonic node downstream of Pkd2 and Ca2+ signaling.","method":"3'-UTR deletion/mutation reporter assays in mouse embryos; RNA pull-down/binding assays; co-immunoprecipitation of Bicc1 with Cnot3; genetic analysis in Bicc1 and Pkd2 mutant mice; Ca2+ manipulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro RNA binding with defined sequence motif, co-IP of complex, in vivo reporter in mouse embryo, epistasis with Pkd2/Ca2+, single study with multiple orthogonal methods","pmids":["34210974"],"is_preprint":false},{"year":2021,"finding":"Bicc1 post-transcriptionally represses dand5 and gdf3 via their 3'-UTRs in Xenopus, zebrafish, and mouse during symmetry breaking. Two distinct Bicc1 functions on dand5 mRNA exist: pre-flow (mRNA stability) and post-flow (translational inhibition). Bicc1-mediated translational repression of dand5 3'-UTR reporter is responsive to Pkd2, placing Bicc1 downstream of Pkd2 flow sensing. Bicc1 cooperates with Dicer1 in this process.","method":"3'-UTR reporter assays; morpholino/CRISPR knockdown in Xenopus and zebrafish; genetic rescue; co-injection experiments with pkd2 manipulations; mRNA stability vs. translation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-species genetic epistasis, 3'-UTR reporters, Pkd2 epistasis, replicated across three vertebrate models","pmids":["34531379"],"is_preprint":false},{"year":2023,"finding":"As an RNA-binding protein, BICC1 binds the 3'-UTR of LCN2 (Lipocalin-2) mRNA and post-transcriptionally upregulates LCN2 expression in pancreatic cancer cells, leading to JAK2/STAT3 activation and CXCL1-driven VEGF-independent angiogenesis.","method":"RNA immunoprecipitation (RIP) of BICC1 with LCN2 3'-UTR; reporter assays; BICC1 knockdown/overexpression in PAAD cells and xenograft mouse models; signaling pathway analysis","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay plus in vivo xenograft phenotype, pathway epistasis, single lab","pmids":["37443111"],"is_preprint":false},{"year":2023,"finding":"ANKS3 C-terminal coiled-coil domain interacts with Bicc1 and inhibits target mRNA binding; ANKS6 recruits to ANKS3 and relieves this inhibition, restoring Bicc1-mediated Dand5 mRNA decay. A CRISPR-truncated ANKS3 causes symmetric (bilateral) mRNA decay, demonstrating that ANKS3 conformation governs the left-right specificity of Bicc1 RNP activity.","method":"AlphaFold structure prediction with biochemical validation by in vitro reconstitution; CRISPR-engineered ANKS3 truncation in mouse; RNA-binding assays; co-immunoprecipitation","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, AlphaFold structure with biochemical validation, CRISPR mouse genetics, multiple orthogonal methods in one study","pmids":["37733651"],"is_preprint":false},{"year":2023,"finding":"Bicc1 SAM-domain head-to-tail polymers are interconnected by KH domains forming a protein meshwork that mediates liquid-to-gel phase transitioning of client mRNAs. ANKS3 disperses Bicc1 granules and releases bound mRNAs, while co-recruitment of ANKS6 by ANKS3 reinstates Bicc1 condensation and ribonucleoparticle assembly.","method":"Live-cell fluorescence microscopy of Bicc1 condensates; co-transfection with ANKS3/ANKS6 constructs; RNA phase-partitioning assays; domain-mapping experiments","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus RNA partitioning assays, multiple constructs, single lab","pmids":["37275520"],"is_preprint":false},{"year":2024,"finding":"BICC1 upregulates IDO1 (indoleamine 2,3-dioxygenase-1) expression, activating tryptophan catabolism in pancreatic cancer cells. Increased tryptophan metabolites drive NAD+ synthesis and oxidative phosphorylation, promoting a stem cell-like phenotype and chemoresistance.","method":"BICC1 knockdown/overexpression in PDAC cells and organoids; metabolomics; IDO1 expression analysis; NAD+ and OXPHOS measurement; xenograft and patient-derived models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with metabolomics and multiple in vivo models, single lab","pmids":["38896624"],"is_preprint":false},{"year":2024,"finding":"NEDD4L E3 ubiquitin ligase mediates ubiquitination and proteasomal degradation of BICC1 protein. NEDD4L overexpression promotes BICC1 ubiquitination and degradation, inhibiting gastric cancer cell EMT and proliferation. BICC1 activates the PI3K/AKT pathway to facilitate cancer progression.","method":"Co-immunoprecipitation to detect NEDD4L–BICC1 interaction; ubiquitination assay; BICC1 knockdown/NEDD4L overexpression in GC cells and xenograft models; PI3K/AKT pathway western blot","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay plus in vivo model, single lab","pmids":["39717922"],"is_preprint":false},{"year":2025,"finding":"BICC1 physically binds Polycystin-1 (PKD1) and Polycystin-2 (PKD2) proteins via distinct protein domains. Bicc1 depletion in conjunction with Pkd1 or Pkd2 loss aggravates PKD severity in Xenopus and mouse models. Human BICC1 hypomorphic variants identified in VEO-PKD patients impacted disease-relevant signaling pathways in genome-edited kidney cells.","method":"Co-immunoprecipitation/biochemical binding assays; Xenopus and mouse double-knockout/depletion studies; CRISPR genome editing of human kidney cells; genetic analysis of ADPKD patient cohort","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical interaction mapping, cross-species genetic epistasis, human patient genetics, engineered cell lines; multiple orthogonal methods in one study","pmids":["41677782","39253489"],"is_preprint":false},{"year":2025,"finding":"N6-methyladenosine (m6A) modification of the conserved AGACGUGAC motif in Dand5 3'-UTR disrupts binding to Bicc1 KH domains in vitro, revealing m6A as a negative regulator of Bicc1 target mRNA recognition. This contrasts with IGF2BP and FMR1 KH domains, for which m6A promotes RNA binding.","method":"In vitro RNA-binding assays comparing m6A-modified vs. unmodified Dand5 3'-UTR oligonucleotides with Bicc1 KH domain protein","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro biochemical assay with defined modified RNA, single lab, single paper","pmids":["40634109"],"is_preprint":false}],"current_model":"BICC1 is a cytoplasmic RNA-binding protein whose N-terminal KH domains bind specific mRNA targets (including AC6, PKIα, LCN2, and Dand5) via a GACGUGAC-containing motif (negatively regulated by m6A modification), while its C-terminal SAM domain self-polymerizes into head-to-tail helical polymers that form phase-transitioning cytoplasmic granules; these granules recruit Argonaute/GW182/Ccr4-Not deadenylase machinery to silence or degrade bound mRNAs, regulate canonical Wnt signaling by inhibiting Dishevelled 2, establish vertebrate left-right asymmetry downstream of Pkd2/Ca2+ by asymmetrically degrading Dand5 mRNA, and are dynamically remodeled by the ciliopathy proteins ANKS3 and ANKS6, while BICC1 itself is subject to ubiquitin-mediated degradation by NEDD4L and physically cooperates with Polycystin-1 and Polycystin-2 in the context of polycystic kidney disease."},"narrative":{"mechanistic_narrative":"BICC1 is a cytoplasmic RNA-binding protein that assembles into self-organizing ribonucleoprotein granules to post-transcriptionally control mRNAs governing kidney tubulomorphogenesis, Wnt signaling, and vertebrate left-right asymmetry [PMID:22641646, PMID:26217012, PMID:34531379]. Target recognition is mediated by its N-terminal KH domains, which bind specific 3'-UTR sequences — preferentially GACR/YGAC elements and a conserved GACGUGAC motif — including AC6, PKIα, and Dand5 transcripts [PMID:22641646, PMID:34210974]; m6A modification of this motif disrupts KH-domain binding, providing a negative input on target recognition [PMID:40634109]. Its C-terminal SAM domain self-polymerizes into a head-to-tail left-handed helix that concentrates BICC1 into cytoplasmic clusters, stabilizes the protein, and is required for both mRNA silencing and inhibition of Dishevelled 2 in the canonical Wnt pathway [PMID:26217012, PMID:29290488]. SAM polymers interconnected by KH domains form a meshwork that drives liquid-to-gel phase transitioning of client mRNAs, and these granules recruit the miRNA/Argonaute–TNRC6A(GW182) silencing machinery and the Ccr4-Not deadenylase (via Cnot3) to repress or degrade bound transcripts [PMID:22641646, PMID:37275520, PMID:34210974]. At the embryonic node, this activity asymmetrically degrades Dand5 mRNA downstream of Pkd2/Ca2+ flow sensing to establish left-right asymmetry, with pre-flow stability control and post-flow translational repression [PMID:34210974, PMID:34531379]. BICC1 granule activity is dynamically remodeled by the ciliopathy proteins ANKS3 and ANKS6: ANKS3 binds BICC1, disperses granules, and inhibits target mRNA binding, while ANKS6 recruitment relieves this inhibition and reinstates condensation, thereby governing the left-right specificity of BICC1 RNP activity [PMID:29290488, PMID:37733651, PMID:37275520]. BICC1 physically binds Polycystin-1 and Polycystin-2, and BICC1 hypomorphic variants in very-early-onset polycystic kidney disease patients aggravate PKD severity, establishing BICC1 as a disease-relevant cooperating factor in ADPKD [PMID:41677782, PMID:39253489]. BICC1 protein abundance is controlled by NEDD4L-mediated ubiquitination and proteasomal degradation [PMID:39717922].","teleology":[{"year":2008,"claim":"Established that BICC1 is an RNA-binding protein and mapped binding to its KH domains, linking this activity directly to disease by showing a PKD-causing mutation abolishes it.","evidence":"In vitro RNA-binding assays with mouse Bicc1 domain-deletion constructs","pmids":["18182784"],"confidence":"Medium","gaps":["No physiological target mRNAs identified","Homoribopolymer binding does not define sequence specificity","Single in vitro method, single lab"]},{"year":2009,"claim":"Connected BICC1 to the ciliopathy-associated ANKS6/SamCystin protein, suggesting BICC1 operates within a larger PKD-relevant complex that may contain RNA.","evidence":"Co-immunoprecipitation of epitope-tagged proteins in IMCD kidney cells","pmids":["19324013"],"confidence":"Medium","gaps":["Single Co-IP in overexpression system","Functional consequence of the interaction unresolved","RNA component inferred, not demonstrated"]},{"year":2010,"claim":"Showed that BICC1 is required for normal renal tubulomorphogenesis, providing a cellular phenotype for its loss relevant to cystogenesis.","evidence":"Stable shRNA knockdown in IMCD cells with 3D morphogenesis and cytoskeletal/adhesion readouts","pmids":["20219263"],"confidence":"Medium","gaps":["Does not connect phenotype to specific mRNA targets","Mechanism linking RNA binding to adhesion/cytoskeleton unknown","Single lab"]},{"year":2011,"claim":"Defined BICC1 as a canonical Wnt pathway inhibitor and assigned domain contributions, with patient mutations functionally validating the SAM and KH domains.","evidence":"Wnt reporter assays with wild-type and mutant human BICC1 plus patient mutation analysis","pmids":["21922595"],"confidence":"Medium","gaps":["Molecular target within Wnt pathway not yet identified","Link between Wnt inhibition and RNA silencing unclear","Reporter-based readout"]},{"year":2012,"claim":"Defined the silencing mechanism: KH domains bind target mRNAs (AC6, PKIα) and recruit specific miRNAs and the Argonaute/GW182 machinery via the SAM domain, with KO mice confirming AC6/cAMP dysregulation in cystic kidneys.","evidence":"RNA-IP, reporter silencing assays, Dicer/Argonaute/GW182 co-IP, and Bicc1 knockout mouse kidney biochemistry","pmids":["22641646"],"confidence":"High","gaps":["Sequence specificity of target recognition not yet defined","Structural basis of SAM-mediated silencing-machinery recruitment unknown"]},{"year":2014,"claim":"Extended BICC1's regulatory reach beyond kidney by placing Pkd2 transcript regulation downstream of BICC1 in osteoblast differentiation, and showed PKD1 loss downregulates BICC1, embedding it in polycystin signaling networks.","evidence":"Heterozygous null mice, siRNA knockdown with Pkd2-overexpression rescue (osteoblasts); IHC/western in Pkd1 knockout mice and cells","pmids":["24789909","24594709"],"confidence":"Medium","gaps":["Direct vs. indirect regulation of Pkd2 transcript by BICC1 not resolved","Mechanism of PKD1-dependent BICC1 downregulation unknown"]},{"year":2015,"claim":"Provided the structural basis for granule formation, showing the SAM domain self-polymerizes into a left-handed helix that concentrates BICC1, stabilizes it, and is required for mRNA silencing and Dishevelled 2 inhibition.","evidence":"SAM structure modeling with interface mutagenesis, subcellular localization, silencing and Wnt reporter assays, protein stability measurements","pmids":["26217012"],"confidence":"High","gaps":["High-resolution polymer structure not yet determined","Regulation of polymerization in vivo unknown"]},{"year":2015,"claim":"Identified a distinct CNS role, showing elevated hippocampal BICC1 promotes depressive behavior and is dynamically downregulated by neuronal activity and ketamine.","evidence":"In vivo hippocampal viral knockdown with behavioral testing and in vitro neuronal BICC1 mRNA measurement","pmids":["25178406"],"confidence":"Medium","gaps":["No neuronal mRNA targets of BICC1 identified","Molecular link between BICC1 and depressive behavior unknown"]},{"year":2017,"claim":"Solved the SAM polymer crystal structure and showed ANKS3 recruits ANKS6 to BICC1 to assemble giant macromolecular complexes, defining the architecture of BICC1 RNP remodeling.","evidence":"X-ray crystallography of the SAM domain plus co-IP and domain mapping of BICC1, ANKS3, ANKS6","pmids":["29290488"],"confidence":"High","gaps":["Functional impact of ANKS3/ANKS6 assembly on mRNA targets not yet tested","How complex size relates to silencing activity unclear"]},{"year":2021,"claim":"Defined the precise RNA sequence specificity (GACGUGAC) and the Ccr4-Not (Cnot3) deadenylase link, establishing BICC1 as the effector that asymmetrically degrades Dand5 mRNA at the node downstream of Pkd2/Ca2+ to break left-right symmetry.","evidence":"Mouse embryo 3'-UTR reporters, RNA pull-down, Cnot3 co-IP, Bicc1/Pkd2 mutant genetics, Ca2+ manipulation; cross-species 3'-UTR reporters and knockdowns in Xenopus, zebrafish, mouse","pmids":["34210974","34531379"],"confidence":"High","gaps":["How flow/Ca2+ signaling switches BICC1 from stabilization to decay/translational repression unknown","Trigger for left-side-specific activity not fully resolved at this stage"]},{"year":2023,"claim":"Revealed that BICC1 granules undergo liquid-to-gel phase transitioning and that ANKS3/ANKS6 act as a switch controlling left-right specificity by toggling BICC1 condensation and target mRNA binding.","evidence":"Live-cell condensate imaging and RNA phase-partitioning assays; AlphaFold-validated in vitro reconstitution, CRISPR ANKS3-truncation mouse, RNA-binding and co-IP assays","pmids":["37275520","37733651"],"confidence":"High","gaps":["What positions ANKS3/ANKS6 asymmetrically across the node unknown","Physiological signal controlling the ANKS3 conformational switch unresolved"]},{"year":2023,"claim":"Showed BICC1 can also stabilize/upregulate a target mRNA (LCN2), driving JAK2/STAT3-dependent angiogenesis in pancreatic cancer, expanding its output beyond repression.","evidence":"BICC1 RIP with LCN2 3'-UTR, reporter assays, knockdown/overexpression in PDAC cells and xenografts, pathway analysis","pmids":["37443111"],"confidence":"Medium","gaps":["Mechanism by which BICC1 upregulates rather than silences LCN2 unclear","Whether granule/SAM polymerization is involved not addressed"]},{"year":2024,"claim":"Identified BICC1 control of IDO1/tryptophan metabolism driving stemness and chemoresistance in PDAC, and identified NEDD4L as the E3 ligase that degrades BICC1 and restrains its pro-tumorigenic PI3K/AKT signaling.","evidence":"Knockdown/overexpression with metabolomics and in vivo models (PDAC); NEDD4L–BICC1 co-IP, ubiquitination assays, gastric cancer cell and xenograft studies","pmids":["38896624","39717922"],"confidence":"Medium","gaps":["Direct vs. indirect regulation of IDO1 by BICC1 not established","Whether NEDD4L-mediated turnover regulates BICC1's RNA-silencing functions unknown"]},{"year":2025,"claim":"Established direct physical cooperation between BICC1 and the polycystins and confirmed BICC1 as a human PKD gene, with hypomorphic variants in VEO-PKD patients aggravating disease.","evidence":"Co-IP/biochemical binding assays, Xenopus and mouse double-depletion studies, CRISPR-edited human kidney cells, ADPKD patient cohort genetics","pmids":["41677782","39253489"],"confidence":"High","gaps":["Functional consequence of PC1/PC2 binding on BICC1 RNA activity not detailed","Mechanism by which hypomorphic variants alter signaling not fully resolved"]},{"year":2025,"claim":"Identified m6A modification of the BICC1 target motif as a negative regulatory input, distinct from other KH-domain proteins, adding an epitranscriptomic layer to target selection.","evidence":"In vitro RNA-binding assays comparing m6A-modified vs. unmodified Dand5 3'-UTR with BICC1 KH-domain protein","pmids":["40634109"],"confidence":"Medium","gaps":["In vivo relevance of m6A-mediated regulation not demonstrated","Whether m6A writers/readers act on BICC1 targets physiologically unknown","Single in vitro assay"]},{"year":null,"claim":"How the cilia-driven Pkd2/Ca2+ flow signal is mechanistically transduced to switch BICC1 between mRNA stabilization, translational repression, and Cnot3-dependent decay — and how ANKS3/ANKS6 condensate remodeling is positioned asymmetrically in vivo — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No molecular link between flow sensing and BICC1 activity switching","Asymmetric positioning signal for ANKS3/ANKS6 remodeling unknown","Structural basis of KH-domain sequence-specific recognition not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,10,18]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,10]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,14]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17]}],"complexes":["BICC1-ANKS3-ANKS6 macromolecular complex","Ccr4-Not deadenylase complex (via Cnot3)","Argonaute/TNRC6A(GW182) silencing complex"],"partners":["ANKS6","ANKS3","CNOT3","TNRC6A","DICER1","PKD1","PKD2","NEDD4L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H694","full_name":"Protein bicaudal C homolog 1","aliases":[],"length_aa":974,"mass_kda":104.8,"function":"Putative RNA-binding protein. Acts as a negative regulator of Wnt signaling. May be involved in regulating gene expression during embryonic development","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H694/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BICC1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BICC1","total_profiled":1310},"omim":[{"mim_id":"617310","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 3; ANKS3","url":"https://www.omim.org/entry/617310"},{"mim_id":"615370","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 6; ANKS6","url":"https://www.omim.org/entry/615370"},{"mim_id":"614295","title":"BICC FAMILY RNA-BINDING PROTEIN 1; BICC1","url":"https://www.omim.org/entry/614295"},{"mim_id":"610928","title":"SRY-BOX 17; SOX17","url":"https://www.omim.org/entry/610928"},{"mim_id":"609416","title":"MICRO RNA 17; MIR17","url":"https://www.omim.org/entry/609416"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":26.8}],"url":"https://www.proteinatlas.org/search/BICC1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9H694","domains":[{"cath_id":"3.30.1370.10","chopping":"47-127","consensus_level":"high","plddt":82.3894,"start":47,"end":127},{"cath_id":"3.30.310.210","chopping":"134-416","consensus_level":"medium","plddt":86.5339,"start":134,"end":416},{"cath_id":"1.10.150.50","chopping":"879-935","consensus_level":"high","plddt":90.4868,"start":879,"end":935}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H694","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H694-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H694-F1-predicted_aligned_error_v6.png","plddt_mean":59.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BICC1","jax_strain_url":"https://www.jax.org/strain/search?query=BICC1"},"sequence":{"accession":"Q9H694","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H694.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H694/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H694"}},"corpus_meta":[{"pmid":"21922595","id":"PMC_21922595","title":"Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21922595","citation_count":73,"is_preprint":false},{"pmid":"24789909","id":"PMC_24789909","title":"Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24789909","citation_count":54,"is_preprint":false},{"pmid":"22641646","id":"PMC_22641646","title":"Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing.","date":"2012","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22641646","citation_count":49,"is_preprint":false},{"pmid":"37443111","id":"PMC_37443111","title":"BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis.","date":"2023","source":"Signal transduction and 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1993)","url":"https://pubmed.ncbi.nlm.nih.gov/29290488","citation_count":22,"is_preprint":false},{"pmid":"30316917","id":"PMC_30316917","title":"Essential roles of neuropeptide VGF regulated TrkB/mTOR/BICC1 signaling and phosphorylation of AMPA receptor subunit GluA1 in the rapid antidepressant-like actions of ketamine in mice.","date":"2018","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/30316917","citation_count":22,"is_preprint":false},{"pmid":"25178406","id":"PMC_25178406","title":"BICC1 expression is elevated in depressed subjects and contributes to depressive behavior in rodents.","date":"2014","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25178406","citation_count":20,"is_preprint":false},{"pmid":"22910460","id":"PMC_22910460","title":"Effect of genetic variant in BICC1 on functional and structural brain changes in 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Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/18182784","citation_count":19,"is_preprint":false},{"pmid":"24594709","id":"PMC_24594709","title":"Loss of polycystin-1 inhibits Bicc1 expression during mouse development.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24594709","citation_count":17,"is_preprint":false},{"pmid":"26440730","id":"PMC_26440730","title":"Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.","date":"2015","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/26440730","citation_count":14,"is_preprint":false},{"pmid":"32714370","id":"PMC_32714370","title":"A 4.6 Mb Inversion Leading to PCDH15-LINC00844 and BICC1-PCDH15 Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32714370","citation_count":10,"is_preprint":false},{"pmid":"31807010","id":"PMC_31807010","title":"FGFR2-BICC1: A Subtype Of FGFR2 Oncogenic Fusion Variant In Cholangiocarcinoma And The Response To Sorafenib.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31807010","citation_count":9,"is_preprint":false},{"pmid":"35809112","id":"PMC_35809112","title":"Circ-BICC1 Knockdown Alleviates Lipopolysaccharide (LPS)-Induced WI-38 Cell Injury Through miR-338-3p/MYD88 Axis.","date":"2022","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35809112","citation_count":5,"is_preprint":false},{"pmid":"37733651","id":"PMC_37733651","title":"Bicc1 ribonucleoprotein complexes specifying organ laterality are licensed by ANKS6-induced structural remodeling of associated ANKS3.","date":"2023","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/37733651","citation_count":5,"is_preprint":false},{"pmid":"30697050","id":"PMC_30697050","title":"Serum BICC1 levels are significantly different in various mood disorders.","date":"2019","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/30697050","citation_count":5,"is_preprint":false},{"pmid":"37275520","id":"PMC_37275520","title":"Antagonistic interactions among structured domains in the multivalent Bicc1-ANKS3-ANKS6 protein network govern phase transitioning of target mRNAs.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37275520","citation_count":4,"is_preprint":false},{"pmid":"32252259","id":"PMC_32252259","title":"Generation of An Endogenous FGFR2-BICC1 Gene Fusion/58 Megabase Inversion Using Single-Plasmid CRISPR/Cas9 Editing in Biliary Cells.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32252259","citation_count":4,"is_preprint":false},{"pmid":"39717922","id":"PMC_39717922","title":"NEDD4L inhibits epithelial-mesenchymal transition in gastric cancer by mediating BICC1 ubiquitination.","date":"2024","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39717922","citation_count":4,"is_preprint":false},{"pmid":"39253489","id":"PMC_39253489","title":"BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39253489","citation_count":1,"is_preprint":false},{"pmid":"40634109","id":"PMC_40634109","title":"m6A methylation inhibits recruitment of the Dand5 3'UTR to the left-right determinant Bicc1.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40634109","citation_count":1,"is_preprint":false},{"pmid":"41677782","id":"PMC_41677782","title":"BICC1 interacts with PKD1 and PKD2 to drive cystogenesis in ADPKD.","date":"2026","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41677782","citation_count":1,"is_preprint":false},{"pmid":"41508907","id":"PMC_41508907","title":"Generation of Mice Harboring Bicc1 Conditional Null Alleles.","date":"2026","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/41508907","citation_count":1,"is_preprint":false},{"pmid":"20446458","id":"PMC_20446458","title":"[Screening and identification of mouse Bicc1 RNAi].","date":"2010","source":"Dong wu xue yan jiu = Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/20446458","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17317,"output_tokens":5037,"usd":0.063753,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13297,"output_tokens":5652,"usd":0.103892,"stage2_stop_reason":"end_turn"},"total_usd":0.167645,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Mouse Bicc1 KH domains bind RNA in vitro; specifically, the third KH domain is necessary and sufficient for homoribopolymer binding in vitro. The jcpk PKD-causing mutation abolishes this RNA-binding activity.\",\n      \"method\": \"In vitro RNA-binding assays with deletion constructs of mBicc1 protein\",\n      \"journal\": \"Nephron. Experimental nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay with domain-deletion constructs, single lab, single method\",\n      \"pmids\": [\"18182784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Bicc1 physically interacts with SamCystin (ANKS6) in kidney cells; SamCystin self-associates and Bicc1–SamCystin interact by co-immunoprecipitation. The Han:SPRD-Cy rat PKD mutation disrupts SamCystin self-association but not the Bicc1–SamCystin interaction. RNA may be a component of the Bicc1–SamCystin complex.\",\n      \"method\": \"Co-immunoprecipitation of epitope-tagged recombinant proteins transiently transfected in IMCD cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP in cell-based system, replicated with mutant variant, single lab\",\n      \"pmids\": [\"19324013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Bicc1 knockdown (shRNA) in IMCD cells disrupts normal tubulomorphogenesis, induces cystogenesis in 3D culture, and causes defects in E-cadherin-based cell–cell adhesion, actin cytoskeleton organization, cell–matrix interactions, proliferation, and apoptosis.\",\n      \"method\": \"Stable shRNA knockdown of Bicc1 in IMCD cells; 3D culture morphogenesis assay, immunofluorescence for E-cadherin and actin\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"20219263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human BICC1 blocks canonical Wnt signaling, largely through its SAM domain. A nonsense mutation in the first KH domain abolishes Wnt inhibitory activity; a missense mutation in the SAM domain (equivalent to full SAM deletion) reduces activity by ~22%.\",\n      \"method\": \"Wnt reporter assays in cell lines with wild-type and mutant BICC1 constructs; patient mutation analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with domain-specific mutants, single lab, consistent with mouse data\",\n      \"pmids\": [\"21922595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bicc1 KH domains bind AC6 mRNA and recruit miR-125a from Dicer; the SAM domain enables silencing through Argonaute and TNRC6A/GW182. Bicc1 similarly recruits miR-27a to silence PKIα mRNA. Loss of Bicc1 leads to upregulation of AC6 and elevated cAMP in cystic kidneys.\",\n      \"method\": \"RNA immunoprecipitation, reporter silencing assays, Bicc1 knockout mouse kidney analysis (cAMP measurement, AC6 expression), co-immunoprecipitation with Dicer/Argonaute/GW182\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, reporter assays, co-IP with silencing machinery, KO mouse biochemistry), single lab with comprehensive mechanistic dissection\",\n      \"pmids\": [\"22641646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Bicc1 regulates Pkd2 transcript levels in osteoblasts; Bicc1 knockdown and Pkd2 knockdown each impair osteoblastogenesis, and Pkd2 overexpression rescues Bicc1-deficiency-dependent osteoblast defects, placing Pkd2 downstream of Bicc1 in osteoblast differentiation.\",\n      \"method\": \"Bicc1 heterozygous null mice (low BMD phenotype), siRNA knockdown of Bicc1 and Pkd2 in osteoblast cultures, rescue by Pkd2 overexpression, co-expression network analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via KD/OE rescue, in vivo mouse model, single lab\",\n      \"pmids\": [\"24789909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of polycystin-1 (PC1/Pkd1) downregulates Bicc1 expression in vitro and in vivo, revealing a molecular link between PKD1 and BICC1 in kidney development.\",\n      \"method\": \"Immunohistochemistry and western blot in Pkd1 knockout mice and Pkd1-depleted cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein expression analysis in KO mouse and cell lines, two orthogonal detection methods, single lab\",\n      \"pmids\": [\"24594709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bicc1 SAM domain self-polymerizes in vitro in a left-handed helix; this polymerization concentrates Bicc1 in cytoplasmic clusters that localize and silence bound mRNA (e.g., AC6). SAM polymerization also stabilizes Bicc1 protein and is required for inhibition of Dishevelled 2 in the Wnt/β-catenin pathway. The bpk mutation (C-terminal SAM extension) phenocopies polymerization-deficient mutants.\",\n      \"method\": \"Structure modeling of SAM domain; SAM interface mutagenesis; subcellular localization by fluorescence microscopy; mRNA silencing reporter assays; Wnt reporter assay; protein stability measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure modeling validated by mutagenesis, multiple functional readouts (localization, silencing, Wnt pathway), single lab with orthogonal methods\",\n      \"pmids\": [\"26217012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BICC1 knockdown in the rat hippocampus protects against CUS-induced anhedonia, establishing a functional role for elevated BICC1 in depressive behavior. Neuronal activity downregulates BICC1 in vitro; acute ketamine rapidly decreases BICC1 mRNA in vivo.\",\n      \"method\": \"In vivo hippocampal knockdown via viral vector, sucrose preference test (CUS model); in vitro neuronal stimulation with BICC1 mRNA measurement\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined behavioral phenotype plus in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"25178406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of Bicc1 SAM polymer determined at high resolution, revealing a canonical head-to-tail SAM polymer with flexibility in subunit interface orientations. ANKS3 recruits ANKS6 to Bicc1, and together the three proteins cooperatively generate giant macromolecular complexes through SAM domain interactions and flanking sequences.\",\n      \"method\": \"X-ray crystallography of Bicc1 SAM domain; co-immunoprecipitation and domain-mapping of full-length and truncated Bicc1, ANKS3, ANKS6 proteins\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical interaction mapping, multiple domain constructs, single rigorous study\",\n      \"pmids\": [\"29290488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bicc1 preferentially recognizes GACR and YGAC sequences and specifically binds a conserved GACGUGAC motif in the proximal Dand5 3'-UTR. Bicc1 interacts with Cnot3 of the Ccr4-Not deadenylase complex, and this interaction is required for leftward Dand5 mRNA decay at the mouse embryonic node downstream of Pkd2 and Ca2+ signaling.\",\n      \"method\": \"3'-UTR deletion/mutation reporter assays in mouse embryos; RNA pull-down/binding assays; co-immunoprecipitation of Bicc1 with Cnot3; genetic analysis in Bicc1 and Pkd2 mutant mice; Ca2+ manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro RNA binding with defined sequence motif, co-IP of complex, in vivo reporter in mouse embryo, epistasis with Pkd2/Ca2+, single study with multiple orthogonal methods\",\n      \"pmids\": [\"34210974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bicc1 post-transcriptionally represses dand5 and gdf3 via their 3'-UTRs in Xenopus, zebrafish, and mouse during symmetry breaking. Two distinct Bicc1 functions on dand5 mRNA exist: pre-flow (mRNA stability) and post-flow (translational inhibition). Bicc1-mediated translational repression of dand5 3'-UTR reporter is responsive to Pkd2, placing Bicc1 downstream of Pkd2 flow sensing. Bicc1 cooperates with Dicer1 in this process.\",\n      \"method\": \"3'-UTR reporter assays; morpholino/CRISPR knockdown in Xenopus and zebrafish; genetic rescue; co-injection experiments with pkd2 manipulations; mRNA stability vs. translation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-species genetic epistasis, 3'-UTR reporters, Pkd2 epistasis, replicated across three vertebrate models\",\n      \"pmids\": [\"34531379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"As an RNA-binding protein, BICC1 binds the 3'-UTR of LCN2 (Lipocalin-2) mRNA and post-transcriptionally upregulates LCN2 expression in pancreatic cancer cells, leading to JAK2/STAT3 activation and CXCL1-driven VEGF-independent angiogenesis.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of BICC1 with LCN2 3'-UTR; reporter assays; BICC1 knockdown/overexpression in PAAD cells and xenograft mouse models; signaling pathway analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay plus in vivo xenograft phenotype, pathway epistasis, single lab\",\n      \"pmids\": [\"37443111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANKS3 C-terminal coiled-coil domain interacts with Bicc1 and inhibits target mRNA binding; ANKS6 recruits to ANKS3 and relieves this inhibition, restoring Bicc1-mediated Dand5 mRNA decay. A CRISPR-truncated ANKS3 causes symmetric (bilateral) mRNA decay, demonstrating that ANKS3 conformation governs the left-right specificity of Bicc1 RNP activity.\",\n      \"method\": \"AlphaFold structure prediction with biochemical validation by in vitro reconstitution; CRISPR-engineered ANKS3 truncation in mouse; RNA-binding assays; co-immunoprecipitation\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, AlphaFold structure with biochemical validation, CRISPR mouse genetics, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37733651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bicc1 SAM-domain head-to-tail polymers are interconnected by KH domains forming a protein meshwork that mediates liquid-to-gel phase transitioning of client mRNAs. ANKS3 disperses Bicc1 granules and releases bound mRNAs, while co-recruitment of ANKS6 by ANKS3 reinstates Bicc1 condensation and ribonucleoparticle assembly.\",\n      \"method\": \"Live-cell fluorescence microscopy of Bicc1 condensates; co-transfection with ANKS3/ANKS6 constructs; RNA phase-partitioning assays; domain-mapping experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus RNA partitioning assays, multiple constructs, single lab\",\n      \"pmids\": [\"37275520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BICC1 upregulates IDO1 (indoleamine 2,3-dioxygenase-1) expression, activating tryptophan catabolism in pancreatic cancer cells. Increased tryptophan metabolites drive NAD+ synthesis and oxidative phosphorylation, promoting a stem cell-like phenotype and chemoresistance.\",\n      \"method\": \"BICC1 knockdown/overexpression in PDAC cells and organoids; metabolomics; IDO1 expression analysis; NAD+ and OXPHOS measurement; xenograft and patient-derived models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with metabolomics and multiple in vivo models, single lab\",\n      \"pmids\": [\"38896624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NEDD4L E3 ubiquitin ligase mediates ubiquitination and proteasomal degradation of BICC1 protein. NEDD4L overexpression promotes BICC1 ubiquitination and degradation, inhibiting gastric cancer cell EMT and proliferation. BICC1 activates the PI3K/AKT pathway to facilitate cancer progression.\",\n      \"method\": \"Co-immunoprecipitation to detect NEDD4L–BICC1 interaction; ubiquitination assay; BICC1 knockdown/NEDD4L overexpression in GC cells and xenograft models; PI3K/AKT pathway western blot\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay plus in vivo model, single lab\",\n      \"pmids\": [\"39717922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BICC1 physically binds Polycystin-1 (PKD1) and Polycystin-2 (PKD2) proteins via distinct protein domains. Bicc1 depletion in conjunction with Pkd1 or Pkd2 loss aggravates PKD severity in Xenopus and mouse models. Human BICC1 hypomorphic variants identified in VEO-PKD patients impacted disease-relevant signaling pathways in genome-edited kidney cells.\",\n      \"method\": \"Co-immunoprecipitation/biochemical binding assays; Xenopus and mouse double-knockout/depletion studies; CRISPR genome editing of human kidney cells; genetic analysis of ADPKD patient cohort\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical interaction mapping, cross-species genetic epistasis, human patient genetics, engineered cell lines; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41677782\", \"39253489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"N6-methyladenosine (m6A) modification of the conserved AGACGUGAC motif in Dand5 3'-UTR disrupts binding to Bicc1 KH domains in vitro, revealing m6A as a negative regulator of Bicc1 target mRNA recognition. This contrasts with IGF2BP and FMR1 KH domains, for which m6A promotes RNA binding.\",\n      \"method\": \"In vitro RNA-binding assays comparing m6A-modified vs. unmodified Dand5 3'-UTR oligonucleotides with Bicc1 KH domain protein\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro biochemical assay with defined modified RNA, single lab, single paper\",\n      \"pmids\": [\"40634109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BICC1 is a cytoplasmic RNA-binding protein whose N-terminal KH domains bind specific mRNA targets (including AC6, PKIα, LCN2, and Dand5) via a GACGUGAC-containing motif (negatively regulated by m6A modification), while its C-terminal SAM domain self-polymerizes into head-to-tail helical polymers that form phase-transitioning cytoplasmic granules; these granules recruit Argonaute/GW182/Ccr4-Not deadenylase machinery to silence or degrade bound mRNAs, regulate canonical Wnt signaling by inhibiting Dishevelled 2, establish vertebrate left-right asymmetry downstream of Pkd2/Ca2+ by asymmetrically degrading Dand5 mRNA, and are dynamically remodeled by the ciliopathy proteins ANKS3 and ANKS6, while BICC1 itself is subject to ubiquitin-mediated degradation by NEDD4L and physically cooperates with Polycystin-1 and Polycystin-2 in the context of polycystic kidney disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BICC1 is a cytoplasmic RNA-binding protein that assembles into self-organizing ribonucleoprotein granules to post-transcriptionally control mRNAs governing kidney tubulomorphogenesis, Wnt signaling, and vertebrate left-right asymmetry [#4, #7, #11]. Target recognition is mediated by its N-terminal KH domains, which bind specific 3'-UTR sequences — preferentially GACR/YGAC elements and a conserved GACGUGAC motif — including AC6, PKIα, and Dand5 transcripts [#4, #10]; m6A modification of this motif disrupts KH-domain binding, providing a negative input on target recognition [#18]. Its C-terminal SAM domain self-polymerizes into a head-to-tail left-handed helix that concentrates BICC1 into cytoplasmic clusters, stabilizes the protein, and is required for both mRNA silencing and inhibition of Dishevelled 2 in the canonical Wnt pathway [#7, #9]. SAM polymers interconnected by KH domains form a meshwork that drives liquid-to-gel phase transitioning of client mRNAs, and these granules recruit the miRNA/Argonaute–TNRC6A(GW182) silencing machinery and the Ccr4-Not deadenylase (via Cnot3) to repress or degrade bound transcripts [#4, #14, #10]. At the embryonic node, this activity asymmetrically degrades Dand5 mRNA downstream of Pkd2/Ca2+ flow sensing to establish left-right asymmetry, with pre-flow stability control and post-flow translational repression [#10, #11]. BICC1 granule activity is dynamically remodeled by the ciliopathy proteins ANKS3 and ANKS6: ANKS3 binds BICC1, disperses granules, and inhibits target mRNA binding, while ANKS6 recruitment relieves this inhibition and reinstates condensation, thereby governing the left-right specificity of BICC1 RNP activity [#9, #13, #14]. BICC1 physically binds Polycystin-1 and Polycystin-2, and BICC1 hypomorphic variants in very-early-onset polycystic kidney disease patients aggravate PKD severity, establishing BICC1 as a disease-relevant cooperating factor in ADPKD [#17]. BICC1 protein abundance is controlled by NEDD4L-mediated ubiquitination and proteasomal degradation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that BICC1 is an RNA-binding protein and mapped binding to its KH domains, linking this activity directly to disease by showing a PKD-causing mutation abolishes it.\",\n      \"evidence\": \"In vitro RNA-binding assays with mouse Bicc1 domain-deletion constructs\",\n      \"pmids\": [\"18182784\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No physiological target mRNAs identified\", \"Homoribopolymer binding does not define sequence specificity\", \"Single in vitro method, single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected BICC1 to the ciliopathy-associated ANKS6/SamCystin protein, suggesting BICC1 operates within a larger PKD-relevant complex that may contain RNA.\",\n      \"evidence\": \"Co-immunoprecipitation of epitope-tagged proteins in IMCD kidney cells\",\n      \"pmids\": [\"19324013\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single Co-IP in overexpression system\", \"Functional consequence of the interaction unresolved\", \"RNA component inferred, not demonstrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that BICC1 is required for normal renal tubulomorphogenesis, providing a cellular phenotype for its loss relevant to cystogenesis.\",\n      \"evidence\": \"Stable shRNA knockdown in IMCD cells with 3D morphogenesis and cytoskeletal/adhesion readouts\",\n      \"pmids\": [\"20219263\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not connect phenotype to specific mRNA targets\", \"Mechanism linking RNA binding to adhesion/cytoskeleton unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined BICC1 as a canonical Wnt pathway inhibitor and assigned domain contributions, with patient mutations functionally validating the SAM and KH domains.\",\n      \"evidence\": \"Wnt reporter assays with wild-type and mutant human BICC1 plus patient mutation analysis\",\n      \"pmids\": [\"21922595\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular target within Wnt pathway not yet identified\", \"Link between Wnt inhibition and RNA silencing unclear\", \"Reporter-based readout\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the silencing mechanism: KH domains bind target mRNAs (AC6, PKIα) and recruit specific miRNAs and the Argonaute/GW182 machinery via the SAM domain, with KO mice confirming AC6/cAMP dysregulation in cystic kidneys.\",\n      \"evidence\": \"RNA-IP, reporter silencing assays, Dicer/Argonaute/GW182 co-IP, and Bicc1 knockout mouse kidney biochemistry\",\n      \"pmids\": [\"22641646\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Sequence specificity of target recognition not yet defined\", \"Structural basis of SAM-mediated silencing-machinery recruitment unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended BICC1's regulatory reach beyond kidney by placing Pkd2 transcript regulation downstream of BICC1 in osteoblast differentiation, and showed PKD1 loss downregulates BICC1, embedding it in polycystin signaling networks.\",\n      \"evidence\": \"Heterozygous null mice, siRNA knockdown with Pkd2-overexpression rescue (osteoblasts); IHC/western in Pkd1 knockout mice and cells\",\n      \"pmids\": [\"24789909\", \"24594709\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs. indirect regulation of Pkd2 transcript by BICC1 not resolved\", \"Mechanism of PKD1-dependent BICC1 downregulation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural basis for granule formation, showing the SAM domain self-polymerizes into a left-handed helix that concentrates BICC1, stabilizes it, and is required for mRNA silencing and Dishevelled 2 inhibition.\",\n      \"evidence\": \"SAM structure modeling with interface mutagenesis, subcellular localization, silencing and Wnt reporter assays, protein stability measurements\",\n      \"pmids\": [\"26217012\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"High-resolution polymer structure not yet determined\", \"Regulation of polymerization in vivo unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a distinct CNS role, showing elevated hippocampal BICC1 promotes depressive behavior and is dynamically downregulated by neuronal activity and ketamine.\",\n      \"evidence\": \"In vivo hippocampal viral knockdown with behavioral testing and in vitro neuronal BICC1 mRNA measurement\",\n      \"pmids\": [\"25178406\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No neuronal mRNA targets of BICC1 identified\", \"Molecular link between BICC1 and depressive behavior unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Solved the SAM polymer crystal structure and showed ANKS3 recruits ANKS6 to BICC1 to assemble giant macromolecular complexes, defining the architecture of BICC1 RNP remodeling.\",\n      \"evidence\": \"X-ray crystallography of the SAM domain plus co-IP and domain mapping of BICC1, ANKS3, ANKS6\",\n      \"pmids\": [\"29290488\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional impact of ANKS3/ANKS6 assembly on mRNA targets not yet tested\", \"How complex size relates to silencing activity unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the precise RNA sequence specificity (GACGUGAC) and the Ccr4-Not (Cnot3) deadenylase link, establishing BICC1 as the effector that asymmetrically degrades Dand5 mRNA at the node downstream of Pkd2/Ca2+ to break left-right symmetry.\",\n      \"evidence\": \"Mouse embryo 3'-UTR reporters, RNA pull-down, Cnot3 co-IP, Bicc1/Pkd2 mutant genetics, Ca2+ manipulation; cross-species 3'-UTR reporters and knockdowns in Xenopus, zebrafish, mouse\",\n      \"pmids\": [\"34210974\", \"34531379\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How flow/Ca2+ signaling switches BICC1 from stabilization to decay/translational repression unknown\", \"Trigger for left-side-specific activity not fully resolved at this stage\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that BICC1 granules undergo liquid-to-gel phase transitioning and that ANKS3/ANKS6 act as a switch controlling left-right specificity by toggling BICC1 condensation and target mRNA binding.\",\n      \"evidence\": \"Live-cell condensate imaging and RNA phase-partitioning assays; AlphaFold-validated in vitro reconstitution, CRISPR ANKS3-truncation mouse, RNA-binding and co-IP assays\",\n      \"pmids\": [\"37275520\", \"37733651\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"What positions ANKS3/ANKS6 asymmetrically across the node unknown\", \"Physiological signal controlling the ANKS3 conformational switch unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed BICC1 can also stabilize/upregulate a target mRNA (LCN2), driving JAK2/STAT3-dependent angiogenesis in pancreatic cancer, expanding its output beyond repression.\",\n      \"evidence\": \"BICC1 RIP with LCN2 3'-UTR, reporter assays, knockdown/overexpression in PDAC cells and xenografts, pathway analysis\",\n      \"pmids\": [\"37443111\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which BICC1 upregulates rather than silences LCN2 unclear\", \"Whether granule/SAM polymerization is involved not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified BICC1 control of IDO1/tryptophan metabolism driving stemness and chemoresistance in PDAC, and identified NEDD4L as the E3 ligase that degrades BICC1 and restrains its pro-tumorigenic PI3K/AKT signaling.\",\n      \"evidence\": \"Knockdown/overexpression with metabolomics and in vivo models (PDAC); NEDD4L–BICC1 co-IP, ubiquitination assays, gastric cancer cell and xenograft studies\",\n      \"pmids\": [\"38896624\", \"39717922\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs. indirect regulation of IDO1 by BICC1 not established\", \"Whether NEDD4L-mediated turnover regulates BICC1's RNA-silencing functions unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established direct physical cooperation between BICC1 and the polycystins and confirmed BICC1 as a human PKD gene, with hypomorphic variants in VEO-PKD patients aggravating disease.\",\n      \"evidence\": \"Co-IP/biochemical binding assays, Xenopus and mouse double-depletion studies, CRISPR-edited human kidney cells, ADPKD patient cohort genetics\",\n      \"pmids\": [\"41677782\", \"39253489\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of PC1/PC2 binding on BICC1 RNA activity not detailed\", \"Mechanism by which hypomorphic variants alter signaling not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified m6A modification of the BICC1 target motif as a negative regulatory input, distinct from other KH-domain proteins, adding an epitranscriptomic layer to target selection.\",\n      \"evidence\": \"In vitro RNA-binding assays comparing m6A-modified vs. unmodified Dand5 3'-UTR with BICC1 KH-domain protein\",\n      \"pmids\": [\"40634109\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance of m6A-mediated regulation not demonstrated\", \"Whether m6A writers/readers act on BICC1 targets physiologically unknown\", \"Single in vitro assay\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cilia-driven Pkd2/Ca2+ flow signal is mechanistically transduced to switch BICC1 between mRNA stabilization, translational repression, and Cnot3-dependent decay — and how ANKS3/ANKS6 condensate remodeling is positioned asymmetrically in vivo — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular link between flow sensing and BICC1 activity switching\", \"Asymmetric positioning signal for ANKS3/ANKS6 remodeling unknown\", \"Structural basis of KH-domain sequence-specific recognition not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 10, 18]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"BICC1-ANKS3-ANKS6 macromolecular complex\",\n      \"Ccr4-Not deadenylase complex (via Cnot3)\",\n      \"Argonaute/TNRC6A(GW182) silencing complex\"\n    ],\n    \"partners\": [\n      \"ANKS6\",\n      \"ANKS3\",\n      \"CNOT3\",\n      \"TNRC6A\",\n      \"DICER1\",\n      \"PKD1\",\n      \"PKD2\",\n      \"NEDD4L\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}