Affinage

BICC1

Protein bicaudal C homolog 1 · UniProt Q9H694

Length
974 aa
Mass
104.8 kDa
Annotated
2026-04-28
32 papers in source corpus 18 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BICC1 is an RNA-binding protein that post-transcriptionally silences target mRNAs to regulate renal tubulogenesis, left-right axis determination, and organ homeostasis. Its N-terminal KH domains (particularly KH3) recognize GACR/YGAC sequence motifs in target 3'-UTRs — including Dand5, AC6, PKIα, gdf3, and LCN2 — while its C-terminal SAM domain self-polymerizes into a left-handed helical scaffold that nucleates cytoplasmic RNA granules undergoing liquid-to-gel phase transitions; these condensates recruit Argonaute, GW182/TNRC6A, miRNAs, and the Ccr4-Not deadenylase complex (via Cnot3) to degrade or translationally repress bound transcripts (PMID:22641646, PMID:26217012, PMID:34210974, PMID:37275520). ANKS3 disperses Bicc1 condensates and inhibits mRNA binding, while ANKS6 counteracts ANKS3 to reinstate ribonucleoparticle assembly, and m6A methylation of target motifs negatively regulates KH-domain RNA recognition (PMID:37733651, PMID:40634109). BICC1 physically interacts with Polycystin-1 and Polycystin-2, and hypomorphic BICC1 variants compound with PKD1/PKD2 mutations to cause very early-onset polycystic kidney disease in humans (PMID:41677782).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Establishing BICC1 as an RNA-binding protein answered the fundamental question of molecular activity: the third KH domain is necessary and sufficient for RNA binding, and a PKD-causing mutation abolishes this activity, directly linking RNA binding to disease pathogenesis.

    Evidence In vitro RNA-binding assays with deletion constructs and jcpk disease mutant in mouse Bicc1

    PMID:18182784

    Open questions at the time
    • Target mRNA identity unknown
    • No defined RNA sequence specificity
    • No in vivo RNA-binding data
  2. 2009 Medium

    Identification of ANKS6 (SamCystin) as a physical interactor of Bicc1 raised the possibility that SAM-domain scaffolding proteins regulate Bicc1 function, connecting two independent PKD gene products into a shared complex.

    Evidence Co-immunoprecipitation of epitope-tagged proteins in IMCD kidney cells

    PMID:19324013

    Open questions at the time
    • Single Co-IP without reciprocal validation or endogenous protein confirmation
    • Functional consequence of Bicc1–ANKS6 interaction not tested
    • RNA component of the complex not characterized
  3. 2010 Medium

    Demonstrating that Bicc1 knockdown causes cystogenesis in 3D kidney cultures established its cell-autonomous requirement for normal tubulomorphogenesis, linking the molecular activity to a disease-relevant cellular phenotype.

    Evidence shRNA knockdown in IMCD cells with 3D culture, E-cadherin and actin readouts

    PMID:20219263

    Open questions at the time
    • Downstream targets responsible for cystogenesis not identified
    • No rescue experiment to confirm specificity
  4. 2011 Medium

    Showing that BICC1 inhibits canonical Wnt signaling and that both KH and SAM domain mutations compromise this activity established a signaling pathway through which BICC1 controls tissue patterning.

    Evidence Wnt reporter assays with wild-type and disease-associated human BICC1 mutants

    PMID:21922595

    Open questions at the time
    • Mechanism of Wnt inhibition not defined
    • Connection between RNA binding and Wnt suppression unclear
  5. 2012 High

    Identification of AC6 and PKIα as direct mRNA targets, and of Argonaute/GW182 as SAM-dependent effectors, established the mechanistic framework: KH domains select target mRNAs while the SAM domain recruits the miRNA silencing machinery to post-transcriptionally repress them.

    Evidence RNA immunoprecipitation, miRNA pulldown, co-IP with Ago/GW182, Bicc1 knockout mouse kidney analysis

    PMID:22641646

    Open questions at the time
    • Structural basis of KH-mRNA recognition unknown
    • Whether all targets use miRNA-dependent silencing unclear
  6. 2015 High

    Structural and functional analysis of SAM domain polymerization revealed that head-to-tail helical self-assembly concentrates Bicc1 in cytoplasmic clusters, stabilizes the protein, and is required for both mRNA silencing and Dishevelled 2 inhibition in Wnt signaling.

    Evidence SAM structure modeling, interface mutagenesis, in vitro polymerization, live-cell imaging of foci, mRNA silencing reporters

    PMID:26217012

    Open questions at the time
    • No atomic-resolution structure of full-length Bicc1
    • How Dvl2 inhibition connects to RNA silencing not resolved
  7. 2017 High

    Crystal structure of the Bicc1-SAM polymer and mapping of the tripartite Bicc1–ANKS3–ANKS6 complex demonstrated that SAM-mediated heterotypic interactions build giant macromolecular assemblies, explaining how accessory proteins modulate Bicc1 condensation.

    Evidence X-ray crystallography of Bicc1-SAM; co-IP and in vivo complex formation with ANKS3 and ANKS6

    PMID:29290488

    Open questions at the time
    • No structure of full Bicc1–ANKS3–ANKS6 complex
    • In vivo stoichiometry unknown
  8. 2021 High

    Two independent studies converged to show that Bicc1 directly binds Dand5 3'-UTR via GACR/YGAC motifs and recruits the Ccr4-Not deadenylase (Cnot3) for mRNA decay at the left-right organizer, downstream of Pkd2/Ca²⁺ signaling — establishing the complete pathway from extracellular flow signal to asymmetric gene silencing.

    Evidence 3'-UTR reporter transgenes in mouse embryos, Bicc1–Cnot3 co-IP, epistasis with Pkd2 in Xenopus/zebrafish/mouse

    PMID:34210974 PMID:34531379

    Open questions at the time
    • How Pkd2/Ca²⁺ signal is transduced to activate Bicc1 is unknown
    • Whether Ccr4-Not and Argonaute/miRNA pathways act on the same or different targets is unresolved
  9. 2023 High

    Three studies resolved how ANKS3 and ANKS6 reciprocally regulate Bicc1: ANKS3 disperses Bicc1 condensates and blocks mRNA binding via its coiled-coil domain, while ANKS6 remodels ANKS3 to reinstate condensation, explaining how the tripartite complex controls spatiotemporal mRNA silencing including asymmetric Dand5 decay.

    Evidence AlphaFold predictions validated by in vitro reconstitution, phase separation assays, CRISPR mouse embryos with ANKS3 truncation

    PMID:37275520 PMID:37733651

    Open questions at the time
    • No in vivo imaging of ANKS3/ANKS6-dependent Bicc1 condensate dynamics at the node
    • Signals controlling ANKS3/ANKS6 activity upstream are unknown
  10. 2023 Medium

    Discovery that BICC1 post-transcriptionally upregulates LCN2 in pancreatic cancer expanded its target repertoire beyond developmental contexts and linked it to JAK2/STAT3-driven angiogenesis, revealing oncogenic gain-of-function roles.

    Evidence RNA immunoprecipitation, 3'-UTR reporters, BICC1 knockdown/overexpression in cells and xenografts

    PMID:37443111

    Open questions at the time
    • Mechanism of mRNA stabilization (vs. silencing of other targets) not explained
    • Whether KH/SAM domain requirements are the same as in developmental targets not tested
  11. 2024 Medium

    Identification of NEDD4L as an E3 ubiquitin ligase for BICC1 established a proteolytic regulatory layer: NEDD4L-mediated ubiquitination and degradation of BICC1 restrains downstream PI3K/AKT activation and EMT in gastric cancer.

    Evidence Co-IP, ubiquitination assays, BICC1 KD/NEDD4L OE in cells and xenograft models

    PMID:39717922

    Open questions at the time
    • Ubiquitination sites on BICC1 not mapped
    • Whether NEDD4L regulates BICC1 in normal kidney or during laterality is unknown
  12. 2025 High

    Physical binding of BICC1 to Polycystin-1 and Polycystin-2, combined with human genetic evidence of compound heterozygosity in early-onset PKD, established BICC1 as a modifier of polycystin function and a bona fide PKD gene in humans.

    Evidence Co-IP, Xenopus and mouse knockout/knockdown epistasis, CRISPR kidney cells, human PKD patient cohort

    PMID:39253489 PMID:41677782

    Open questions at the time
    • Whether BICC1–polycystin interaction is direct or mediated by shared complexes not fully resolved
    • Functional consequence of binding (signaling vs. trafficking vs. RNA regulation) unclear
  13. 2025 Medium

    Demonstration that m6A modification of the conserved AGACGUGAC motif disrupts Bicc1 KH domain binding introduced epitranscriptomic regulation as a mechanism controlling target mRNA recruitment, distinguishing Bicc1 from other KH-domain proteins where m6A promotes binding.

    Evidence In vitro RNA-binding assays comparing m6A-modified and unmodified RNAs with KH domain pulldowns

    PMID:40634109

    Open questions at the time
    • No in vivo evidence that m6A modification regulates Dand5 decay or laterality
    • Writers/erasers responsible for m6A at Bicc1 target sites not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Pkd2-dependent Ca²⁺ signals are transduced to activate Bicc1-mediated mRNA decay, and how the same protein achieves target-specific silencing vs. stabilization in different cellular contexts, remain the central unresolved questions.
  • Signal transduction between Pkd2/Ca²⁺ and Bicc1 activation is undefined
  • No structural model of full-length Bicc1 bound to target RNA
  • Basis for context-dependent mRNA stabilization vs. degradation is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
ANKS3ANKS6CNOT3DVL2NEDD4LPKD1PKD2TNRC6A
Complex memberships
Bicc1-ANKS3-ANKS6 complexBicc1-Ccr4-Not deadenylase complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Mouse Bicc1 binds homoribopolymers in vitro via its KH domains; specifically, the third KH domain is necessary and sufficient for in vitro RNA binding. A PKD-causing mutation in the jcpk mouse abolishes this RNA binding activity. In vitro RNA-binding assays with deletion constructs of mBicc1 Nephron. Experimental nephrology High 18182784
2009 Bicc1 physically interacts with SamCystin (ANKS6) in kidney cells; SamCystin self-associates, and RNA may be an important component of the Bicc1-SamCystin complex. The PKD-causing mutation in the Han:SPRD-Cy rat disrupts SamCystin self-association but not the Bicc1-SamCystin interaction. Co-immunoprecipitation of epitope-tagged recombinant proteins in IMCD cells Biochemical and biophysical research communications Medium 19324013
2010 Bicc1 knockdown in IMCD cells disrupts normal tubulomorphogenesis and induces cystogenesis in 3D cultures, associated with defects in E-cadherin-based cell-cell adhesion, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis. shRNA knockdown in IMCD cells with 3D culture tubulomorphogenesis assay, E-cadherin localization, and actin staining European journal of cell biology Medium 20219263
2011 Human BICC1, like its mouse counterpart, blocks canonical Wnt signaling. A nonsense mutation in the first KH domain abolishes Wnt inhibitory activity; a missense mutation in the SAM domain causes ~22% loss of activity equivalent to complete SAM domain deletion. Wnt signaling reporter assays with wild-type and mutant BICC1 constructs in cell-based assays Human mutation Medium 21922595
2012 Bicc1 KH domains independently bind AC6 mRNA and recruit miR-125a from Dicer, while the SAM domain enables silencing by Argonaute and TNRC6A/GW182. Bicc1 similarly induces silencing of PKIα mRNA by miR-27a. Loss of Bicc1 causes upregulation of cAMP and AC6 in cystic kidneys. RNA immunoprecipitation, miRNA pulldown, co-immunoprecipitation with Argonaute/GW182, Bicc1 knockout mouse analysis Journal of molecular cell biology High 22641646
2014 Bicc1 regulates Pkd2 transcript levels to control osteoblastogenesis; knockdown of Bicc1 impairs osteoblastogenesis, and Bicc1 deficiency-dependent osteoblast defects are rescued by Pkd2 overexpression. Bicc1 knockdown in osteoblasts, Pkd2 overexpression rescue, coexpression network analysis, heterozygous null mice The Journal of clinical investigation Medium 24789909
2015 Bicc1 SAM domain self-polymerizes in vitro in a left-handed helix; SAM-SAM interface concentrates Bicc1 in cytoplasmic clusters to localize and silence bound mRNA. Defective polymerization decreases Bicc1 stability and attenuates inhibition of Dishevelled 2 in the Wnt/β-catenin pathway. Aberrant C-terminal extension of SAM in bpk mutant Bicc1 phenocopies these defects. SAM domain structure modeling, site-directed mutagenesis of SAM interface residues, in vitro polymerization assays, live cell imaging of cytoplasmic foci, mRNA silencing reporter assays Molecular and cellular biology High 26217012
2017 Crystal structure of Bicc1-SAM polymer reveals a canonical SAM polymer with high flexibility in subunit interface orientations. ANKS3 recruits ANKS6 to Bicc1, and together the three proteins cooperatively form giant macromolecular complexes governed by SAM domains, flanking sequences, and SAM-independent protein-protein and protein-mRNA interactions. X-ray crystallography of Bicc1-SAM polymer; domain mapping of Bicc1, ANKS3, ANKS6 interactions by co-immunoprecipitation and in vivo complex formation assays Structure (London, England : 1993) High 29290488
2021 The first 200 nucleotides of the Dand5 3'-UTR are necessary and sufficient for left-sided mRNA decay and mediate responses to Ca2+, Pkd2, and Bicc1. Bicc1 preferentially recognizes GACR and YGAC sequences and specifically binds a conserved GACGUGAC motif in the proximal Dand5 3'-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is required for Dand5 mRNA decay at the node. 3'-UTR reporter transgene assays in mouse embryos, Ca2+/Pkd2/Bicc1 epistasis, RNA sequence motif analysis, co-immunoprecipitation of Bicc1 with Cnot3, CRISPR/genetic knockouts Nature communications High 34210974
2021 Bicc1 acts as a post-transcriptional regulator of dand5 and gdf3 mRNAs via their 3'-UTRs in Xenopus, zebrafish, and mouse. Two distinct Bicc1 functions on dand5 mRNA were observed: affecting mRNA stability pre-flow and flow-induced translational inhibition post-flow. Bicc1-mediated translational repression is responsive to Pkd2, suggesting a Pkd2 signal triggers Bicc1-mediated dand5 inhibition during symmetry breaking. Bicc1 cooperates with Dicer1 in this process. Morpholino knockdown in Xenopus and zebrafish, CRISPR/genetic knockout in mouse, 3'-UTR reporter assays, epistasis with pkd2 Nature communications High 34531379
2023 As an RNA-binding protein, BICC1 binds to the 3'-UTR of LCN2 mRNA and post-transcriptionally upregulates LCN2 expression in pancreatic cancer cells, leading to JAK2/STAT3 activation and CXCL1-driven VEGF-independent angiogenesis. RNA immunoprecipitation, 3'-UTR reporter assays, BICC1 knockdown/overexpression in cells and mouse xenografts Signal transduction and targeted therapy Medium 37443111
2023 ANKS3 C-terminal coiled-coil domain interacts with Bicc1 and inhibits binding of target mRNAs; ANKS6 relieves this inhibition by remodeling ANKS3 conformation, thus licensing Bicc1 ribonucleoprotein complex formation. A CRISPR-engineered ANKS3 truncation causes symmetric (non-lateralized) Bicc1-mediated Dand5 mRNA decay. AlphaFold structure predictions, in vitro reconstitution of protein complexes, biochemical validation of interactions, CRISPR engineering in mouse embryos PLoS biology High 37733651
2023 Bicc1 SAM domain-mediated head-to-tail polymers are interconnected by KH domains in a protein meshwork that mediates liquid-to-gel transitioning of client transcripts. ANKS3 disperses these granules and releases bound mRNAs, while co-recruitment of ANKS6 by ANKS3 reinstates Bicc1 condensation and ribonucleoparticle assembly. Phase separation/condensate assays, live-cell imaging, domain-specific mutants, co-localization studies iScience Medium 37275520
2024 NEDD4L ubiquitin ligase mediates ubiquitination and proteasomal degradation of BICC1 protein in gastric cancer cells, thereby inhibiting BICC1-driven PI3K/AKT pathway activation, EMT, and tumor progression. Co-immunoprecipitation, ubiquitination assays, BICC1 knockdown/NEDD4L overexpression in cells and xenograft mouse models The Kaohsiung journal of medical sciences Medium 39717922
2024 BICC1 activates tryptophan catabolism in pancreatic cancer by upregulating IDO1 expression post-transcriptionally, increasing tryptophan metabolites that contribute to NAD+ synthesis and oxidative phosphorylation, promoting cancer stem cell-like phenotype and chemoresistance. BICC1 knockdown/overexpression, IDO1 expression analysis, metabolomic assays, pancreatic cancer xenograft and organoid models Science advances Medium 38896624
2025 BICC1 physically binds to Polycystin-1 (PKD1) and Polycystin-2 (PKD2) proteins via distinct protein domains. Depletion of Bicc1 in conjunction with Pkd1 or Pkd2 in Xenopus and mouse models aggravates PKD, and hypomorphic BICC1 variants in human patients with very early-onset PKD show compound heterozygosity with PKD1/PKD2 variants. Biochemical co-immunoprecipitation, knockout/knockdown studies in Xenopus and mouse, CRISPR-engineered human kidney cells, human genetic cohort analysis eLife High 39253489 41677782
2025 N6-methyladenosine (m6A) modification of a conserved AGACGUGAC motif in the Dand5 3'-UTR disrupts binding to Bicc1 KH domains in vitro, identifying m6A as a negative regulator of Bicc1-mRNA recruitment. This is in contrast to IGF2BPs and FMR1, where m6A promotes KH domain-RNA recognition. In vitro RNA-binding assays with m6A-modified vs. unmodified RNA, KH domain pulldowns RNA (New York, N.Y.) Medium 40634109

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia. Human mutation 72 21922595
2014 Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density. The Journal of clinical investigation 54 24789909
2012 Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing. Journal of molecular cell biology 49 22641646
2020 miR-101-3p and miR-199b-5p promote cell apoptosis in oral cancer by targeting BICC1. Molecular and cellular probes 44 32259627
2023 BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis. Signal transduction and targeted therapy 43 37443111
2021 Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex. Nature communications 42 34210974
2009 The polycystic kidney disease-related proteins Bicc1 and SamCystin interact. Biochemical and biophysical research communications 41 19324013
2021 Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5. Nature communications 34 34531379
2010 Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion. European journal of cell biology 29 20219263
2017 The antidepressant-like effects of biperiden may involve BDNF/TrkB signaling-mediated BICC1 expression in the hippocampus and prefrontal cortex of mice. Pharmacology, biochemistry, and behavior 26 28216067
2015 Bicc1 Polymerization Regulates the Localization and Silencing of Bound mRNA. Molecular and cellular biology 26 26217012
2024 BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism. Science advances 23 38896624
2017 Crystal Structure of Bicc1 SAM Polymer and Mapping of Interactions between the Ciliopathy-Associated Proteins Bicc1, ANKS3, and ANKS6. Structure (London, England : 1993) 22 29290488
2018 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. Brain research bulletin 21 30316917
2014 BICC1 expression is elevated in depressed subjects and contributes to depressive behavior in rodents. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20 25178406
2012 Effect of genetic variant in BICC1 on functional and structural brain changes in depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 19 22910460
2008 K homology domains of the mouse polycystic kidney disease-related protein, Bicaudal-C (Bicc1), mediate RNA binding in vitro. Nephron. Experimental nephrology 19 18182784
2014 Loss of polycystin-1 inhibits Bicc1 expression during mouse development. PloS one 17 24594709
2015 Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones. The pharmacogenomics journal 14 26440730
2020 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. Frontiers in genetics 10 32714370
2019 FGFR2-BICC1: A Subtype Of FGFR2 Oncogenic Fusion Variant In Cholangiocarcinoma And The Response To Sorafenib. OncoTargets and therapy 9 31807010
2023 Bicc1 ribonucleoprotein complexes specifying organ laterality are licensed by ANKS6-induced structural remodeling of associated ANKS3. PLoS biology 5 37733651
2022 Circ-BICC1 Knockdown Alleviates Lipopolysaccharide (LPS)-Induced WI-38 Cell Injury Through miR-338-3p/MYD88 Axis. Biochemical genetics 5 35809112
2019 Serum BICC1 levels are significantly different in various mood disorders. Neuropsychiatric disease and treatment 5 30697050
2024 NEDD4L inhibits epithelial-mesenchymal transition in gastric cancer by mediating BICC1 ubiquitination. The Kaohsiung journal of medical sciences 4 39717922
2023 Antagonistic interactions among structured domains in the multivalent Bicc1-ANKS3-ANKS6 protein network govern phase transitioning of target mRNAs. iScience 4 37275520
2020 Generation of An Endogenous FGFR2-BICC1 Gene Fusion/58 Megabase Inversion Using Single-Plasmid CRISPR/Cas9 Editing in Biliary Cells. International journal of molecular sciences 4 32252259
2026 Generation of Mice Harboring Bicc1 Conditional Null Alleles. Genesis (New York, N.Y. : 2000) 1 41508907
2026 BICC1 interacts with PKD1 and PKD2 to drive cystogenesis in ADPKD. eLife 1 41677782
2025 BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD. bioRxiv : the preprint server for biology 1 39253489
2025 m6A methylation inhibits recruitment of the Dand5 3'UTR to the left-right determinant Bicc1. RNA (New York, N.Y.) 1 40634109
2010 [Screening and identification of mouse Bicc1 RNAi]. Dong wu xue yan jiu = Zoological research 0 20446458