Affinage

ANKS6

Ankyrin repeat and SAM domain-containing protein 6 · UniProt Q68DC2

Length
871 aa
Mass
92.2 kDa
Annotated
2026-04-28
21 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKS6 is a ciliary inversin compartment scaffold that integrates kinase signaling, ribonucleoprotein regulation, and transcriptional control in epithelial morphogenesis. It directly binds and activates the NEK8 kinase through its kinase domain while simultaneously connecting NEK8 to INVS/NPHP2 and NPHP3, forming a nephronophthisis signaling module in which ANKS6 is itself phosphorylated by NEK8 in a manner dependent on ciliary NPHP3 localization (PMID:23793029, PMID:25599650, PMID:29395339). Through its SAM domain, ANKS6 caps ANKS3 polymers and cooperatively assembles with ANKS3 and BICC1 into macromolecular condensates that regulate Bicc1 mRNA phase transitioning and ribonucleoprotein granule dynamics, with disease-causing mutations R823W and I747N selectively disrupting the ANKS3 and BICC1 interactions respectively (PMID:24998259, PMID:29290488, PMID:37733651, PMID:37275520). ANKS6 also binds YAP1, TAZ, and TEAD4 to promote their transcriptional activity, and loss of Anks6 causes bile duct malformations and nephronophthisis-associated cystic kidney disease (PMID:32886109, PMID:21119215).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    Establishing that the R823W mutation is sufficient to cause polycystic kidney disease resolved whether ANKS6 dysfunction is directly causative of cystogenesis rather than merely associated.

    Evidence Transgenic rat overexpressing mutant Anks6(R823W) in renal epithelium developed dominant-negative cystic disease with enhanced proliferation and c-myc expression

    PMID:21119215

    Open questions at the time
    • Mechanism by which R823W acts as dominant-negative was unknown
    • Direct molecular targets of ANKS6 unidentified at this stage
    • Relationship to ciliary function not established
  2. 2013 High

    Identifying ANKS6 as a central hub connecting NEK8, INVS, and NPHP3 at the ciliary inversin compartment established the molecular logic of the nephronophthisis signaling module and explained how distinct NPHP gene products converge.

    Evidence Reciprocal Co-IP, zebrafish/Xenopus knockdown, and identification of HIF1AN-mediated hydroxylation of ANKS6 and INVS

    PMID:23793029

    Open questions at the time
    • Functional consequence of HIF1AN hydroxylation on module activity unknown
    • Directionality of signal flow through the module unresolved
  3. 2014 High

    Solving the crystal structure of the ANKS3-SAM/ANKS6-SAM complex revealed the atomic basis of ANKS6 SAM domain interactions and demonstrated that R823W destabilizes the SAM fold, explaining loss of ANKS3 binding.

    Evidence X-ray crystallography of ANKS3-SAM polymer and ANKS3-SAM/ANKS6-SAM heterodimer, mutagenesis, in vitro binding assays

    PMID:24998259

    Open questions at the time
    • Downstream signaling consequences of ANKS3-ANKS6 disruption unclear
    • Whether additional SAM-domain partners exist was not tested
  4. 2015 High

    Demonstrating that ANKS6 both activates NEK8 kinase and requires NEK8 for its own ciliary localization established a mutual-dependence relationship, while the I747N mutation defined a second SAM-domain interaction surface specific for BICC1.

    Evidence Kinase activity assays, Co-IP, and comparative analysis of Anks6(Streaker) and Nek8(Roc) mouse mutants; ENU mutagenesis screen identifying I747N in mouse

    PMID:25599650 PMID:26039630

    Open questions at the time
    • NEK8 substrates downstream of ANKS6-mediated activation not identified
    • How I747N and R823W mutations produce overlapping yet distinct phenotypes at the cellular level
  5. 2017 High

    Showing that ANKS3 recruits ANKS6 to BICC1 and that the three proteins cooperatively form giant macromolecular complexes revealed a hierarchical assembly mechanism dependent on combined SAM and non-SAM interactions.

    Evidence Crystal structure of Bicc1-SAM polymer, Co-IP, domain-mapping of full-length constructs

    PMID:29290488

    Open questions at the time
    • Functional RNA targets of the ANKS3-ANKS6-BICC1 complex unknown
    • Stoichiometry and dynamics of the complex in vivo unresolved
  6. 2018 High

    Establishing that NPHP3 ciliary localization is required for NEK8-mediated phosphorylation of ANKS6 defined ANKS6 as a signal mediator that relays ciliary events to the cytoplasm.

    Evidence Nphp3 G2A knock-in mouse with defective myristoylation/ciliary targeting; phosphorylation analysis of ANKS6

    PMID:29395339

    Open questions at the time
    • Identity of ANKS6 phosphorylation sites not mapped
    • Cytoplasmic effectors of phosphorylated ANKS6 unknown
  7. 2020 High

    Discovery that ANKS6 binds YAP1/TAZ/TEAD4 and promotes their transcriptional activity identified a non-ciliary effector output, explaining bile duct morphogenesis defects in Anks6 knockouts as Hippo pathway dysregulation.

    Evidence Anks6 KO mouse with ductal plate malformations, Co-IP of ANKS6 with YAP1/TAZ/TEAD4

    PMID:32886109

    Open questions at the time
    • Whether ANKS6 regulation of Hippo signaling is cilium-dependent or independent unclear
    • Direct versus indirect mechanism of ANKS6 promotion of YAP/TAZ activity not distinguished
  8. 2022 Medium

    Patient-derived fibroblasts confirmed that ANKS6 deficiency impairs inversin compartment integrity, cilia length, and YAP nuclear localization in human cells, while liver-specific knockout revealed macrophage-driven inflammation as a downstream driver of portal fibrosis.

    Evidence Patient fibroblasts with immunofluorescence/pathway analysis; liver-specific Anks6 KO with clodronate liposome macrophage depletion rescuing fibrosis

    PMID:34740236 PMID:35032404

    Open questions at the time
    • Whether ciliary and Hippo/Wnt phenotypes represent a single linear pathway or parallel outputs unresolved
    • Cell-autonomous versus non-cell-autonomous contributions to kidney pathology not distinguished
  9. 2023 High

    Reconstitution and live-imaging studies revealed a dual regulatory cycle in which ANKS3 disperses Bicc1 condensates and releases mRNAs, while ANKS6 co-recruitment by ANKS3 restores Bicc1 polymerization and mRNA sequestration, establishing ANKS6 as a positive regulator of ribonucleoprotein phase transitioning.

    Evidence In vitro reconstitution with AlphaFold-guided mutagenesis, CRISPR truncations in mouse, live-cell imaging of condensate dynamics, RNA binding assays

    PMID:37275520 PMID:37733651

    Open questions at the time
    • Specific mRNA targets regulated by this ANKS3-ANKS6-BICC1 cycle in vivo not identified
    • Whether phase-transition regulation connects to NEK8 kinase activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of NEK8 substrates downstream of ANKS6-mediated activation, the specific ANKS6 phosphorylation sites and their functional consequences, the in vivo RNA targets of the ANKS6-ANKS3-BICC1 condensate cycle, and whether ANKS6 regulation of Hippo signaling is cilium-dependent.
  • NEK8 downstream substrates unidentified
  • ANKS6 phosphosite mapping lacking
  • In vivo mRNA targets of BICC1 condensates regulated by ANKS6 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005929 cilium 4 GO:0005829 cytosol 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
ANKS3BICC1INVSNEK8NPHP3TAZTEAD4YAP1
Complex memberships
ANKS3-ANKS6-BICC1 ribonucleoprotein complexInversin compartment complex (ANKS6-NEK8-INVS-NPHP3)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 ANKS6 localizes to the proximal cilium (inversin compartment) and functions as a central component of a nephronophthisis module, directly connecting NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS, altering the composition of the ANKS6-INVS-NPHP3 module. Co-immunoprecipitation, knockdown in zebrafish and Xenopus laevis, network analysis, identification of HIF1AN as hydroxylase Nature genetics High 23793029
2015 ANKS6 is both a substrate and activator of the ciliary kinase NEK8: ANKS6 binds to the NEK8 kinase domain to activate it, while ANKS6 itself requires NEK8 for proper localization to the ciliary inversin compartment. The Anks6(Streaker) mouse mutation reduces ANKS6 interaction with NEK8, precluding NEK8 activation, whereas the Nek8(Roc) mutation inactivates NEK8 kinase function while preserving ANKS6 localization. Co-immunoprecipitation, mouse genetic models (Anks6(Streaker) and Nek8(Roc) point mutations), kinase activity assays, immunofluorescence localization Nature communications High 25599650
2014 The SAM domain of ANKS6 directly binds one end of ANKS3-SAM polymers, forming a heterodimeric complex. The disease-causing R823W point mutation dramatically destabilizes the ANKS6 SAM domain, abolishing its interaction with ANKS3-SAM. Crystal structures of the ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex were determined. X-ray crystallography, in vitro binding assays, mutagenesis (R823W), biochemical characterization of SAM domain interactions BMC structural biology High 24998259
2018 INV (NPHP2/INVS) and NPHP3 cooperate in the ciliary inversin compartment to promote phosphorylation of ANKS6 by NEK8. Loss of ciliary NPHP3 (via mutation of its UNC119-binding myristoylation signal) impairs ANKS6 phosphorylation and causes accumulation of non-phosphorylated ANKS6 in cystic kidneys, identifying ANKS6 as a signal mediator linking cilia to the cytoplasm. Knock-in mouse model (Nphp3 G2A) with defective ciliary localization signal, phosphorylation analysis, immunofluorescence, co-immunoprecipitation Kidney international High 29395339
2017 ANKS3 recruits ANKS6 to BICC1, and together the three proteins cooperatively form giant macromolecular complexes through combined SAM domain interactions, flanking sequences, and SAM-independent protein-protein and protein-mRNA interactions. Neither ANKS3 nor ANKS6 alone formed macroscopic homopolymers in vivo. Crystal structure of Bicc1-SAM polymer, co-immunoprecipitation, in vivo interaction mapping of full-length and domain constructs Structure High 29290488
2015 ANKS6 SAM domain interacts with BICC1 in addition to ANKS3; the I747N mutation in mouse ANKS6 SAM domain disrupts the ANKS6-BICC1 interaction (distinct from R823W which disrupts ANKS6-ANKS3), and causes renal cysts, demonstrating the SAM domain mediates different protein complexes critical for kidney structure. ENU mutagenesis screen, co-immunoprecipitation, comparative phenotypic analysis of rat (R823W) and mouse (I747N) models Kidney international Medium 26039630
2015 ANKS3 and ANKS6 interact directly through their SAM domains, and ANKS3 co-localizes with ANKS6 in mouse renal cilia. Yeast two-hybrid and co-immunoprecipitation confirmed the interaction, with amino acid 823 in ANKS6 being critical for binding. Yeast two-hybrid, co-immunoprecipitation, in vivo ciliary co-localization by immunofluorescence PloS one Medium 26327442
2020 ANKS6 binds to Hippo pathway effector proteins YAP1, TAZ, and TEAD4 and promotes their transcriptional activity. Loss of Anks6 in knockout mice causes dysregulation of YAP transcriptional activity in biliary epithelial cells, leading to bile duct morphogenesis defects and ductal plate malformations, establishing ANKS6 as an antagonist of Hippo signaling during liver development. Anks6 knockout mouse model, co-immunoprecipitation (ANKS6 with YAP1/TAZ/TEAD4), biochemical analyses, histology, expression studies Human molecular genetics High 32886109
2010 Transgenic overexpression of the mutant Anks6(p.R823W) in renal tubular epithelium causes polycystic kidney disease in a dominant-negative fashion, establishing a causal link between the R823W mutation and cystogenesis, with cyst development accompanied by enhanced c-myc expression, proliferation, apoptosis, and lack of p21 up-regulation. Transgenic rat model overexpressing mutant Anks6(R823W), Northern blot, in situ hybridization, histology The American journal of pathology Medium 21119215
2014 Loss-of-function mutations in ANKS6 are associated with increased levels of total and active β-catenin in precystic tubuli in Han:SPRD Cy/+ rats, suggesting that ANKS6 mutations may contribute to nephronophthisis through dysregulation of Wnt/β-catenin signaling. Immunohistochemistry in human embryonic kidney tissue and rat model, β-catenin activity assays Journal of the American Society of Nephrology : JASN Low 24610927
2022 ANKS6 deficiency in patient-derived fibroblasts leads to impaired integrity of the ciliary inversin compartment, reduced cilia length, dysregulation of YAP nuclear localization, disrupted ciliary YAP localization, altered Wnt target gene transcription, and deranged subcellular localization of endocytic recycling compartment components. Patient-derived fibroblasts, immunofluorescence, YAP localization analysis, β-catenin/GSK3β phosphorylation analysis Human molecular genetics Medium 34740236
2023 ANKS6 regulates Bicc1 ribonucleoprotein complex assembly: ANKS6 induces structural remodeling of associated ANKS3, modulating ANKS3's C-terminal coiled-coil domain interaction with Bicc1 that otherwise inhibits mRNA binding. In vitro reconstitution and AlphaFold structure predictions revealed a novel ANKS3-Bicc1 interaction mode regulated by ANKS6. In vitro reconstitution, AlphaFold structure prediction with biochemical validation, CRISPR-engineered truncations in mouse, mRNA decay assays PLoS biology High 37733651
2023 ANKS6, when co-recruited by ANKS3, reinstates Bicc1 condensation and ribonucleoparticle assembly after ANKS3-mediated dispersal of Bicc1 granules. ANKS3 disperses Bicc1 granules and releases bound mRNAs, while ANKS6 co-recruitment by ANKS3 restores Bicc1 polymerization and mRNA sequestration, representing a dual regulatory mechanism for Bicc1 phase transitioning. Live cell imaging of condensate/granule dynamics, RNA binding assays, co-immunoprecipitation, overexpression/knockdown in cell lines iScience Medium 37275520
2024 In C. elegans, the Inversin complex (containing INVS/MLT-4, NEK8/NEKL-2, and the ANKS6 ortholog) is activated by dimerization. Stimulated dimerization of MLT-4 (INVS) or NEKL-2 (NEK8) using optogenetics is sufficient to activate the complex, and dimerization of NEKL-2 bypasses a lethal MLT-4 mutant, demonstrating that dynamic switching between an active dimer and an inactive monomer gates Inversin complex output. C. elegans genetics, genome engineering (RFP tags, monomerization), optogenetic stimulation of dimerization, gain-of-function allele characterization bioRxivpreprint Medium bio_10.1101_2024.05.17.594761
2022 In Anks6 liver-specific knockout mice, portal fibrosis development coincides with accumulation of inflammatory M1-like macrophages in the periportal tissue; depletion of macrophages with clodronate liposomes reduced inflammatory gene expression, fibrosis, and biliary dysfunction, establishing a causal role for macrophage-driven inflammation downstream of ANKS6 deficiency in hepatic fibrosis. Liver-specific Anks6 knockout mouse, clodronate liposome macrophage depletion, flow cytometry, gene expression analysis, histology FASEB journal Medium 35032404

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature genetics 170 23793029
2015 ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nature communications 47 25599650
2014 Characterization of the SAM domain of the PKD-related protein ANKS6 and its interaction with ANKS3. BMC structural biology 41 24998259
2014 Mutations in ANKS6 cause a nephronophthisis-like phenotype with ESRD. Journal of the American Society of Nephrology : JASN 33 24610927
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
2010 Transgenic overexpression of Anks6(p.R823W) causes polycystic kidney disease in rats. The American journal of pathology 22 21119215
2015 The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes. Kidney international 19 26039630
2020 Loss of Anks6 leads to YAP deficiency and liver abnormalities. Human molecular genetics 14 32886109
2018 The Inv compartment of renal cilia is an intraciliary signal-activating center to phosphorylate ANKS6. Kidney international 14 29395339
2015 ANKS3 Co-Localises with ANKS6 in Mouse Renal Cilia and Is Associated with Vasopressin Signaling and Apoptosis In Vivo in Mice. PloS one 11 26327442
2022 Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation. Human molecular genetics 10 34740236
2016 Influence of the R823W mutation on the interaction of the ANKS6-ANKS3: insights from molecular dynamics simulation and free energy analysis. Journal of biomolecular structure & dynamics 8 26295479
2022 Mitigation of portal fibrosis and cholestatic liver disease in ANKS6-deficient livers by macrophage depletion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 35032404
2019 Clinical and Pathological Features of a Newborn With Compound Heterozygous ANKS6 Variants. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 6 31635528
2023 Bicc1 ribonucleoprotein complexes specifying organ laterality are licensed by ANKS6-induced structural remodeling of associated ANKS3. PLoS biology 5 37733651
2023 Antagonistic interactions among structured domains in the multivalent Bicc1-ANKS3-ANKS6 protein network govern phase transitioning of target mRNAs. iScience 4 37275520
2019 Metabolic perturbations caused by depletion of nephronophthisis factor Anks6 in mIMCD3 cells. Metabolomics : Official journal of the Metabolomic Society 4 31041607
2019 Whole-exome sequencing identifies a novel compound heterozygous mutation of ANKS6 gene in a Chinese nephronophthisis patient. Clinica chimica acta; international journal of clinical chemistry 4 31678577
2024 ANKS6 Variants Underlie Polycystic Kidneys in Prenatal and Neonatal Cases. Genes 1 39596574
2023 Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency. Clinical genetics 1 37525964
2026 A Novel Anks6 Nonsense Variant Promotes Polycystic Kidney Disease in Han:SPRD-Cy Rats and its Homozygosity is Prenatally Lethal. Kidney360 0 41811399