Affinage

ANKS6

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

Length
871 aa
Mass
92.2 kDa
Annotated
2026-06-09
21 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKS6 is a ciliary inversin-compartment protein that functions as the central organizer of a nephronophthisis signaling module governing kidney morphogenesis, organ laterality, and bile duct development (PMID:23793029). Within the proximal cilium, ANKS6 binds the kinase domain of NEK8 to activate the kinase and in turn requires NEK8 for its own localization to the inversin compartment; this reciprocal dependence is dissected by the Anks6(Streaker) and Nek8(Roc) mouse alleles (PMID:25599650). ANKS6 itself is a NEK8 substrate whose phosphorylation is cooperatively promoted by INV and NPHP3, positioning ANKS6 as a signal mediator that relays information from the cilium to the cytoplasm to control kidney morphogenesis (PMID:29395339). Through its SAM domain, ANKS6 binds the end of an ANKS3-SAM polymer, and ANKS3 in turn recruits ANKS6 to BICC1 to build giant macromolecular ribonucleoprotein assemblies (PMID:24998259, PMID:29290488); ANKS6 remodels ANKS3 to relieve an autoinhibitory interaction that otherwise blocks BICC1 binding to the Dand5 3' UTR, thereby regulating mRNA decay and left-right laterality (PMID:37733651). The disease-causing SAM-domain mutations partition these activities — R823W destabilizes the ANKS6 SAM domain and abolishes the ANKS3 interaction, whereas I747N selectively disrupts the BICC1 interaction, and either lesion causes cystic kidney disease (PMID:24998259, PMID:26039630). Beyond the cilium, ANKS6 antagonizes Hippo signaling by binding YAP1, TAZ, and TEAD4 to promote their transcriptional activity, and its loss in liver drives YAP dysregulation, bile duct malformation, and macrophage-driven periportal fibrosis (PMID:32886109, PMID:35032404).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2013 High

    Established that ANKS6 is not an isolated factor but the centerpiece of a defined ciliary nephronophthisis module, answering where ANKS6 acts and with which NPHP proteins.

    Evidence Co-IP, immunofluorescence localization, and knockdown in zebrafish and Xenopus with renal/laterality phenotypes

    PMID:23793029

    Open questions at the time
    • Did not define the biochemical activity of ANKS6 within the module
    • Mechanism by which the module controls morphogenesis unresolved
  2. 2013 Medium

    Tested how the module is regulated, showing the oxygen sensor HIF1AN hydroxylates ANKS6 and INVS to alter module composition.

    Evidence Biochemical hydroxylation assay, Co-IP, and Xenopus knockdown

    PMID:23793029

    Open questions at the time
    • Hydroxylation sites and stoichiometry not fully mapped
    • Physiological oxygen-dependence in mammalian kidney not established
  3. 2015 High

    Defined the enzymatic relationship at the module's core: ANKS6 binds and activates NEK8 and depends on NEK8 for ciliary localization, separating activation from localization with distinct mutant alleles.

    Evidence Reciprocal Co-IP, Anks6(Streaker) and Nek8(Roc) mouse mutants, and kinase activity assays

    PMID:25599650

    Open questions at the time
    • Downstream NEK8 substrates beyond ANKS6 not identified
    • Structural basis of ANKS6-NEK8 kinase-domain binding unresolved
  4. 2014 High

    Resolved the structural basis of ANKS6 self-assembly, showing its SAM domain caps an ANKS3-SAM polymer and that R823W destabilizes the domain to abolish binding.

    Evidence X-ray crystallography of ANKS3-SAM polymer and ANKS3/ANKS6-SAM complex with mutagenesis

    PMID:24998259

    Open questions at the time
    • Functional consequence of polymer capping in cilia not directly tested
    • Does not address the separate BICC1 interaction
  5. 2015 Medium

    Showed the ANKS6 SAM domain mediates two genetically separable interactions, with I747N disrupting BICC1 binding and R823W disrupting ANKS3 binding, each independently causing cystic kidney disease.

    Evidence ENU mutagenesis screen, Co-IP, and comparative phenotyping in rat and mouse

    PMID:26039630 PMID:26327442

    Open questions at the time
    • Structural mechanism distinguishing the two SAM interactions not resolved
    • Relative contribution of each interaction to disease severity unclear
  6. 2010 Medium

    Demonstrated causality between the Anks6(R823W) mutation and cystogenesis in a dominant-negative manner, linking the lesion to proliferation, apoptosis, and c-myc dysregulation.

    Evidence Transgenic rat with tubule-specific Anks6(R823W) overexpression, Northern blot, in situ hybridization, histology

    PMID:21119215

    Open questions at the time
    • Molecular pathway connecting R823W to c-myc/proliferation not defined
    • Dominant-negative target not identified
  7. 2018 Medium

    Established that INV and NPHP3 cooperatively promote NEK8-mediated ANKS6 phosphorylation, defining ANKS6 as a cilium-to-cytoplasm signal mediator whose phosphorylation is lost in cystic kidneys.

    Evidence Nphp3 G2A knock-in mice, phosphorylation/western readouts, comparison with Inv mutants

    PMID:29395339

    Open questions at the time
    • Phosphosites on ANKS6 not mapped
    • Downstream effectors of phospho-ANKS6 not identified
  8. 2017 High

    Showed ANKS3 recruits ANKS6 to BICC1 so the three cooperatively form giant macromolecular complexes, with neither ANKS protein homopolymerizing alone in vivo.

    Evidence Crystal structure of Bicc1-SAM polymer, Co-IP, and domain-mapping complex assays

    PMID:29290488

    Open questions at the time
    • Functional output of the giant complexes not directly assayed here
    • SAM-independent contributions not fully delineated
  9. 2023 Medium

    Defined the RNA-regulatory mechanism: ANKS6 remodels ANKS3 to relieve autoinhibition and license BICC1 binding to Dand5 mRNA, and oppositely tunes BICC1 condensation, linking the module to laterality and mRNA decay.

    Evidence AlphaFold predictions, in vitro reconstitution, CRISPR ANKS3 truncation in zebrafish, mRNA decay and condensate/phase-transition assays

    PMID:37275520 PMID:37733651

    Open questions at the time
    • In vivo confirmation of Dand5 mRNA control by ANKS6 in mammals limited
    • How ciliary signaling couples to RNP regulation unresolved
  10. 2020 Medium

    Extended ANKS6 function to liver, showing it antagonizes Hippo signaling by binding YAP1/TAZ/TEAD4 to promote their transcription, with loss causing bile duct malformation and fibrosis.

    Evidence Anks6 knockout mouse, Co-IP with YAP1/TAZ/TEAD4, gene expression and histology

    PMID:32886109

    Open questions at the time
    • Direct vs indirect nature of YAP/TAZ/TEAD4 binding not structurally resolved
    • Link between ciliary ANKS6 and Hippo regulation unclear
  11. 2022 Medium

    Connected ANKS6 deficiency to disease cell biology, showing impaired inversin-compartment integrity, YAP/Wnt dysregulation, and macrophage-driven periportal fibrosis as a causal inflammatory mechanism.

    Evidence Patient-derived fibroblasts with orthogonal readouts; liver-specific Anks6 KO with clodronate macrophage depletion

    PMID:34740236 PMID:35032404

    Open questions at the time
    • Signal linking ANKS6 loss to M1 macrophage recruitment not identified
    • Direct mechanism coupling cilia defects to YAP/Wnt imbalance unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ciliary signaling, NEK8-dependent phosphorylation, SAM-domain assembly, and downstream YAP/Wnt and BICC1-RNP outputs are integrated into a single coherent control of kidney and liver morphogenesis remains unresolved.
  • No unified model linking phospho-state of ANKS6 to its scaffolding and transcriptional roles
  • ANKS6 phosphosites and their functional consequences uncharacterized
  • Direct structural basis for YAP1/TAZ/TEAD4 binding 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 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005929 cilium 3 GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ANKS3BICC1INVSNEK8NPHP3TAZTEAD4YAP1
Complex memberships
ANKS3-ANKS6-BICC1 ribonucleoprotein complexANKS6-NEK8-INVS-NPHP3 inversin-compartment module

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 forms a molecular module with NEK8 (NPHP9), INVS (NPHP2), and NPHP3. Knockdown in zebrafish and Xenopus causes renal/laterality defects consistent with loss of other NPHP proteins, placing ANKS6 at the center of this nephronophthisis module. Co-immunoprecipitation, subcellular localization by immunofluorescence, knockdown in zebrafish and Xenopus laevis with phenotypic readout, network analysis Nature genetics High 23793029
2013 The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS, and this hydroxylation alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus phenocopies loss of other NPHP proteins. Biochemical hydroxylation assay, co-immunoprecipitation, Xenopus knockdown with phenotypic readout Nature genetics Medium 23793029
2015 ANKS6 is a substrate and activator of the ciliary kinase NEK8: ANKS6 binds to the NEK8 kinase domain to activate it, and ANKS6 requires NEK8 for its localization to the ciliary inversin compartment (IC). The Anks6(Streaker) mouse mutation decreases ANKS6-NEK8 interaction and prevents NEK8 activation; the Nek8(Roc) mutation inactivates NEK8 kinase while preserving ANKS6 localization. Co-immunoprecipitation, in vivo mouse genetic analysis (Anks6 Streaker and Nek8 Roc mutants), kinase activity assays, immunofluorescence localization Nature communications High 25599650
2014 The SAM domain of ANKS6 directly binds to the SAM domain of ANKS3. Crystal structures of ANKS3-SAM polymer and the ANKS3-SAM/ANKS6-SAM complex reveal that ANKS3-SAM polymerizes and ANKS6-SAM binds to one end of the polymer. The disease-causing R823W mutation dramatically destabilizes the ANKS6 SAM domain, abolishing interaction with ANKS3-SAM. X-ray crystallography (crystal structures of ANKS3-SAM polymer and ANKS3-SAM/ANKS6-SAM complex), biochemical binding assays, site-directed mutagenesis BMC structural biology High 24998259
2017 ANKS3 recruits ANKS6 to BICC1, and together the three proteins cooperatively generate giant macromolecular complexes. Neither ANKS3 nor ANKS6 alone formed macroscopic homopolymers in vivo. A crystal structure of Bicc1-SAM polymer reveals a canonical head-to-tail polymer with flexible subunit interface orientations; SAM domains and flanking sequences as well as SAM-independent interactions shape these assemblies. Crystal structure of Bicc1-SAM polymer, co-immunoprecipitation, mapping of domain interactions with full-length and truncated proteins, in vivo complex formation assays Structure High 29290488
2015 The I747N missense mutation in the ANKS6 SAM domain (identified by ENU mutagenesis in mice) disrupts the interaction between ANKS6 and BICC1 (but not ANKS3-ANKS6 interaction, which is disrupted by R823W in rats), demonstrating that the ANKS6 SAM domain mediates distinct interactions with ANKS3 and BICC1, and that either disruption can cause cystic kidney disease. ENU mutagenesis screen, co-immunoprecipitation, comparative phenotype analysis in rat and mouse models Kidney international Medium 26039630
2015 ANKS3 and ANKS6 directly interact through their SAM domains; the rat R823W mutation at position 823 of ANKS6 is key for ANKS3 binding. ANKS3 co-localizes with ANKS6 in mouse renal cilia in vivo. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence localization in mouse renal cilia, LNA antisense knockdown PloS one Medium 26327442
2018 INV and NPHP3 cooperate in the inversin compartment of renal cilia to promote ANKS6 phosphorylation by NEK8. Loss of ciliary NPHP3 (via disruption of UNC119-dependent myristoylation signal) impairs ANKS6 phosphorylation without altering ANKS6 ciliary localization, and non-phosphorylated ANKS6 accumulates at high levels in cystic kidneys. ANKS6 functions as a signal mediator linking cilia to the cytoplasm to regulate kidney morphogenesis. Generation of Nphp3 G2A knock-in mice, immunofluorescence, phosphorylation assays/western blot, comparison with Inv mutant mice Kidney international Medium 29395339
2010 Transgenic overexpression of the R823W Anks6 mutant in rat renal tubular epithelium causes polycystic kidney disease in a dominant-negative manner, demonstrating a causal link between the Anks6(R823W) mutation and cystogenesis. Cyst development is accompanied by enhanced c-myc expression, continuous proliferation, apoptosis, de-differentiation, and absence of p21 translational up-regulation. Transgenic rat model with renal tubular-specific overexpression of Anks6(p.R823W), Northern blot, in situ hybridization, histology The American journal of pathology Medium 21119215
2020 ANKS6 is required for bile duct morphogenesis and cholangiocyte differentiation in the liver. Loss of Anks6 causes ciliary abnormalities, ductal plate remodeling defects, and periportal fibrosis. Mechanistically, ANKS6 antagonizes Hippo signaling by binding to YAP1, TAZ, and TEAD4 and promoting their transcriptional activity; loss of ANKS6 leads to YAP transcriptional dysregulation in bile duct epithelial cells. Anks6 knockout mouse model, co-immunoprecipitation (ANKS6 with YAP1/TAZ/TEAD4), gene expression analyses, histology, biochemical assays Human molecular genetics Medium 32886109
2022 ANKS6 deficiency in patient-derived fibroblasts impairs the integrity of the ciliary inversin compartment (reduced cilia length), causes dysregulation of Hippo signaling through nuclear YAP imbalance and disrupted ciliary YAP localization, and alters Wnt target gene transcription and active β-catenin/GSK3β expression. ANKS6 deficiency also deranges subcellular localization of endocytic recycling compartment components upon ciliation. Patient-derived fibroblast in vitro model, immunofluorescence, western blot, transcriptional activity assays, immunohistochemistry on renal biopsies Human molecular genetics Medium 34740236
2023 ANKS6 regulates BICC1 ribonucleoprotein (RNP) complex assembly and organ laterality determination. ANKS6 induces structural remodeling of ANKS3, relieving an inhibitory interaction between ANKS3's C-terminal coiled-coil domain and BICC1 that otherwise blocks target mRNA (Dand5 3' UTR) binding. This dual regulation is validated by in vitro reconstitution and AlphaFold structure predictions. AlphaFold structure predictions, in vitro reconstitution of protein complexes, CRISPR-engineered ANKS3 truncation in zebrafish, mRNA decay assays, biochemical binding assays PLoS biology Medium 37733651
2023 ANKS6, recruited by ANKS3, reinstates BICC1 condensation and ribonucleoparticle assembly after ANKS3-mediated dispersal of Bicc1 granules, demonstrating that ANKS6 and ANKS3 exert opposing regulatory effects on Bicc1 phase transitioning and client mRNA immobilization. Cell-based condensate/granule assays, co-immunoprecipitation, RNA binding assays, live-cell imaging of phase transitioning iScience Medium 37275520
2022 ANKS6-deficient livers exhibit accumulation of inflammatory M1-like macrophages in periportal fibrotic tissue, and macrophage depletion by clodronate liposomes reduces inflammatory gene expression, fibrosis, and biliary dysfunction in liver-specific Anks6 KO mice, establishing a causal role for macrophage-mediated inflammation in ANKS6-deficiency-associated congenital hepatic fibrosis. Liver-specific Anks6 KO mouse model, clodronate liposome macrophage depletion, flow cytometry, gene expression analysis, histology FASEB journal Medium 35032404
2014 In the Han:SPRD Cy/+ rat model, increased levels of both total and active β-catenin were detected in precystic tubuli, suggesting ANKS6 mutations may contribute to cystogenesis via dysregulation of Wnt/β-catenin signaling. Immunohistochemistry in Han:SPRD Cy/+ rat kidney tissue Journal of the American Society of Nephrology Low 24610927

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

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