Affinage

ANKRD17

Ankyrin repeat domain-containing protein 17 · UniProt O75179

Round 2 corrected
Length
2603 aa
Mass
274.3 kDa
Annotated
2026-04-28
46 papers in source corpus 11 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKRD17 is a large, multifunctional ankyrin repeat scaffold protein that participates in cell cycle progression, innate immune signaling, Hippo pathway co-activation, and neurodevelopment. It serves as a Cyclin E/Cdk2 substrate that facilitates loading of replication factors Cdc6 and PCNA onto DNA to promote S-phase entry, and its depletion triggers p53/p21-dependent cell cycle arrest (PMID:19150984). ANKRD17 amplifies RIG-I/MDA5–MAVS-mediated type I interferon responses and NOD1/NOD2-driven pro-inflammatory signaling through direct physical interactions mediated by its ankyrin repeat domain (PMID:22328336, PMID:23711367), and it functions as a YAP co-factor in Hippo pathway target gene expression (PMID:27877230). Heterozygous loss-of-function variants cause Chopra–Amiel–Gordon syndrome, a neurodevelopmental disorder associated with synaptic and mitochondrial dysfunction (PMID:33909992, PMID:40604385).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 High

    Identification of ANKRD17 as a Cyclin E/Cdk2 substrate that promotes DNA replication factor loading established its role as a cell cycle regulator required for the G1/S transition.

    Evidence TAP-tag purification, Co-IP, in vitro kinase assay, siRNA knockdown with cell cycle analysis in human cell lines

    PMID:19150984

    Open questions at the time
    • How Cdk2-mediated phosphorylation of ANKRD17 mechanistically regulates Cdc6/PCNA loading is unknown
    • No structural model of the ANKRD17–replication factor complexes exists
    • Whether ANKRD17's cell cycle function is linked to its ankyrin repeat domain is untested
  2. 2009 High

    Genetic knockout in mice revealed that Ankrd17 is essential for embryonic vascular maturation, establishing an in vivo developmental requirement beyond cell culture proliferation.

    Evidence Ankrd17 homozygous knockout mice with histological and marker gene analysis

    PMID:19619540

    Open questions at the time
    • The cell-autonomous versus non-cell-autonomous basis of the vascular smooth muscle cell defect is unresolved
    • Why vSMC differentiation markers are paradoxically upregulated in mutants is unexplained
  3. 2012 High

    Discovery that ANKRD17 physically interacts with RIG-I, MDA5, and MAVS and enhances RLR-mediated IFN-β induction revealed a second major function as a positive innate immune signaling scaffold.

    Evidence Reciprocal Co-IP, domain mapping of ankyrin repeats, gain- and loss-of-function with IRF-3/NF-κB/IFN-β reporter assays

    PMID:22328336

    Open questions at the time
    • The stoichiometry and dynamics of ANKRD17 within the RLR signalosome are undefined
    • Whether ANKRD17's immune and cell cycle roles are coordinately regulated is unknown
  4. 2013 Medium

    Extending innate immune involvement, ANKRD17 was shown to bind NOD2 and support NOD1/NOD2-dependent pro-inflammatory responses, broadening its scope from RLR to NLR pathways.

    Evidence Co-IP with domain mapping, siRNA knockdown, overexpression, Shigella infection assay in myeloid and epithelial cells

    PMID:23711367

    Open questions at the time
    • The structural basis for ANKRD17 engaging both RLR and NLR components via different domains awaits detailed mapping
    • Single-lab finding not yet independently replicated
  5. 2016 Medium

    Demonstrating that ANKRD17 (Mask2) is required for YAP-driven transcription of Hippo pathway target genes connected this scaffold to growth-regulatory signaling beyond the cell cycle machinery.

    Evidence siRNA knockdown and overexpression with cell proliferation, migration, and target gene expression assays in bladder cancer cells

    PMID:27877230

    Open questions at the time
    • Whether ANKRD17 binds YAP directly or via intermediates is unresolved
    • The domain within ANKRD17 mediating Hippo co-activation is not mapped
  6. 2021 Medium

    Influenza A virus PA-X protein was found to target ANKRD17's ankyrin repeats to suppress RLR-mediated immunity, providing evidence that pathogens actively antagonize ANKRD17's immune scaffold function.

    Evidence Co-IP, domain mapping, Ankrd17 knockout and overexpression with immune signaling readouts during IAV infection

    PMID:33241870

    Open questions at the time
    • Whether other viral immune evasion proteins similarly target ANKRD17 is unexplored
    • Mechanism by which PA-X binding inhibits ANKRD17's scaffolding activity is undefined
  7. 2021 Medium

    Human genetic studies established that heterozygous ANKRD17 loss-of-function causes Chopra–Amiel–Gordon syndrome, linking the protein to neurodevelopment and revealing haploinsufficiency as the disease mechanism.

    Evidence Multi-family cohort genetics, protein structural modeling of ankyrin repeat-disrupting missense variants, scRNA-seq of developing human brain

    PMID:33909992

    Open questions at the time
    • No in vitro or cellular reconstitution of how specific variants disrupt ANKRD17 function
    • Which of ANKRD17's known molecular roles (cell cycle, immune, Hippo) is most critical in neural progenitors is unknown
  8. 2025 Medium

    Mouse haploinsufficiency models recapitulated neurobehavioral deficits and revealed synaptic protein dysregulation and mitochondrial dysfunction, providing mechanistic correlates for the human neurodevelopmental phenotype.

    Evidence Ankrd17 heterozygous mice and knockdown models with behavioral testing (Morris water maze, social behavior), synaptic and mitochondrial protein profiling

    PMID:40604385

    Open questions at the time
    • Direct molecular link between ANKRD17 and mitochondrial function has not been established
    • Whether synaptic defects are cell-autonomous is unresolved
  9. 2025 Medium

    ANKRD17 overexpression was shown to promote liver tumor metastasis by upregulating DDR1, placing ANKRD17 in a pro-metastatic signaling axis.

    Evidence Overexpression and knockdown with invasion/migration assays and DDR1 epistasis in mouse liver tumors and human liver cell lines

    PMID:40458187

    Open questions at the time
    • Whether ANKRD17 regulates DDR1 transcriptionally or post-transcriptionally is not defined
    • Relevance to human liver cancer is based on cell lines; clinical validation is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ANKRD17 integrates its cell cycle, innate immune, Hippo pathway, and neurodevelopmental functions through its multi-domain architecture remains the central unresolved question.
  • No high-resolution structure of full-length ANKRD17 or its key domain complexes exists
  • The logic governing which function dominates in a given cellular context is unknown
  • Whether ANKRD17's essential SLiM identified by base editing links to its known interaction partners requires validation beyond preprint

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 1 R-HSA-1640170 Cell Cycle 1
Partners
CCNE1CDK2DDX58IFIH1MAVSNOD2PCNAYAP1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 ANKRD17 (Ankrd17) was identified as a novel substrate of Cyclin E/Cdk2. It associates with Cyclin E/Cdk2 via an RXL motif at its C-terminus and is phosphorylated at Ser1791, Ser1794, and Ser2150. ANKRD17 interacts with DNA replication factors MCM family members, Cdc6, and PCNA in the nucleus, and its depletion reduces Cdc6 and PCNA loading onto DNA, blocking S-phase entry and upregulating p53 and p21. TAP-tag purification, Co-immunoprecipitation, siRNA knockdown, in vitro kinase assay, cell cycle analysis The Journal of biological chemistry High 19150984
2009 Homozygous knockout of Ankrd17 in mice causes embryonic lethality between E10.5 and E11.5 due to cardiovascular defects, including hemorrhage and drastically reduced vascular smooth muscle cells (vSMCs) surrounding vessels, indicating Ankrd17 is essential for vascular maturation. Notably, vSMC differentiation marker genes were paradoxically upregulated in mutant embryos. Gene targeting/knockout mouse, histology, marker gene expression analysis FEBS letters High 19619540
2012 Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated innate immune signaling. It physically interacts with RIG-I, MDA5, and VISA (MAVS), and its ankyrin repeat domain is required for these interactions. Overexpression of Ankrd17 enhances RIG-I/MDA5-VISA interaction and promotes IRF-3 and NF-κB activation and IFN-β transcription, while knockdown impairs RLR signaling. Co-immunoprecipitation, overexpression, siRNA knockdown, reporter assays (IRF-3, NF-κB, IFN-β luciferase), domain mapping European journal of immunology High 22328336
2013 Ankrd17 is a novel binding partner of NOD2 (and functionally involved in NOD1 signaling), with its N-terminal domain mediating NOD2 binding. Knockdown and overexpression showed Ankrd17 is required for NOD1/NOD2-mediated pro-inflammatory responses in human myeloid and epithelial cells and contributes to responses induced by Shigella flexneri infection, but not to type I interferon responses triggered by Sendai virus. Co-immunoprecipitation, domain mapping, siRNA knockdown, overexpression, bacterial infection assays, reporter assays FEBS letters Medium 23711367
2011 Murine cytomegalovirus (MCMV) IE3 protein interacts with Ankrd17, with the N-terminal 1–148 residues of IE3 responsible for the interaction, as identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation. Yeast two-hybrid, co-immunoprecipitation, domain mapping Journal of Huazhong University of Science and Technology. Medical sciences Low 21671165
2012 ANKRD17 expression in mouse testis is predominantly restricted to pachytene spermatocytes and round spermatids; ANKRD17 protein is diffusely distributed throughout the nucleus of pachytene cells but excluded from the XY body and other heterochromatic regions, supporting a role in meiotic prophase. In situ hybridization, immunofluorescence in developing mouse testis Biology of reproduction Medium 22190705
2021 Influenza A virus PA-X protein interacts with Ankrd17 via Ankrd17's N-terminal ankyrin repeat domain, preferring PA-X over PA. This interaction suppresses Ankrd17-mediated innate immune (RLR pathway) responses. Ankrd17 knockout and overexpression experiments confirmed that PA-X significantly modulates the Ankrd17-dependent host immune response to IAV infection. Co-immunoprecipitation, domain mapping, Ankrd17 knockout and overexpression, immune signaling assays Microbiology and immunology Medium 33241870
2021 Heterozygous loss-of-function ANKRD17 variants cause a neurodevelopmental syndrome (Chopra-Amiel-Gordon syndrome) via haploinsufficiency. Protein modeling indicates that missense variants disrupt ankyrin repeat stability through alteration of core structural residues. Single-cell RNA-seq data confirmed ANKRD17 expression across multiple stages of neurogenesis in the developing human telencephalon. Clinical cohort genetics, protein structural modeling, single-cell RNA-seq American journal of human genetics Medium 33909992
2025 Ankrd17 haploinsufficiency in mouse models produces deficits in social behavior, spatial learning and memory, and elevated anxiety. Ankrd17 knockdown in neural contexts is associated with dysregulation of synaptic proteins and mitochondrial function, and impaired neural circuits. Mouse behavioral assays (social behavior, Morris water maze), Ankrd17 knockdown, synaptic and mitochondrial protein analysis Journal of neurodevelopmental disorders Medium 40604385
2025 ANKRD17 overexpression in mouse liver tumors and human liver cell lines increases tumor load, EMT marker expression, cellular motility, and invasion. ANKRD17 upregulates the pro-metastatic receptor DDR1, and DDR1 suppression reduces motility and invasion without affecting AKT signaling, placing DDR1 downstream of ANKRD17 in a pro-metastatic pathway. Reverse genetics (overexpression and knockdown), in vitro invasion/migration assays, EMT marker analysis, DDR1 suppression epistasis iScience Medium 40458187
2016 Mask2 (the human ANKRD17 ortholog, also called ANKRD17) is required for YAP-induced bladder cancer cell growth and migration. Knockdown of Mask2 suppresses YAP-driven upregulation of Hippo pathway target genes and inhibits YAP-induced cell growth and migration, establishing Mask2/ANKRD17 as a functional co-factor of YAP in the Hippo pathway. siRNA knockdown, overexpression, cell proliferation and migration assays, target gene expression analysis Journal of Cancer Medium 27877230
2024 A disease-associated ANKRD17 mutation affects an essential short linear motif (SLiM) required for normal cell proliferation. Genome-wide base editing screening identified this SLiM as functionally important, and binding partners for ANKRD17's essential SLiM were identified, providing mechanistic insight into how the ANKRD17 mutation causes cellular dysfunction. Base editing genome-wide screen, SLiM mutagenesis, binding partner identification by proteomics bioRxivpreprint Medium

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2013 Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nature genetics 463 23535732
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2009 The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. The Journal of biological chemistry 224 19815555
2017 Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification. Nature communications 221 28524877
2009 A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing to productive HIV-1 replication. The Journal of biological chemistry 211 19460752
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2007 Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proceedings of the National Academy of Sciences of the United States of America 204 17609381
2019 Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells. Cell reports 178 30995489
2010 A human MAP kinase interactome. Nature methods 165 20936779
1998 Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 150 9734811
2020 Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation. Cells 146 32344865
2012 Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Molecular & cellular proteomics : MCP 145 22586326
2012 The GtaR protein negatively regulates transcription of the gtaRI operon and modulates gene transfer agent (RcGTA) expression in Rhodobacter capsulatus. Molecular microbiology 45 22211723
2009 Identification and functional analysis of a novel cyclin e/cdk2 substrate ankrd17. The Journal of biological chemistry 42 19150984
2012 Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling. European journal of immunology 29 22328336
2013 A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses. FEBS letters 27 23711367
2021 Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism. American journal of human genetics 26 33909992
2016 Transcriptional cofactor Mask2 is required for YAP-induced cell growth and migration in bladder cancer cell. Journal of Cancer 24 27877230
2009 Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular integrity during embryogenesis. FEBS letters 24 19619540
2023 Effect of miR-493-5p on proliferation and differentiation of myoblast by targeting ANKRD17. Cell and tissue research 7 37178193
2012 Experimental validation of Ankrd17 and Anapc10, two novel meiotic genes predicted by computational models in mice. Biology of reproduction 6 22190705
2021 Influenza A virus protein PA-X suppresses host Ankrd17-mediated immune responses. Microbiology and immunology 5 33241870
2025 Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder. Journal of neurodevelopmental disorders 3 40604385
2023 A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report. SAGE open medical case reports 2 37456926
2011 Murine cytomegalovirus IE3 protein interacts with Ankrd17. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 2 21671165
2025 ANKRD17 induces pro-survival signaling pathways that enhance cellular invasion and migration during hepatocellular carcinoma tumorigenesis. iScience 1 40458187
2023 Erratum: Transcriptional cofactor Mask2 is required for YAP-induced cell growth and migration in bladder cancer cell: Erratum. Journal of Cancer 1 38021162
2024 Case report: Whole exome sequencing reveals a novel splicing variant of ANKRD17 gene in a Chinese male juvenile with developmental delay and transient tic disorder. Frontiers in genetics 0 39315309