{"gene":"ANKRD17","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2009,"finding":"ANKRD17 is a substrate of cyclin E/Cdk2; it associates with cyclin E/Cdk2 in an RXL-dependent manner and is phosphorylated by cyclin E/Cdk2 at Ser1791, Ser1794, and Ser2150. ANKRD17 interacts with DNA replication factors MCM family members, Cdc6, and PCNA, and its depletion decreases loading of Cdc6 and PCNA onto DNA, indicating a direct role in DNA replication initiation.","method":"TAP tag purification, co-immunoprecipitation, in vitro kinase assay, RXL motif mutagenesis, siRNA knockdown with DNA replication readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphorylation assay with site identification by mutagenesis, reciprocal Co-IP, and functional knockdown with specific chromatin-loading readout, all in single study with multiple orthogonal methods","pmids":["19150984"],"is_preprint":false},{"year":2009,"finding":"ANKRD17 is localized to the nucleus and contains an NES and NLS in its middle region; it is ubiquitously expressed and overexpression promotes S-phase entry while depletion inhibits DNA replication and blocks cell cycle progression, upregulating p53 and p21.","method":"siRNA knockdown, overexpression, flow cytometry, immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cell cycle phenotype and p53/p21 readout, single lab but multiple methods","pmids":["19150984"],"is_preprint":false},{"year":2009,"finding":"Ankrd17 knockout mice die between E10.5 and E11.5 with cardiovascular defects including serious hemorrhages and drastically reduced vascular smooth muscle cells (vSMCs) surrounding vessels, demonstrating that ANKRD17 is essential for vascular maturation; vSMC differentiation marker genes were paradoxically up-regulated in mutant embryos.","method":"Gene targeting (knockout mouse), histological analysis, marker gene expression analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific developmental phenotype, multiple markers assessed in single rigorous study","pmids":["19619540"],"is_preprint":false},{"year":2012,"finding":"ANKRD17 interacts with RIG-I, MDA5, and VISA (MAVS) and positively regulates RLR-mediated innate immune signaling; the ankyrin repeat domain of ANKRD17 is required for its interaction with RIG-I and for enhancing the interaction of RIG-I and MDA5 with VISA, leading to upregulation of IRF-3, NF-κB activation, and IFN-β transcription.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, reporter assays (IRF-3 and NF-κB luciferase), domain mapping","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, knockdown and overexpression with defined signaling readouts, single lab","pmids":["22328336"],"is_preprint":false},{"year":2013,"finding":"ANKRD17 binds Nod2 via its N-terminal domain and is functionally required for Nod1- and Nod2-mediated pro-inflammatory responses in human myeloid and epithelial cells, including responses to Shigella flexneri infection, but does not contribute to type I interferon responses induced by Sendai virus.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, overexpression, Shigella infection assay, NF-κB reporter","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping plus KD/OE with specific bacterial and viral challenge readouts, single lab","pmids":["23711367"],"is_preprint":false},{"year":2011,"finding":"ANKRD17 (Gtar) interacts with murine cytomegalovirus IE3 protein; yeast two-hybrid and co-immunoprecipitation mapping showed the N-terminal 1–148 residues of IE3 are responsible for the interaction.","method":"Yeast two-hybrid screening, co-immunoprecipitation, domain mapping","journal":"Journal of Huazhong University of Science and Technology. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and yeast two-hybrid, single lab, no functional follow-up","pmids":["21671165"],"is_preprint":false},{"year":2012,"finding":"In mouse testis, ANKRD17 expression is predominantly restricted to pachytene spermatocytes and round spermatids, with diffuse nuclear distribution in pachytene cells but exclusion from the XY body and heterochromatic regions, indicating a role during meiotic prophase.","method":"In situ hybridization, immunofluorescence in developing mouse testis","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization experiment without functional consequence demonstrated, single study","pmids":["22190705"],"is_preprint":false},{"year":2016,"finding":"ANKRD17 (Mask2) is required as a transcriptional cofactor for YAP-induced cell growth and migration in bladder cancer cells; knockdown of Mask2 suppresses YAP-driven upregulation of Hippo pathway target genes and reverses YAP-induced proliferation and migration.","method":"siRNA knockdown, overexpression, cell growth and migration assays, target gene expression analysis","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KD with defined YAP target gene and phenotypic readouts, multiple assays, single lab","pmids":["27877230"],"is_preprint":false},{"year":2021,"finding":"Influenza A virus PA-X protein directly binds ANKRD17 and suppresses ANKRD17-mediated innate immune signaling; the N-terminal ankyrin repeats of ANKRD17 are the key domain for interaction with PA-X (but not PA), and PA-X preferentially binds ANKRD17 over PA. ANKRD17 knockout confirmed that PA-X attenuates the Ankrd17-dependent immune response.","method":"Protein interaction screening, co-immunoprecipitation, domain mapping, ANKRD17 knockout and overexpression in cells with IAV infection","journal":"Microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping, KO and OE functional validation, single lab","pmids":["33241870"],"is_preprint":false},{"year":2025,"finding":"ANKRD17 overexpression in mouse liver tumors and human liver cell lines increases EMT marker expression, cellular motility, and invasion; knockdown reverses these effects. The pro-metastatic DDR1 gene is upregulated by ANKRD17 overexpression, and DDR1 suppression reduces motility and invasion without affecting AKT signaling, placing DDR1 downstream of ANKRD17 in HCC metastatic signaling.","method":"Reverse genetics (mouse liver tumor model), overexpression, knockdown, cell migration and invasion assays, DDR1 suppression epistasis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO/OE with defined phenotype plus epistasis experiment with DDR1, single lab","pmids":["40458187"],"is_preprint":false},{"year":2024,"finding":"A disease-associated ANKRD17 mutation affects an essential short linear motif (SLiM) required for normal cell proliferation, with a binding partner identified through the proteome-wide SLiM dependency map, providing mechanistic insight into ANKRD17 pathogenicity.","method":"Base editing SLiM mutagenesis screen (7,293 SLiM-containing regions, 80,473 mutations in HAP1 and RPE1 cells), binding partner identification","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pan-proteome screen with specific mention of ANKRD17 SLiM, preprint, limited mechanistic detail for this specific gene in abstract","pmids":[],"is_preprint":true},{"year":2025,"finding":"Ankrd17 haploinsufficiency in mouse models causes deficits in social behavior, spatial learning and memory, and elevated anxiety, associated with dysregulation of synaptic proteins, impaired mitochondrial function, and disrupted neural circuits following Ankrd17 knockdown.","method":"Ankrd17 haploinsufficiency mouse model, behavioral assays, synaptic protein analysis, mitochondrial function assays, neural circuit analysis after knockdown","journal":"Journal of neurodevelopmental disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD/haploinsufficiency with defined behavioral and molecular phenotypes including multiple readouts, single lab","pmids":["40604385"],"is_preprint":false}],"current_model":"ANKRD17 is an ankyrin repeat-containing nuclear protein that functions as a downstream effector of cyclin E/Cdk2 (phosphorylated at Ser1791/1794/2150 via an RXL docking motif) to promote DNA replication by interacting with MCM proteins, Cdc6, and PCNA; it also acts as a positive regulator of innate immune signaling through interaction with RIG-I/MDA5/VISA and Nod1/Nod2 complexes via its ankyrin repeat domain, a function targeted by influenza PA-X; additionally, it serves as a transcriptional cofactor for YAP in Hippo pathway signaling, is essential for vascular maturation during embryogenesis, and haploinsufficiency disrupts synaptic and mitochondrial function leading to neurodevelopmental phenotypes."},"narrative":{"mechanistic_narrative":"ANKRD17 is a ubiquitously expressed, nucleocytoplasmically shuttling ankyrin-repeat protein that couples cell-cycle progression to DNA replication and serves as a positive regulator of innate immune signaling [PMID:19150984, PMID:22328336]. As a substrate of cyclin E/Cdk2, ANKRD17 docks via an RXL motif and is phosphorylated at Ser1791, Ser1794, and Ser2150; it associates with the MCM helicase components, Cdc6, and PCNA, and is required for loading of Cdc6 and PCNA onto chromatin, promoting replication initiation and S-phase entry [PMID:19150984]. Its depletion arrests the cell cycle with upregulation of p53 and p21 [PMID:19150984]. Through its ankyrin repeat domain ANKRD17 binds the RNA-sensing receptors RIG-I and MDA5 and enhances their engagement of the adaptor VISA/MAVS to drive IRF-3, NF-κB, and IFN-β activation, while its N-terminal domain binds Nod2 to support Nod1/Nod2-dependent pro-inflammatory responses to bacterial challenge such as Shigella flexneri [PMID:22328336, PMID:23711367]; this immune-scaffolding function is antagonized by the influenza A virus PA-X protein, which binds the N-terminal ankyrin repeats [PMID:33241870]. ANKRD17 additionally acts as a transcriptional cofactor required for YAP-driven target-gene expression, proliferation, and migration [PMID:27877230], and promotes EMT, motility, and invasion in hepatocellular carcinoma by upregulating DDR1 [PMID:40458187]. Genetically, ANKRD17 is essential for embryonic vascular maturation, with knockout mice dying at midgestation from hemorrhage and loss of vascular smooth muscle cells [PMID:19619540], and haploinsufficiency produces neurodevelopmental phenotypes accompanied by synaptic and mitochondrial dysfunction [PMID:40604385].","teleology":[{"year":2009,"claim":"Established ANKRD17 as a direct cyclin E/Cdk2 effector that physically links the replication licensing and initiation machinery, answering how this previously uncharacterized protein participates in cell-cycle control.","evidence":"TAP purification, in vitro kinase assay with phosphosite mutagenesis, reciprocal Co-IP, and siRNA knockdown with chromatin-loading readout in mammalian cells","pmids":["19150984"],"confidence":"High","gaps":["Functional consequence of the three Cdk2 phosphosites on replication factor binding not dissected","Whether ANKRD17 acts catalytically or as a scaffold at origins unresolved","Structural basis of MCM/Cdc6/PCNA engagement unknown"]},{"year":2009,"claim":"Defined the subcellular trafficking and cell-cycle phenotype of ANKRD17, showing it is nuclear with NES/NLS signals and that its loss arrests proliferation via a p53/p21 checkpoint.","evidence":"Immunofluorescence localization, overexpression/knockdown with flow cytometry in mammalian cells","pmids":["19150984"],"confidence":"Medium","gaps":["Trigger for nuclear export/import not identified","Whether p53/p21 induction is a direct effect or secondary to replication stress unclear"]},{"year":2009,"claim":"Demonstrated an essential in vivo role in vascular maturation, showing ANKRD17 function extends beyond cultured-cell proliferation to organismal development.","evidence":"Constitutive knockout mouse with histology and vSMC marker analysis","pmids":["19619540"],"confidence":"High","gaps":["Cell-autonomous versus non-autonomous requirement in vSMCs not separated","Mechanism linking replication role to vascular phenotype unaddressed","Paradoxical marker upregulation unexplained"]},{"year":2012,"claim":"Identified ANKRD17 as a positive regulator of RLR antiviral signaling, recasting it as an innate immune scaffold acting through its ankyrin repeat domain.","evidence":"Reciprocal Co-IP, domain mapping, knockdown/overexpression with IRF-3 and NF-κB reporters in mammalian cells","pmids":["22328336"],"confidence":"Medium","gaps":["Whether ANKRD17 stably assembles into RIG-I/MDA5/VISA complexes versus transiently bridges them unresolved","Relationship to its nuclear replication role not reconciled"]},{"year":2013,"claim":"Extended the immune function to cytosolic bacterial sensing, showing ANKRD17 binds Nod2 via its N-terminus and is required for Nod1/Nod2 responses but dispensable for type I IFN to Sendai virus.","evidence":"Co-IP, domain mapping, knockdown/overexpression with Shigella flexneri infection and NF-κB reporter in myeloid and epithelial cells","pmids":["23711367"],"confidence":"Medium","gaps":["Apparent discrepancy with RLR/IFN role across pathways not mechanistically explained","Direct versus indirect requirement in NOD signaling not distinguished"]},{"year":2016,"claim":"Placed ANKRD17 in the Hippo pathway as a transcriptional cofactor required for YAP-driven oncogenic outputs.","evidence":"siRNA knockdown/overexpression with YAP target-gene expression and growth/migration assays in bladder cancer cells","pmids":["27877230"],"confidence":"Medium","gaps":["Direct physical interaction with YAP not demonstrated","How a replication/immune protein cofactors transcription unresolved"]},{"year":2021,"claim":"Revealed viral antagonism of ANKRD17 immune function, identifying its N-terminal ankyrin repeats as the binding interface for influenza A PA-X.","evidence":"Interaction screening, Co-IP, domain mapping, ANKRD17 knockout/overexpression with IAV infection","pmids":["33241870"],"confidence":"Medium","gaps":["Downstream signaling steps blocked by PA-X binding not mapped","Whether PA-X displaces RIG-I or NOD partners from the same domain untested"]},{"year":2025,"claim":"Implicated ANKRD17 in HCC metastasis through a DDR1-dependent, AKT-independent pro-invasive axis.","evidence":"Mouse liver tumor model with overexpression/knockdown and DDR1 suppression epistasis in invasion assays","pmids":["40458187"],"confidence":"Medium","gaps":["Mechanism by which ANKRD17 upregulates DDR1 unknown","Relationship to YAP cofactor activity not tested"]},{"year":2025,"claim":"Connected ANKRD17 dosage to neurodevelopment, showing haploinsufficiency disrupts behavior alongside synaptic and mitochondrial defects.","evidence":"Haploinsufficiency mouse model with behavioral assays, synaptic protein and mitochondrial function analyses, and circuit analysis after knockdown","pmids":["40604385"],"confidence":"Medium","gaps":["Causal link between molecular defects and behavior not established","Which ANKRD17 molecular activity underlies the neuronal phenotype unknown"]},{"year":2024,"claim":"Pinpointed a disease-associated ANKRD17 short linear motif required for proliferation and identified its binding partner, offering a route to pathogenic mechanism.","evidence":"Proteome-wide base-editing SLiM dependency screen in HAP1 and RPE1 cells (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint with limited gene-specific mechanistic detail","Identity and pathway of the SLiM partner not detailed in available evidence","Link between the SLiM and the established replication/immune functions unclear"]},{"year":null,"claim":"How ANKRD17's distinct nuclear replication, cytoplasmic immune-scaffolding, and transcriptional-cofactor activities are integrated within one protein — and which underlies its developmental and neurodevelopmental requirements — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model defining how ankyrin repeats and the central SLiM-bearing region partition functions","No unifying mechanism connecting replication, immune, Hippo, and EMT roles","Tissue-specific partner usage not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]}],"complexes":[],"partners":["CCNE1","CDK2","PCNA","CDC6","RIGI","IFIH1","MAVS","NOD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75179","full_name":"Ankyrin repeat domain-containing protein 17","aliases":["Gene trap ankyrin repeat protein","Serologically defined breast cancer antigen NY-BR-16"],"length_aa":2603,"mass_kda":274.3,"function":"Could play pivotal roles in cell cycle and DNA regulation (PubMed:19150984). Involved in innate immune defense against viruse by positively regulating the viral dsRNA receptors DDX58 and IFIH1 signaling pathways (PubMed:22328336). Involves in NOD2- and NOD1-mediated responses to bacteria suggesting a role in innate antibacterial immune pathways too (PubMed:23711367). Target of enterovirus 71 which is the major etiological agent of HFMD (hand, foot and mouth disease) (PubMed:17276651). Could play a central role for the formation and/or maintenance of the blood vessels of the circulation system (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O75179/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD17","classification":"Not Classified","n_dependent_lines":202,"n_total_lines":1208,"dependency_fraction":0.1672185430463576},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132466","cell_line_id":"CID001386","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"HOXB6","stoichiometry":4.0},{"gene":"ANKHD1","stoichiometry":0.2},{"gene":"LONP1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"KIAA0368","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001386","total_profiled":1310},"omim":[{"mim_id":"619504","title":"CHOPRA-AMIEL-GORDON SYNDROME; CAGS","url":"https://www.omim.org/entry/619504"},{"mim_id":"615929","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 17; ANKRD17","url":"https://www.omim.org/entry/615929"},{"mim_id":"248510","title":"MANNOSIDOSIS, BETA A, LYSOSOMAL; MANSB","url":"https://www.omim.org/entry/248510"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANKRD17"},"hgnc":{"alias_symbol":["GTAR","KIAA0697","FLJ22206","NY-BR-16","MASK2"],"prev_symbol":[]},"alphafold":{"accession":"O75179","domains":[{"cath_id":"1.25.40.20","chopping":"238-334","consensus_level":"medium","plddt":87.3971,"start":238,"end":334},{"cath_id":"1.25.40.20","chopping":"623-721","consensus_level":"medium","plddt":92.6989,"start":623,"end":721},{"cath_id":"1.25.40.20","chopping":"1355-1463","consensus_level":"medium","plddt":91.9277,"start":1355,"end":1463},{"cath_id":"3.30.1370.10","chopping":"1727-1802","consensus_level":"medium","plddt":80.7696,"start":1727,"end":1802}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75179","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75179-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75179-F1-predicted_aligned_error_v6.png","plddt_mean":53.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKRD17","jax_strain_url":"https://www.jax.org/strain/search?query=ANKRD17"},"sequence":{"accession":"O75179","fasta_url":"https://rest.uniprot.org/uniprotkb/O75179.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75179/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75179"}},"corpus_meta":[{"pmid":"22211723","id":"PMC_22211723","title":"The GtaR protein negatively regulates transcription of the gtaRI operon and modulates gene transfer agent (RcGTA) expression in Rhodobacter capsulatus.","date":"2012","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22211723","citation_count":45,"is_preprint":false},{"pmid":"19150984","id":"PMC_19150984","title":"Identification and functional analysis of a novel cyclin e/cdk2 substrate ankrd17.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19150984","citation_count":43,"is_preprint":false},{"pmid":"22328336","id":"PMC_22328336","title":"Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22328336","citation_count":29,"is_preprint":false},{"pmid":"33909992","id":"PMC_33909992","title":"Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.","date":"2021","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33909992","citation_count":28,"is_preprint":false},{"pmid":"23711367","id":"PMC_23711367","title":"A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23711367","citation_count":27,"is_preprint":false},{"pmid":"27877230","id":"PMC_27877230","title":"Transcriptional cofactor Mask2 is required for YAP-induced cell growth and migration in bladder cancer cell.","date":"2016","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27877230","citation_count":24,"is_preprint":false},{"pmid":"19619540","id":"PMC_19619540","title":"Ankrd17, an ubiquitously expressed ankyrin factor, is essential for the vascular integrity during embryogenesis.","date":"2009","source":"FEBS 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33241870","citation_count":5,"is_preprint":false},{"pmid":"40604385","id":"PMC_40604385","title":"Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder.","date":"2025","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/40604385","citation_count":4,"is_preprint":false},{"pmid":"37456926","id":"PMC_37456926","title":"A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report.","date":"2023","source":"SAGE open medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/37456926","citation_count":3,"is_preprint":false},{"pmid":"21671165","id":"PMC_21671165","title":"Murine cytomegalovirus IE3 protein interacts with Ankrd17.","date":"2011","source":"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","url":"https://pubmed.ncbi.nlm.nih.gov/21671165","citation_count":2,"is_preprint":false},{"pmid":"40458187","id":"PMC_40458187","title":"ANKRD17 induces pro-survival signaling pathways that enhance cellular invasion and migration during hepatocellular carcinoma tumorigenesis.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40458187","citation_count":1,"is_preprint":false},{"pmid":"38021162","id":"PMC_38021162","title":"Erratum: Transcriptional cofactor Mask2 is required for YAP-induced cell growth and migration in bladder cancer cell: Erratum.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38021162","citation_count":1,"is_preprint":false},{"pmid":"39315309","id":"PMC_39315309","title":"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.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39315309","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.11.612445","title":"A proteome-wide dependency map of protein interaction motifs","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.11.612445","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.27.24319460","title":"Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations","date":"2025-01-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.24319460","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10185,"output_tokens":2913,"usd":0.037125,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10317,"output_tokens":3837,"usd":0.073755,"stage2_stop_reason":"end_turn"},"total_usd":0.11088,"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\": 2009,\n      \"finding\": \"ANKRD17 is a substrate of cyclin E/Cdk2; it associates with cyclin E/Cdk2 in an RXL-dependent manner and is phosphorylated by cyclin E/Cdk2 at Ser1791, Ser1794, and Ser2150. ANKRD17 interacts with DNA replication factors MCM family members, Cdc6, and PCNA, and its depletion decreases loading of Cdc6 and PCNA onto DNA, indicating a direct role in DNA replication initiation.\",\n      \"method\": \"TAP tag purification, co-immunoprecipitation, in vitro kinase assay, RXL motif mutagenesis, siRNA knockdown with DNA replication readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphorylation assay with site identification by mutagenesis, reciprocal Co-IP, and functional knockdown with specific chromatin-loading readout, all in single study with multiple orthogonal methods\",\n      \"pmids\": [\"19150984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ANKRD17 is localized to the nucleus and contains an NES and NLS in its middle region; it is ubiquitously expressed and overexpression promotes S-phase entry while depletion inhibits DNA replication and blocks cell cycle progression, upregulating p53 and p21.\",\n      \"method\": \"siRNA knockdown, overexpression, flow cytometry, immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cell cycle phenotype and p53/p21 readout, single lab but multiple methods\",\n      \"pmids\": [\"19150984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ankrd17 knockout mice die between E10.5 and E11.5 with cardiovascular defects including serious hemorrhages and drastically reduced vascular smooth muscle cells (vSMCs) surrounding vessels, demonstrating that ANKRD17 is essential for vascular maturation; vSMC differentiation marker genes were paradoxically up-regulated in mutant embryos.\",\n      \"method\": \"Gene targeting (knockout mouse), histological analysis, marker gene expression analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific developmental phenotype, multiple markers assessed in single rigorous study\",\n      \"pmids\": [\"19619540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ANKRD17 interacts with RIG-I, MDA5, and VISA (MAVS) and positively regulates RLR-mediated innate immune signaling; the ankyrin repeat domain of ANKRD17 is required for its interaction with RIG-I and for enhancing the interaction of RIG-I and MDA5 with VISA, leading to upregulation of IRF-3, NF-κB activation, and IFN-β transcription.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, reporter assays (IRF-3 and NF-κB luciferase), domain mapping\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, knockdown and overexpression with defined signaling readouts, single lab\",\n      \"pmids\": [\"22328336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANKRD17 binds Nod2 via its N-terminal domain and is functionally required for Nod1- and Nod2-mediated pro-inflammatory responses in human myeloid and epithelial cells, including responses to Shigella flexneri infection, but does not contribute to type I interferon responses induced by Sendai virus.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, overexpression, Shigella infection assay, NF-κB reporter\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping plus KD/OE with specific bacterial and viral challenge readouts, single lab\",\n      \"pmids\": [\"23711367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ANKRD17 (Gtar) interacts with murine cytomegalovirus IE3 protein; yeast two-hybrid and co-immunoprecipitation mapping showed the N-terminal 1–148 residues of IE3 are responsible for the interaction.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and yeast two-hybrid, single lab, no functional follow-up\",\n      \"pmids\": [\"21671165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In mouse testis, ANKRD17 expression is predominantly restricted to pachytene spermatocytes and round spermatids, with diffuse nuclear distribution in pachytene cells but exclusion from the XY body and heterochromatic regions, indicating a role during meiotic prophase.\",\n      \"method\": \"In situ hybridization, immunofluorescence in developing mouse testis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization experiment without functional consequence demonstrated, single study\",\n      \"pmids\": [\"22190705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANKRD17 (Mask2) is required as a transcriptional cofactor for YAP-induced cell growth and migration in bladder cancer cells; knockdown of Mask2 suppresses YAP-driven upregulation of Hippo pathway target genes and reverses YAP-induced proliferation and migration.\",\n      \"method\": \"siRNA knockdown, overexpression, cell growth and migration assays, target gene expression analysis\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KD with defined YAP target gene and phenotypic readouts, multiple assays, single lab\",\n      \"pmids\": [\"27877230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Influenza A virus PA-X protein directly binds ANKRD17 and suppresses ANKRD17-mediated innate immune signaling; the N-terminal ankyrin repeats of ANKRD17 are the key domain for interaction with PA-X (but not PA), and PA-X preferentially binds ANKRD17 over PA. ANKRD17 knockout confirmed that PA-X attenuates the Ankrd17-dependent immune response.\",\n      \"method\": \"Protein interaction screening, co-immunoprecipitation, domain mapping, ANKRD17 knockout and overexpression in cells with IAV infection\",\n      \"journal\": \"Microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping, KO and OE functional validation, single lab\",\n      \"pmids\": [\"33241870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANKRD17 overexpression in mouse liver tumors and human liver cell lines increases EMT marker expression, cellular motility, and invasion; knockdown reverses these effects. The pro-metastatic DDR1 gene is upregulated by ANKRD17 overexpression, and DDR1 suppression reduces motility and invasion without affecting AKT signaling, placing DDR1 downstream of ANKRD17 in HCC metastatic signaling.\",\n      \"method\": \"Reverse genetics (mouse liver tumor model), overexpression, knockdown, cell migration and invasion assays, DDR1 suppression epistasis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO/OE with defined phenotype plus epistasis experiment with DDR1, single lab\",\n      \"pmids\": [\"40458187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A disease-associated ANKRD17 mutation affects an essential short linear motif (SLiM) required for normal cell proliferation, with a binding partner identified through the proteome-wide SLiM dependency map, providing mechanistic insight into ANKRD17 pathogenicity.\",\n      \"method\": \"Base editing SLiM mutagenesis screen (7,293 SLiM-containing regions, 80,473 mutations in HAP1 and RPE1 cells), binding partner identification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pan-proteome screen with specific mention of ANKRD17 SLiM, preprint, limited mechanistic detail for this specific gene in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ankrd17 haploinsufficiency in mouse models causes deficits in social behavior, spatial learning and memory, and elevated anxiety, associated with dysregulation of synaptic proteins, impaired mitochondrial function, and disrupted neural circuits following Ankrd17 knockdown.\",\n      \"method\": \"Ankrd17 haploinsufficiency mouse model, behavioral assays, synaptic protein analysis, mitochondrial function assays, neural circuit analysis after knockdown\",\n      \"journal\": \"Journal of neurodevelopmental disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD/haploinsufficiency with defined behavioral and molecular phenotypes including multiple readouts, single lab\",\n      \"pmids\": [\"40604385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKRD17 is an ankyrin repeat-containing nuclear protein that functions as a downstream effector of cyclin E/Cdk2 (phosphorylated at Ser1791/1794/2150 via an RXL docking motif) to promote DNA replication by interacting with MCM proteins, Cdc6, and PCNA; it also acts as a positive regulator of innate immune signaling through interaction with RIG-I/MDA5/VISA and Nod1/Nod2 complexes via its ankyrin repeat domain, a function targeted by influenza PA-X; additionally, it serves as a transcriptional cofactor for YAP in Hippo pathway signaling, is essential for vascular maturation during embryogenesis, and haploinsufficiency disrupts synaptic and mitochondrial function leading to neurodevelopmental phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKRD17 is a ubiquitously expressed, nucleocytoplasmically shuttling ankyrin-repeat protein that couples cell-cycle progression to DNA replication and serves as a positive regulator of innate immune signaling [#0, #3]. As a substrate of cyclin E/Cdk2, ANKRD17 docks via an RXL motif and is phosphorylated at Ser1791, Ser1794, and Ser2150; it associates with the MCM helicase components, Cdc6, and PCNA, and is required for loading of Cdc6 and PCNA onto chromatin, promoting replication initiation and S-phase entry [#0, #1]. Its depletion arrests the cell cycle with upregulation of p53 and p21 [#1]. Through its ankyrin repeat domain ANKRD17 binds the RNA-sensing receptors RIG-I and MDA5 and enhances their engagement of the adaptor VISA/MAVS to drive IRF-3, NF-\\u03baB, and IFN-\\u03b2 activation, while its N-terminal domain binds Nod2 to support Nod1/Nod2-dependent pro-inflammatory responses to bacterial challenge such as Shigella flexneri [#3, #4]; this immune-scaffolding function is antagonized by the influenza A virus PA-X protein, which binds the N-terminal ankyrin repeats [#8]. ANKRD17 additionally acts as a transcriptional cofactor required for YAP-driven target-gene expression, proliferation, and migration [#7], and promotes EMT, motility, and invasion in hepatocellular carcinoma by upregulating DDR1 [#9]. Genetically, ANKRD17 is essential for embryonic vascular maturation, with knockout mice dying at midgestation from hemorrhage and loss of vascular smooth muscle cells [#2], and haploinsufficiency produces neurodevelopmental phenotypes accompanied by synaptic and mitochondrial dysfunction [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ANKRD17 as a direct cyclin E/Cdk2 effector that physically links the replication licensing and initiation machinery, answering how this previously uncharacterized protein participates in cell-cycle control.\",\n      \"evidence\": \"TAP purification, in vitro kinase assay with phosphosite mutagenesis, reciprocal Co-IP, and siRNA knockdown with chromatin-loading readout in mammalian cells\",\n      \"pmids\": [\n        \"19150984\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of the three Cdk2 phosphosites on replication factor binding not dissected\",\n        \"Whether ANKRD17 acts catalytically or as a scaffold at origins unresolved\",\n        \"Structural basis of MCM/Cdc6/PCNA engagement unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the subcellular trafficking and cell-cycle phenotype of ANKRD17, showing it is nuclear with NES/NLS signals and that its loss arrests proliferation via a p53/p21 checkpoint.\",\n      \"evidence\": \"Immunofluorescence localization, overexpression/knockdown with flow cytometry in mammalian cells\",\n      \"pmids\": [\n        \"19150984\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Trigger for nuclear export/import not identified\",\n        \"Whether p53/p21 induction is a direct effect or secondary to replication stress unclear\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated an essential in vivo role in vascular maturation, showing ANKRD17 function extends beyond cultured-cell proliferation to organismal development.\",\n      \"evidence\": \"Constitutive knockout mouse with histology and vSMC marker analysis\",\n      \"pmids\": [\n        \"19619540\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-autonomous versus non-autonomous requirement in vSMCs not separated\",\n        \"Mechanism linking replication role to vascular phenotype unaddressed\",\n        \"Paradoxical marker upregulation unexplained\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified ANKRD17 as a positive regulator of RLR antiviral signaling, recasting it as an innate immune scaffold acting through its ankyrin repeat domain.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, knockdown/overexpression with IRF-3 and NF-\\u03baB reporters in mammalian cells\",\n      \"pmids\": [\n        \"22328336\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ANKRD17 stably assembles into RIG-I/MDA5/VISA complexes versus transiently bridges them unresolved\",\n        \"Relationship to its nuclear replication role not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the immune function to cytosolic bacterial sensing, showing ANKRD17 binds Nod2 via its N-terminus and is required for Nod1/Nod2 responses but dispensable for type I IFN to Sendai virus.\",\n      \"evidence\": \"Co-IP, domain mapping, knockdown/overexpression with Shigella flexneri infection and NF-\\u03baB reporter in myeloid and epithelial cells\",\n      \"pmids\": [\n        \"23711367\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Apparent discrepancy with RLR/IFN role across pathways not mechanistically explained\",\n        \"Direct versus indirect requirement in NOD signaling not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ANKRD17 in the Hippo pathway as a transcriptional cofactor required for YAP-driven oncogenic outputs.\",\n      \"evidence\": \"siRNA knockdown/overexpression with YAP target-gene expression and growth/migration assays in bladder cancer cells\",\n      \"pmids\": [\n        \"27877230\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction with YAP not demonstrated\",\n        \"How a replication/immune protein cofactors transcription unresolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed viral antagonism of ANKRD17 immune function, identifying its N-terminal ankyrin repeats as the binding interface for influenza A PA-X.\",\n      \"evidence\": \"Interaction screening, Co-IP, domain mapping, ANKRD17 knockout/overexpression with IAV infection\",\n      \"pmids\": [\n        \"33241870\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling steps blocked by PA-X binding not mapped\",\n        \"Whether PA-X displaces RIG-I or NOD partners from the same domain untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ANKRD17 in HCC metastasis through a DDR1-dependent, AKT-independent pro-invasive axis.\",\n      \"evidence\": \"Mouse liver tumor model with overexpression/knockdown and DDR1 suppression epistasis in invasion assays\",\n      \"pmids\": [\n        \"40458187\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ANKRD17 upregulates DDR1 unknown\",\n        \"Relationship to YAP cofactor activity not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ANKRD17 dosage to neurodevelopment, showing haploinsufficiency disrupts behavior alongside synaptic and mitochondrial defects.\",\n      \"evidence\": \"Haploinsufficiency mouse model with behavioral assays, synaptic protein and mitochondrial function analyses, and circuit analysis after knockdown\",\n      \"pmids\": [\n        \"40604385\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal link between molecular defects and behavior not established\",\n        \"Which ANKRD17 molecular activity underlies the neuronal phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed a disease-associated ANKRD17 short linear motif required for proliferation and identified its binding partner, offering a route to pathogenic mechanism.\",\n      \"evidence\": \"Proteome-wide base-editing SLiM dependency screen in HAP1 and RPE1 cells (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint with limited gene-specific mechanistic detail\",\n        \"Identity and pathway of the SLiM partner not detailed in available evidence\",\n        \"Link between the SLiM and the established replication/immune functions unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANKRD17's distinct nuclear replication, cytoplasmic immune-scaffolding, and transcriptional-cofactor activities are integrated within one protein — and which underlies its developmental and neurodevelopmental requirements — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model defining how ankyrin repeats and the central SLiM-bearing region partition functions\",\n        \"No unifying mechanism connecting replication, immune, Hippo, and EMT roles\",\n        \"Tissue-specific partner usage not mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [\n          0,\n          3,\n          4\n        ]\n      },\n      {\n        \"term_id\": \"GO:0140110\",\n        \"supporting_discovery_ids\": [\n          7\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [\n          1,\n          6\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-69306\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1640170\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [\n          3,\n          4\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [\n          7\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CCNE1\",\n      \"CDK2\",\n      \"PCNA\",\n      \"CDC6\",\n      \"RIGI\",\n      \"IFIH1\",\n      \"MAVS\",\n      \"NOD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}