{"gene":"ANKHD1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2013,"finding":"Drosophila Mask (ANKHD1 ortholog) forms a complex with Yorkie (Yki) and its binding partner Scalloped (Sd) on target-gene promoters and is essential for Yki to drive transcription of target genes and tissue growth; the human homolog ANKHD1 (MASK1) complexes with YAP and is required for full YAP activity.","method":"Genome-wide RNAi screen in Drosophila S2 cells, co-immunoprecipitation, in vivo Drosophila genetics, human cell complementation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — two independent papers replicated in same year using RNAi screen, Co-IP, and in vivo validation; human ortholog function confirmed","pmids":["23333314","23333315"],"is_preprint":false},{"year":2006,"finding":"ANKHD1 protein is detected in the cytosolic and membrane fraction of cells and co-immunoprecipitates with SHP2 in K562 and LNCaP cell lines, suggesting a role as a scaffolding protein.","method":"Subcellular fractionation, co-immunoprecipitation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, Co-IP evidence with partial functional follow-up","pmids":["16956752"],"is_preprint":false},{"year":2014,"finding":"ANKHD1 silencing in prostate cancer cells decreases YAP1 expression and activation, reduces CCNA2 (Cyclin A) expression, delays cell cycle progression at S phase, and suppresses tumor xenograft growth, identifying ANKHD1 as a positive regulator of YAP1 in the Hippo pathway.","method":"shRNA knockdown, flow cytometry, xenograft mouse model, Western blot","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular and in vivo phenotype, pathway placement established","pmids":["24726915"],"is_preprint":false},{"year":2012,"finding":"ANKHD1 is highly expressed in multiple myeloma cells; lentiviral shRNA-mediated ANKHD1 silencing inhibits proliferation, delays S-to-G2M cell cycle progression, and upregulates the CDK inhibitor p21 regardless of p53 status.","method":"Lentiviral shRNA knockdown, flow cytometry, Western blot","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cell cycle phenotype and molecular readout","pmids":["23142581"],"is_preprint":false},{"year":2014,"finding":"ANKHD1 interacts with SIVA (pro-apoptotic protein) via co-immunoprecipitation; ANKHD1 silencing leads to Stathmin 1 inactivation, reduced cell migration and xenograft tumor growth, likely by inhibiting the SIVA/Stathmin 1 association, while ANKHD1 promotes leukemia cell proliferation and migration through the Stathmin 1 pathway.","method":"Yeast two-hybrid screen, co-immunoprecipitation, lentiviral shRNA knockdown, xenograft mouse model","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — interaction identified by two methods; functional consequence demonstrated in vitro and in vivo","pmids":["25523139"],"is_preprint":false},{"year":2014,"finding":"ANKHD1 directly represses the p21 promoter (confirmed by ChIP and luciferase assay) and co-immunoprecipitates with p21 in multiple myeloma cells; ANKHD1 shuttles between cytoplasm and nucleus (nuclear accumulation upon Leptomycin B treatment).","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase reporter assay, confocal microscopy with Leptomycin B treatment","journal":"European journal of cancer (Oxford, England : 1990)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, CoIP, luciferase, live-cell imaging) in single study","pmids":["25483783"],"is_preprint":false},{"year":2005,"finding":"A splice variant of ANKHD1 lacking the KH domain (VBARP) is primarily localized in the cytoplasm; siRNA knockdown demonstrates it is essential for cell survival through regulation of caspases, indicating an anti-apoptotic function.","method":"siRNA knockdown, subcellular fractionation, caspase assays, immunofluorescence","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — localization and function established by direct experiment with molecular readout","pmids":["16098192"],"is_preprint":false},{"year":2018,"finding":"ANKHD1 binds to tumor-suppressing miRNAs (miR-29a, miR-205, miR-196a) via its KH domain (confirmed by RNA-immunoprecipitation); ANKHD1 suppresses these miRNAs to drive renal cell carcinoma proliferation by upregulating CCND1.","method":"RNA-immunoprecipitation, bioinformatics, siRNA knockdown, cell cycle analysis, quantitative PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by RIP; functional consequence established by KD","pmids":["29695508"],"is_preprint":false},{"year":2019,"finding":"The ankyrin repeat domain (ARD) of ANKHD1 dimerizes; the first 15 ankyrin repeats mediate dimerization and the latter 10 ankyrin repeats deform membranes into tubules and vesicles via an adjacent amphipathic helix and curved positively-charged surface analogous to BAR domains. ANKHD1 knockdown revealed its role in negative regulation of early endosome enlargement.","method":"In vitro membrane deformation assay, structural/domain analysis, co-immunoprecipitation for dimerization, ANKHD1 knockdown with endosome imaging","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 — reconstituted membrane deformation in vitro; domain-deletion analysis; functional knockdown validation","pmids":["31255983"],"is_preprint":false},{"year":2018,"finding":"Drosophila MASK (ANKHD1 ortholog) is identified as a positive regulator of Domeless (cytokine receptor) dimerization and protein levels in a genome-wide RNAi screen; human ANKHD1 similarly regulates JAK/STAT signaling and levels of a subset of cytokine receptors in human cells.","method":"Genome-wide RNAi screen, JAK/STAT reporter assay, receptor dimerization assay, ANKHD1 knockdown in human cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — unbiased genome-wide screen followed by mechanistic validation in both fly and human cells","pmids":["29848658"],"is_preprint":false},{"year":2017,"finding":"In Drosophila, Mask (ANKHD1 ortholog) is directly targeted by miR-285 to suppress Yorkie (Yki) activity and downregulate cyclin E expression in subperineurial glia; this miR-285–Yki/Mask double-negative feedback loop maintains appropriate subperineurial glia ploidy and blood-brain barrier integrity.","method":"Luciferase reporter assay for miR-285 targeting of Mask, genetic epistasis, loss-of-function and gain-of-function in Drosophila, cyclin E expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo methods, epistasis, direct miRNA-target validation","pmids":["28265104"],"is_preprint":false},{"year":2017,"finding":"Mask (ANKHD1 ortholog) promotes autophagy flux by enhancing lysosomal function and is necessary and sufficient for promoting expression of vacuolar (V)-type ATPases in a TFEB-independent manner; loss of Mask function worsens, and gain of Mask function mitigates, degeneration caused by MAPT/TAU or FUS protein aggregation in Drosophila models.","method":"Drosophila eye and muscle models (loss- and gain-of-function genetics), autophagy flux assays, lysosome acidification assays, V-ATPase expression analysis, epistasis with autophagy pathway mutants","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo methods with genetic epistasis, specific molecular mechanism identified","pmids":["28806139"],"is_preprint":false},{"year":2015,"finding":"Loss of Mask (ANKHD1 ortholog) function rescues mitochondrial and behavioral defects in Drosophila pink1 and parkin mutants; Mask genetically interacts with Parkin to modulate mitochondrial morphology and negatively regulates Parkin recruitment to mitochondria; an intact autophagy pathway is required for this rescue.","method":"Drosophila genetics (loss-of-function mask in pink1/parkin mutant backgrounds), mitochondrial morphology imaging, Parkin recruitment assay, autophagosome co-localization, epistasis with autophagy mutants","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple pathway mutants, direct localization experiment, strong mechanistic resolution","pmids":["25743185"],"is_preprint":false},{"year":2021,"finding":"Mask (ANKHD1 ortholog) negatively affects microtubule (MT) stability in Drosophila larval muscles and motor neurons; the ankyrin repeat-containing N-terminal domain is sufficient for this effect; Mask negatively regulates the MT-associated protein Jupiter in motor neuron axons; mask genetically interacts with stathmin in regulation of axon transport and synaptic terminal stability.","method":"Drosophila loss-of-function genetics, MT polymer length measurement, neuromuscular junction imaging, structure-function domain deletion analysis, genetic epistasis with stathmin and Jupiter","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — domain dissection, genetic epistasis, direct cellular phenotype imaging in multiple tissues","pmids":["34553767"],"is_preprint":false},{"year":2018,"finding":"ANKHD1 silencing in colorectal cancer cells reduces YAP1 expression and increases YAP1 phosphorylation, inhibits AKT signaling, and suppresses EMT markers (MMP2, MMP9, vimentin, Snail, ZEB1) while increasing E-cadherin; YAP1 overexpression reverses ANKHD1 knockdown effects, placing ANKHD1 upstream of YAP1/AKT/EMT.","method":"shRNA knockdown, YAP1 rescue overexpression, Western blot, in vitro migration/invasion assays, in vivo xenograft","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis by rescue experiment; multiple molecular readouts","pmids":["30555746"],"is_preprint":false},{"year":2021,"finding":"SMYD3 promotes cisplatin resistance in NSCLC in an ANKHD1-dependent manner; SMYD3 and ANKHD1 physically interact (co-immunoprecipitation and co-localization by immunofluorescence); SMYD3 transcriptionally regulates CDK2 via its promoter (ChIP); ANKHD1 overexpression abolishes the sensitizing effect of SMYD3 knockdown in vivo.","method":"Co-immunoprecipitation, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), shRNA knockdown, xenograft mouse model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by two methods; in vivo epistasis demonstrated","pmids":["33773404"],"is_preprint":false},{"year":2020,"finding":"ANKHD1 targets lncRNA LINC00346 and enhances its stability; LINC00346 binds ZNF655 mRNA via Alu elements and facilitates its degradation via STAU1-mediated mRNA decay; ZNF655 targets the ANKHD1 promoter, forming a feedback loop that regulates glioma angiogenesis.","method":"RIP (RNA immunoprecipitation), RNA pulldown, reporter assay, ChIP, shRNA knockdown, in vivo angiogenesis assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods establishing mechanistic loop","pmids":["32464549"],"is_preprint":false},{"year":2022,"finding":"ANKHD1 and lncRNA MALAT1 interact (confirmed by RIP and RNA pulldown); ANKHD1/MALAT1/YAP1 form a feedback loop that promotes YAP1 transcriptional coactivation and enhances radioresistance of colorectal cancer via the YAP1/AKT axis.","method":"RNA immunoprecipitation (RIP), RNA pulldown, shRNA knockdown, in vitro and in vivo irradiation assays, Western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by two biochemical methods; functional consequence established in vitro and in vivo","pmids":["35110552"],"is_preprint":false},{"year":2020,"finding":"Mask (ANKHD1 ortholog) is required for correct distribution and accumulation of adherens junctions and appropriate cytoskeletal organization during Drosophila pupal eye morphogenesis; RNA-sequencing revealed Mask regulates expression of cell adhesion, cytoskeletal, cell survival, and signal transduction genes; FER and Vinc are validated downstream targets.","method":"Drosophila loss-of-function genetics, RNA-sequencing, confocal imaging of adherens junctions and cytoskeleton, genetic epistasis with Hippo pathway and downstream targets","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptome plus validated targets with genetic epistasis","pmids":["32464117"],"is_preprint":false}],"current_model":"ANKHD1 is a large scaffolding protein with ankyrin repeat domains (mediating protein–protein interactions and membrane deformation via BAR domain-like activity) and a KH domain (mediating miRNA/RNA binding); it acts as a cofactor for YAP/Yki in the Hippo pathway by forming complexes on target-gene promoters, regulates JAK/STAT signaling by stabilizing cytokine receptor levels, interacts with SHP2, SIVA, SMYD3, and MALAT1, suppresses p21 transcription, modulates microtubule stability and endosomal trafficking, promotes autophagy through lysosomal V-ATPase upregulation, and negatively regulates Parkin recruitment to mitochondria, collectively driving cell proliferation, survival, and cancer progression."},"narrative":{"teleology":[{"year":2005,"claim":"The initial characterization of a cytoplasmic ANKHD1 splice variant (VBARP) established that the gene product has an anti-apoptotic function mediated through caspase regulation, providing the first functional link to cell survival.","evidence":"siRNA knockdown with caspase assays and subcellular fractionation in human cells","pmids":["16098192"],"confidence":"Medium","gaps":["Only a splice variant studied; full-length ANKHD1 function not addressed","Mechanism of caspase regulation not defined"]},{"year":2006,"claim":"Detection of ANKHD1 in cytosolic and membrane fractions and its co-immunoprecipitation with the phosphatase SHP2 suggested a scaffolding role, opening the question of which signaling pathways ANKHD1 organizes.","evidence":"Subcellular fractionation and co-immunoprecipitation in K562 and LNCaP cells","pmids":["16956752"],"confidence":"Medium","gaps":["SHP2 interaction not validated by reciprocal pull-down or in vivo methods","Functional consequence of ANKHD1–SHP2 interaction not demonstrated"]},{"year":2012,"claim":"ANKHD1 knockdown in multiple myeloma cells revealed its requirement for proliferation and S-to-G2/M progression, with p21 upregulation as a key downstream event independent of p53, establishing ANKHD1 as a cell-cycle regulator.","evidence":"Lentiviral shRNA knockdown, flow cytometry, Western blot in multiple myeloma lines","pmids":["23142581"],"confidence":"Medium","gaps":["Mechanism of p21 regulation (direct vs. indirect) not yet resolved","Limited to myeloma cell lines"]},{"year":2013,"claim":"Two independent studies demonstrated that Drosophila Mask/human ANKHD1 complexes with Yki/YAP on target-gene promoters and is essential for Yki/YAP transcriptional activity and tissue growth, definitively placing ANKHD1 as a Hippo pathway cofactor.","evidence":"Genome-wide RNAi screens in Drosophila, co-immunoprecipitation, in vivo Drosophila genetics, human cell complementation","pmids":["23333314","23333315"],"confidence":"High","gaps":["Structural basis of ANKHD1–YAP interaction not resolved","Whether ANKHD1 contributes YAP-independent transcriptional activity unclear"]},{"year":2014,"claim":"Three studies extended ANKHD1 function: it directly represses the p21 promoter (ChIP-validated), interacts with the pro-apoptotic protein SIVA to regulate Stathmin 1 and migration, and its knockdown in prostate cancer reduces YAP1 expression and xenograft growth, solidifying its oncogenic role across cancer types.","evidence":"ChIP, luciferase reporter, co-IP, yeast two-hybrid, shRNA knockdown, xenograft models in myeloma, leukemia, and prostate cancer cells","pmids":["25483783","25523139","24726915"],"confidence":"Medium","gaps":["Whether p21 repression is YAP-dependent or a parallel mechanism unclear","SIVA interaction domain on ANKHD1 not mapped"]},{"year":2015,"claim":"Genetic studies in Drosophila showed that loss of Mask rescues pink1/parkin mutant phenotypes and that Mask negatively regulates Parkin recruitment to mitochondria in an autophagy-dependent manner, linking ANKHD1 to mitophagy regulation.","evidence":"Drosophila loss-of-function genetics in pink1/parkin backgrounds, mitochondrial morphology imaging, Parkin recruitment and autophagosome co-localization assays","pmids":["25743185"],"confidence":"High","gaps":["Mechanism by which Mask inhibits Parkin recruitment not molecularly defined","Not confirmed in mammalian systems"]},{"year":2017,"claim":"Two discoveries revealed that Mask promotes autophagy by upregulating V-ATPase expression (TFEB-independent) to enhance lysosomal function, and that Mask is itself a target of miR-285 in a double-negative feedback loop controlling Yki activity in glia, demonstrating tissue-specific regulation of and by ANKHD1.","evidence":"Drosophila gain/loss-of-function genetics, autophagy flux and lysosome acidification assays, luciferase reporter for miR-285 targeting, genetic epistasis","pmids":["28806139","28265104"],"confidence":"High","gaps":["Transcription factor mediating Mask-dependent V-ATPase expression unknown","Whether the miR-285–Mask loop is conserved in mammals not tested"]},{"year":2018,"claim":"ANKHD1's KH domain was shown to bind tumor-suppressive miRNAs (miR-29a, miR-205, miR-196a), suppressing their function to upregulate Cyclin D1 in renal carcinoma; separately, ANKHD1 was identified as a positive regulator of JAK/STAT signaling by stabilizing cytokine receptor levels in both Drosophila and human cells.","evidence":"RNA-immunoprecipitation for miRNA binding, genome-wide RNAi screen for JAK/STAT, receptor dimerization and level assays, knockdown in human cells","pmids":["29695508","29848658","30555746"],"confidence":"High","gaps":["Specificity of KH domain for particular miRNAs vs. broader RNA targets not fully defined","Whether JAK/STAT regulation occurs through membrane-shaping activity or a distinct mechanism unclear"]},{"year":2019,"claim":"Reconstitution experiments demonstrated that the ANKHD1 ankyrin repeat domain dimerizes and its C-terminal repeats deform membranes into tubules via an amphipathic helix and curved surface analogous to BAR domains, establishing ANKHD1 as a membrane-shaping protein that restricts early endosome size.","evidence":"In vitro membrane deformation assay, domain-deletion structural analysis, ANKHD1 knockdown with endosome imaging","pmids":["31255983"],"confidence":"High","gaps":["No high-resolution structure of the ARD in the membrane-bound state","Cargo specificity of ANKHD1-mediated endosomal trafficking unknown"]},{"year":2020,"claim":"ANKHD1 was found to regulate lncRNA LINC00346 stability and to participate in STAU1-mediated mRNA decay of ZNF655 in a feedback loop promoting glioma angiogenesis, and separately to control adherens junction distribution and cytoskeletal gene expression during Drosophila eye morphogenesis.","evidence":"RIP, RNA pulldown, ChIP, shRNA knockdown, in vivo angiogenesis assays; Drosophila genetics, RNA-seq, confocal imaging","pmids":["32464549","32464117"],"confidence":"Medium","gaps":["LINC00346 findings from single study, not independently replicated","Whether morphogenetic roles require membrane-deforming activity not tested"]},{"year":2021,"claim":"The ANKHD1 N-terminal ankyrin repeats were shown to negatively regulate microtubule stability and the MT-associated protein Jupiter in Drosophila neurons and muscles, with genetic interaction with Stathmin; separately, SMYD3 was found to promote cisplatin resistance through physical interaction with ANKHD1.","evidence":"Drosophila domain-deletion genetics, MT polymer measurements, NMJ imaging; co-IP and co-localization in NSCLC cells, xenograft epistasis","pmids":["34553767","33773404"],"confidence":"Medium","gaps":["Direct biochemical mechanism of MT destabilization by ANKHD1 not established","SMYD3–ANKHD1 interface and whether SMYD3 methylates ANKHD1 unknown"]},{"year":2022,"claim":"ANKHD1 was shown to bind lncRNA MALAT1 and form a feedback loop with YAP1 that enhances YAP1 transcriptional coactivation and radioresistance in colorectal cancer via the YAP1/AKT axis, adding RNA-scaffolded amplification to its Hippo pathway cofactor role.","evidence":"RIP, RNA pulldown, shRNA knockdown, in vitro and in vivo irradiation assays in colorectal cancer models","pmids":["35110552"],"confidence":"Medium","gaps":["Structural basis of MALAT1–ANKHD1 interaction not defined","Whether MALAT1 binding is KH-domain-dependent not tested"]},{"year":null,"claim":"Major unresolved questions include: the structural basis for ANKHD1's selective engagement with YAP versus other partners, whether the membrane-deforming and transcriptional cofactor functions are coordinated or independent, the identity of direct substrates or targets of ANKHD1's RNA-binding KH domain genome-wide, and whether the mitophagy and V-ATPase regulatory functions observed in Drosophila are conserved in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length ANKHD1 or its domain complexes","Genome-wide RNA target profiling (CLIP-seq) not performed","Mammalian validation of autophagy/mitophagy functions lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,16,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,0,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,9,10,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,2,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8]}],"complexes":[],"partners":["YAP1","SHP2","SIVA1","SMYD3","MALAT1","STMN1"],"other_free_text":[]},"mechanistic_narrative":"ANKHD1 is a large, multi-domain scaffolding protein that functions as a transcriptional cofactor in the Hippo/YAP pathway, a membrane-deforming regulator of endosomal trafficking, and an RNA-binding modulator of gene expression, collectively promoting cell proliferation and survival. Its ankyrin repeat domain dimerizes and deforms membranes via a BAR domain-like mechanism to regulate early endosome size, while also modulating microtubule stability and adherens junction organization [PMID:31255983, PMID:34553767, PMID:32464117]. ANKHD1 complexes with YAP/Yki on target-gene promoters to drive transcription of cell-cycle genes, directly represses the p21 promoter, and binds tumor-suppressive miRNAs and the lncRNA MALAT1 through its KH domain to further amplify proliferative signaling [PMID:23333314, PMID:25483783, PMID:29695508, PMID:35110552]. Additionally, ANKHD1 positively regulates JAK/STAT signaling by stabilizing cytokine receptor levels, promotes autophagy through V-ATPase upregulation, and negatively regulates Parkin recruitment to mitochondria [PMID:29848658, PMID:28806139, PMID:25743185]."},"prefetch_data":{"uniprot":{"accession":"Q8IWZ3","full_name":"Ankyrin repeat and KH domain-containing protein 1","aliases":["HIV-1 Vpr-binding ankyrin repeat protein","Multiple ankyrin repeats single KH domain","hMASK"],"length_aa":2542,"mass_kda":269.5,"function":"May play a role as a scaffolding protein that may be associated with the abnormal phenotype of leukemia cells. Isoform 2 may possess an antiapoptotic effect and protect cells during normal cell survival through its regulation of caspases","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8IWZ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKHD1","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD17","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"PHAX","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANKHD1","total_profiled":1310},"omim":[{"mim_id":"610500","title":"ANKYRIN REPEAT AND KH DOMAIN-CONTAINING PROTEIN 1; ANKHD1","url":"https://www.omim.org/entry/610500"},{"mim_id":"603483","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4E-BINDING PROTEIN 3; EIF4EBP3","url":"https://www.omim.org/entry/603483"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANKHD1"},"hgnc":{"alias_symbol":["MASK","FLJ20288","FLJ11979","FLJ10042","FLJ14127","KIAA1085","MASK1"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWZ3","domains":[{"cath_id":"1.25.40.20","chopping":"432-531","consensus_level":"medium","plddt":88.9074,"start":432,"end":531},{"cath_id":"1.25.40.20","chopping":"1317-1450","consensus_level":"medium","plddt":88.662,"start":1317,"end":1450},{"cath_id":"3.30.1370.10","chopping":"1696-1777","consensus_level":"medium","plddt":77.0473,"start":1696,"end":1777}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWZ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWZ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWZ3-F1-predicted_aligned_error_v6.png","plddt_mean":54.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKHD1","jax_strain_url":"https://www.jax.org/strain/search?query=ANKHD1"},"sequence":{"accession":"Q8IWZ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWZ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWZ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWZ3"}},"corpus_meta":[{"pmid":"16796549","id":"PMC_16796549","title":"A fast and symmetric DUST implementation to mask low-complexity DNA sequences.","date":"2006","source":"Journal of computational biology : a journal of computational molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16796549","citation_count":356,"is_preprint":false},{"pmid":"12112190","id":"PMC_12112190","title":"Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson's disease.","date":"2002","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/12112190","citation_count":150,"is_preprint":false},{"pmid":"26148220","id":"PMC_26148220","title":"MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation.","date":"2015","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/26148220","citation_count":135,"is_preprint":false},{"pmid":"20133393","id":"PMC_20133393","title":"Extracellular water may mask actual muscle atrophy during aging.","date":"2010","source":"The journals of gerontology. 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pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26245688","citation_count":8,"is_preprint":false},{"pmid":"25825568","id":"PMC_25825568","title":"Cobalamin deficiency can mask depleted body iron reserves.","date":"2014","source":"Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/25825568","citation_count":8,"is_preprint":false},{"pmid":"38798080","id":"PMC_38798080","title":"Whispers in the Wind: Face Mask Sampling for Mycobacterium tuberculosis Detection in Children With Pulmonary Tuberculosis.","date":"2024","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38798080","citation_count":8,"is_preprint":false},{"pmid":"34891823","id":"PMC_34891823","title":"Enhanced Rotated Mask R-CNN for Chromosome Segmentation.","date":"2021","source":"Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference","url":"https://pubmed.ncbi.nlm.nih.gov/34891823","citation_count":7,"is_preprint":false},{"pmid":"38742980","id":"PMC_38742980","title":"Multifunctional FFP2 Face Mask for White Light Disinfection and Pathogens Detection using Hybrid Nanostructures and Optical Metasurfaces.","date":"2024","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38742980","citation_count":7,"is_preprint":false},{"pmid":"38776728","id":"PMC_38776728","title":"KaryoXpert: An accurate chromosome segmentation and classification framework for karyotyping analysis without training with manually labeled metaphase-image mask annotations.","date":"2024","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38776728","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46893,"output_tokens":4467,"usd":0.103842},"stage2":{"model":"claude-opus-4-6","input_tokens":7945,"output_tokens":3451,"usd":0.189},"total_usd":0.292842,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Mask (ANKHD1 ortholog) forms a complex with Yorkie (Yki) and its binding partner Scalloped (Sd) on target-gene promoters and is essential for Yki to drive transcription of target genes and tissue growth; the human homolog ANKHD1 (MASK1) complexes with YAP and is required for full YAP activity.\",\n      \"method\": \"Genome-wide RNAi screen in Drosophila S2 cells, co-immunoprecipitation, in vivo Drosophila genetics, human cell complementation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent papers replicated in same year using RNAi screen, Co-IP, and in vivo validation; human ortholog function confirmed\",\n      \"pmids\": [\"23333314\", \"23333315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ANKHD1 protein is detected in the cytosolic and membrane fraction of cells and co-immunoprecipitates with SHP2 in K562 and LNCaP cell lines, suggesting a role as a scaffolding protein.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP evidence with partial functional follow-up\",\n      \"pmids\": [\"16956752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANKHD1 silencing in prostate cancer cells decreases YAP1 expression and activation, reduces CCNA2 (Cyclin A) expression, delays cell cycle progression at S phase, and suppresses tumor xenograft growth, identifying ANKHD1 as a positive regulator of YAP1 in the Hippo pathway.\",\n      \"method\": \"shRNA knockdown, flow cytometry, xenograft mouse model, Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular and in vivo phenotype, pathway placement established\",\n      \"pmids\": [\"24726915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ANKHD1 is highly expressed in multiple myeloma cells; lentiviral shRNA-mediated ANKHD1 silencing inhibits proliferation, delays S-to-G2M cell cycle progression, and upregulates the CDK inhibitor p21 regardless of p53 status.\",\n      \"method\": \"Lentiviral shRNA knockdown, flow cytometry, Western blot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cell cycle phenotype and molecular readout\",\n      \"pmids\": [\"23142581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANKHD1 interacts with SIVA (pro-apoptotic protein) via co-immunoprecipitation; ANKHD1 silencing leads to Stathmin 1 inactivation, reduced cell migration and xenograft tumor growth, likely by inhibiting the SIVA/Stathmin 1 association, while ANKHD1 promotes leukemia cell proliferation and migration through the Stathmin 1 pathway.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, lentiviral shRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction identified by two methods; functional consequence demonstrated in vitro and in vivo\",\n      \"pmids\": [\"25523139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANKHD1 directly represses the p21 promoter (confirmed by ChIP and luciferase assay) and co-immunoprecipitates with p21 in multiple myeloma cells; ANKHD1 shuttles between cytoplasm and nucleus (nuclear accumulation upon Leptomycin B treatment).\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase reporter assay, confocal microscopy with Leptomycin B treatment\",\n      \"journal\": \"European journal of cancer (Oxford, England : 1990)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, CoIP, luciferase, live-cell imaging) in single study\",\n      \"pmids\": [\"25483783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A splice variant of ANKHD1 lacking the KH domain (VBARP) is primarily localized in the cytoplasm; siRNA knockdown demonstrates it is essential for cell survival through regulation of caspases, indicating an anti-apoptotic function.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, caspase assays, immunofluorescence\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — localization and function established by direct experiment with molecular readout\",\n      \"pmids\": [\"16098192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANKHD1 binds to tumor-suppressing miRNAs (miR-29a, miR-205, miR-196a) via its KH domain (confirmed by RNA-immunoprecipitation); ANKHD1 suppresses these miRNAs to drive renal cell carcinoma proliferation by upregulating CCND1.\",\n      \"method\": \"RNA-immunoprecipitation, bioinformatics, siRNA knockdown, cell cycle analysis, quantitative PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by RIP; functional consequence established by KD\",\n      \"pmids\": [\"29695508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ankyrin repeat domain (ARD) of ANKHD1 dimerizes; the first 15 ankyrin repeats mediate dimerization and the latter 10 ankyrin repeats deform membranes into tubules and vesicles via an adjacent amphipathic helix and curved positively-charged surface analogous to BAR domains. ANKHD1 knockdown revealed its role in negative regulation of early endosome enlargement.\",\n      \"method\": \"In vitro membrane deformation assay, structural/domain analysis, co-immunoprecipitation for dimerization, ANKHD1 knockdown with endosome imaging\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted membrane deformation in vitro; domain-deletion analysis; functional knockdown validation\",\n      \"pmids\": [\"31255983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila MASK (ANKHD1 ortholog) is identified as a positive regulator of Domeless (cytokine receptor) dimerization and protein levels in a genome-wide RNAi screen; human ANKHD1 similarly regulates JAK/STAT signaling and levels of a subset of cytokine receptors in human cells.\",\n      \"method\": \"Genome-wide RNAi screen, JAK/STAT reporter assay, receptor dimerization assay, ANKHD1 knockdown in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide screen followed by mechanistic validation in both fly and human cells\",\n      \"pmids\": [\"29848658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila, Mask (ANKHD1 ortholog) is directly targeted by miR-285 to suppress Yorkie (Yki) activity and downregulate cyclin E expression in subperineurial glia; this miR-285–Yki/Mask double-negative feedback loop maintains appropriate subperineurial glia ploidy and blood-brain barrier integrity.\",\n      \"method\": \"Luciferase reporter assay for miR-285 targeting of Mask, genetic epistasis, loss-of-function and gain-of-function in Drosophila, cyclin E expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo methods, epistasis, direct miRNA-target validation\",\n      \"pmids\": [\"28265104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mask (ANKHD1 ortholog) promotes autophagy flux by enhancing lysosomal function and is necessary and sufficient for promoting expression of vacuolar (V)-type ATPases in a TFEB-independent manner; loss of Mask function worsens, and gain of Mask function mitigates, degeneration caused by MAPT/TAU or FUS protein aggregation in Drosophila models.\",\n      \"method\": \"Drosophila eye and muscle models (loss- and gain-of-function genetics), autophagy flux assays, lysosome acidification assays, V-ATPase expression analysis, epistasis with autophagy pathway mutants\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo methods with genetic epistasis, specific molecular mechanism identified\",\n      \"pmids\": [\"28806139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Mask (ANKHD1 ortholog) function rescues mitochondrial and behavioral defects in Drosophila pink1 and parkin mutants; Mask genetically interacts with Parkin to modulate mitochondrial morphology and negatively regulates Parkin recruitment to mitochondria; an intact autophagy pathway is required for this rescue.\",\n      \"method\": \"Drosophila genetics (loss-of-function mask in pink1/parkin mutant backgrounds), mitochondrial morphology imaging, Parkin recruitment assay, autophagosome co-localization, epistasis with autophagy mutants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple pathway mutants, direct localization experiment, strong mechanistic resolution\",\n      \"pmids\": [\"25743185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mask (ANKHD1 ortholog) negatively affects microtubule (MT) stability in Drosophila larval muscles and motor neurons; the ankyrin repeat-containing N-terminal domain is sufficient for this effect; Mask negatively regulates the MT-associated protein Jupiter in motor neuron axons; mask genetically interacts with stathmin in regulation of axon transport and synaptic terminal stability.\",\n      \"method\": \"Drosophila loss-of-function genetics, MT polymer length measurement, neuromuscular junction imaging, structure-function domain deletion analysis, genetic epistasis with stathmin and Jupiter\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain dissection, genetic epistasis, direct cellular phenotype imaging in multiple tissues\",\n      \"pmids\": [\"34553767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANKHD1 silencing in colorectal cancer cells reduces YAP1 expression and increases YAP1 phosphorylation, inhibits AKT signaling, and suppresses EMT markers (MMP2, MMP9, vimentin, Snail, ZEB1) while increasing E-cadherin; YAP1 overexpression reverses ANKHD1 knockdown effects, placing ANKHD1 upstream of YAP1/AKT/EMT.\",\n      \"method\": \"shRNA knockdown, YAP1 rescue overexpression, Western blot, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis by rescue experiment; multiple molecular readouts\",\n      \"pmids\": [\"30555746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMYD3 promotes cisplatin resistance in NSCLC in an ANKHD1-dependent manner; SMYD3 and ANKHD1 physically interact (co-immunoprecipitation and co-localization by immunofluorescence); SMYD3 transcriptionally regulates CDK2 via its promoter (ChIP); ANKHD1 overexpression abolishes the sensitizing effect of SMYD3 knockdown in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), shRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by two methods; in vivo epistasis demonstrated\",\n      \"pmids\": [\"33773404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANKHD1 targets lncRNA LINC00346 and enhances its stability; LINC00346 binds ZNF655 mRNA via Alu elements and facilitates its degradation via STAU1-mediated mRNA decay; ZNF655 targets the ANKHD1 promoter, forming a feedback loop that regulates glioma angiogenesis.\",\n      \"method\": \"RIP (RNA immunoprecipitation), RNA pulldown, reporter assay, ChIP, shRNA knockdown, in vivo angiogenesis assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods establishing mechanistic loop\",\n      \"pmids\": [\"32464549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANKHD1 and lncRNA MALAT1 interact (confirmed by RIP and RNA pulldown); ANKHD1/MALAT1/YAP1 form a feedback loop that promotes YAP1 transcriptional coactivation and enhances radioresistance of colorectal cancer via the YAP1/AKT axis.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pulldown, shRNA knockdown, in vitro and in vivo irradiation assays, Western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by two biochemical methods; functional consequence established in vitro and in vivo\",\n      \"pmids\": [\"35110552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mask (ANKHD1 ortholog) is required for correct distribution and accumulation of adherens junctions and appropriate cytoskeletal organization during Drosophila pupal eye morphogenesis; RNA-sequencing revealed Mask regulates expression of cell adhesion, cytoskeletal, cell survival, and signal transduction genes; FER and Vinc are validated downstream targets.\",\n      \"method\": \"Drosophila loss-of-function genetics, RNA-sequencing, confocal imaging of adherens junctions and cytoskeleton, genetic epistasis with Hippo pathway and downstream targets\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome plus validated targets with genetic epistasis\",\n      \"pmids\": [\"32464117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKHD1 is a large scaffolding protein with ankyrin repeat domains (mediating protein–protein interactions and membrane deformation via BAR domain-like activity) and a KH domain (mediating miRNA/RNA binding); it acts as a cofactor for YAP/Yki in the Hippo pathway by forming complexes on target-gene promoters, regulates JAK/STAT signaling by stabilizing cytokine receptor levels, interacts with SHP2, SIVA, SMYD3, and MALAT1, suppresses p21 transcription, modulates microtubule stability and endosomal trafficking, promotes autophagy through lysosomal V-ATPase upregulation, and negatively regulates Parkin recruitment to mitochondria, collectively driving cell proliferation, survival, and cancer progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANKHD1 is a large, multi-domain scaffolding protein that functions as a transcriptional cofactor in the Hippo/YAP pathway, a membrane-deforming regulator of endosomal trafficking, and an RNA-binding modulator of gene expression, collectively promoting cell proliferation and survival. Its ankyrin repeat domain dimerizes and deforms membranes via a BAR domain-like mechanism to regulate early endosome size, while also modulating microtubule stability and adherens junction organization [PMID:31255983, PMID:34553767, PMID:32464117]. ANKHD1 complexes with YAP/Yki on target-gene promoters to drive transcription of cell-cycle genes, directly represses the p21 promoter, and binds tumor-suppressive miRNAs and the lncRNA MALAT1 through its KH domain to further amplify proliferative signaling [PMID:23333314, PMID:25483783, PMID:29695508, PMID:35110552]. Additionally, ANKHD1 positively regulates JAK/STAT signaling by stabilizing cytokine receptor levels, promotes autophagy through V-ATPase upregulation, and negatively regulates Parkin recruitment to mitochondria [PMID:29848658, PMID:28806139, PMID:25743185].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The initial characterization of a cytoplasmic ANKHD1 splice variant (VBARP) established that the gene product has an anti-apoptotic function mediated through caspase regulation, providing the first functional link to cell survival.\",\n      \"evidence\": \"siRNA knockdown with caspase assays and subcellular fractionation in human cells\",\n      \"pmids\": [\"16098192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only a splice variant studied; full-length ANKHD1 function not addressed\", \"Mechanism of caspase regulation not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Detection of ANKHD1 in cytosolic and membrane fractions and its co-immunoprecipitation with the phosphatase SHP2 suggested a scaffolding role, opening the question of which signaling pathways ANKHD1 organizes.\",\n      \"evidence\": \"Subcellular fractionation and co-immunoprecipitation in K562 and LNCaP cells\",\n      \"pmids\": [\"16956752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SHP2 interaction not validated by reciprocal pull-down or in vivo methods\", \"Functional consequence of ANKHD1–SHP2 interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ANKHD1 knockdown in multiple myeloma cells revealed its requirement for proliferation and S-to-G2/M progression, with p21 upregulation as a key downstream event independent of p53, establishing ANKHD1 as a cell-cycle regulator.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, flow cytometry, Western blot in multiple myeloma lines\",\n      \"pmids\": [\"23142581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p21 regulation (direct vs. indirect) not yet resolved\", \"Limited to myeloma cell lines\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two independent studies demonstrated that Drosophila Mask/human ANKHD1 complexes with Yki/YAP on target-gene promoters and is essential for Yki/YAP transcriptional activity and tissue growth, definitively placing ANKHD1 as a Hippo pathway cofactor.\",\n      \"evidence\": \"Genome-wide RNAi screens in Drosophila, co-immunoprecipitation, in vivo Drosophila genetics, human cell complementation\",\n      \"pmids\": [\"23333314\", \"23333315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ANKHD1–YAP interaction not resolved\", \"Whether ANKHD1 contributes YAP-independent transcriptional activity unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Three studies extended ANKHD1 function: it directly represses the p21 promoter (ChIP-validated), interacts with the pro-apoptotic protein SIVA to regulate Stathmin 1 and migration, and its knockdown in prostate cancer reduces YAP1 expression and xenograft growth, solidifying its oncogenic role across cancer types.\",\n      \"evidence\": \"ChIP, luciferase reporter, co-IP, yeast two-hybrid, shRNA knockdown, xenograft models in myeloma, leukemia, and prostate cancer cells\",\n      \"pmids\": [\"25483783\", \"25523139\", \"24726915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p21 repression is YAP-dependent or a parallel mechanism unclear\", \"SIVA interaction domain on ANKHD1 not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic studies in Drosophila showed that loss of Mask rescues pink1/parkin mutant phenotypes and that Mask negatively regulates Parkin recruitment to mitochondria in an autophagy-dependent manner, linking ANKHD1 to mitophagy regulation.\",\n      \"evidence\": \"Drosophila loss-of-function genetics in pink1/parkin backgrounds, mitochondrial morphology imaging, Parkin recruitment and autophagosome co-localization assays\",\n      \"pmids\": [\"25743185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Mask inhibits Parkin recruitment not molecularly defined\", \"Not confirmed in mammalian systems\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two discoveries revealed that Mask promotes autophagy by upregulating V-ATPase expression (TFEB-independent) to enhance lysosomal function, and that Mask is itself a target of miR-285 in a double-negative feedback loop controlling Yki activity in glia, demonstrating tissue-specific regulation of and by ANKHD1.\",\n      \"evidence\": \"Drosophila gain/loss-of-function genetics, autophagy flux and lysosome acidification assays, luciferase reporter for miR-285 targeting, genetic epistasis\",\n      \"pmids\": [\"28806139\", \"28265104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor mediating Mask-dependent V-ATPase expression unknown\", \"Whether the miR-285–Mask loop is conserved in mammals not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ANKHD1's KH domain was shown to bind tumor-suppressive miRNAs (miR-29a, miR-205, miR-196a), suppressing their function to upregulate Cyclin D1 in renal carcinoma; separately, ANKHD1 was identified as a positive regulator of JAK/STAT signaling by stabilizing cytokine receptor levels in both Drosophila and human cells.\",\n      \"evidence\": \"RNA-immunoprecipitation for miRNA binding, genome-wide RNAi screen for JAK/STAT, receptor dimerization and level assays, knockdown in human cells\",\n      \"pmids\": [\"29695508\", \"29848658\", \"30555746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity of KH domain for particular miRNAs vs. broader RNA targets not fully defined\", \"Whether JAK/STAT regulation occurs through membrane-shaping activity or a distinct mechanism unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution experiments demonstrated that the ANKHD1 ankyrin repeat domain dimerizes and its C-terminal repeats deform membranes into tubules via an amphipathic helix and curved surface analogous to BAR domains, establishing ANKHD1 as a membrane-shaping protein that restricts early endosome size.\",\n      \"evidence\": \"In vitro membrane deformation assay, domain-deletion structural analysis, ANKHD1 knockdown with endosome imaging\",\n      \"pmids\": [\"31255983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the ARD in the membrane-bound state\", \"Cargo specificity of ANKHD1-mediated endosomal trafficking unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ANKHD1 was found to regulate lncRNA LINC00346 stability and to participate in STAU1-mediated mRNA decay of ZNF655 in a feedback loop promoting glioma angiogenesis, and separately to control adherens junction distribution and cytoskeletal gene expression during Drosophila eye morphogenesis.\",\n      \"evidence\": \"RIP, RNA pulldown, ChIP, shRNA knockdown, in vivo angiogenesis assays; Drosophila genetics, RNA-seq, confocal imaging\",\n      \"pmids\": [\"32464549\", \"32464117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LINC00346 findings from single study, not independently replicated\", \"Whether morphogenetic roles require membrane-deforming activity not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The ANKHD1 N-terminal ankyrin repeats were shown to negatively regulate microtubule stability and the MT-associated protein Jupiter in Drosophila neurons and muscles, with genetic interaction with Stathmin; separately, SMYD3 was found to promote cisplatin resistance through physical interaction with ANKHD1.\",\n      \"evidence\": \"Drosophila domain-deletion genetics, MT polymer measurements, NMJ imaging; co-IP and co-localization in NSCLC cells, xenograft epistasis\",\n      \"pmids\": [\"34553767\", \"33773404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of MT destabilization by ANKHD1 not established\", \"SMYD3–ANKHD1 interface and whether SMYD3 methylates ANKHD1 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ANKHD1 was shown to bind lncRNA MALAT1 and form a feedback loop with YAP1 that enhances YAP1 transcriptional coactivation and radioresistance in colorectal cancer via the YAP1/AKT axis, adding RNA-scaffolded amplification to its Hippo pathway cofactor role.\",\n      \"evidence\": \"RIP, RNA pulldown, shRNA knockdown, in vitro and in vivo irradiation assays in colorectal cancer models\",\n      \"pmids\": [\"35110552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MALAT1–ANKHD1 interaction not defined\", \"Whether MALAT1 binding is KH-domain-dependent not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: the structural basis for ANKHD1's selective engagement with YAP versus other partners, whether the membrane-deforming and transcriptional cofactor functions are coordinated or independent, the identity of direct substrates or targets of ANKHD1's RNA-binding KH domain genome-wide, and whether the mitophagy and V-ATPase regulatory functions observed in Drosophila are conserved in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length ANKHD1 or its domain complexes\", \"Genome-wide RNA target profiling (CLIP-seq) not performed\", \"Mammalian validation of autophagy/mitophagy functions lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 16, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 0, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 9, 10, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 2, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YAP1\", \"SHP2\", \"SIVA1\", \"SMYD3\", \"MALAT1\", \"STMN1\"],\n    \"other_free_text\": []\n  }\n}\n```"}