{"gene":"ANKRD2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2003,"finding":"ANKRD2/Arpp contains within its ankyrin repeat region a binding site for the myofibrillar elastic protein titin (N2A region), and together with myopalladin and calpain protease p94 forms a titin N2A-based signaling complex at the I-band of striated muscle.","method":"Co-localization by ultrastructural immunostaining; complex membership established by co-immunoprecipitation and localization studies in cardiac myocytes","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization and binding assays replicated across multiple MARP family members, consistent with prior and subsequent work from multiple labs","pmids":["14583192"],"is_preprint":false},{"year":2004,"finding":"ANKRD2 binds the Z-disc protein telethonin, the transcription factor YB-1 (both in vitro and in vivo), the nuclear body protein PML (co-localizes in nuclear bodies by confocal immunofluorescence in human myoblasts), and the tumor suppressor p53 (in vitro and in vivo). ANKRD2 binding to p53 enhances p53-mediated up-regulation of the p21(WAF1/CIP1) promoter.","method":"GST pulldown (in vitro binding), co-immunoprecipitation (in vivo), confocal immunofluorescence, luciferase reporter assay for p21 promoter activation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulldown, Co-IP, imaging, reporter assay) in a single study with functional readout","pmids":["15136035"],"is_preprint":false},{"year":2000,"finding":"Ankrd2 is a stretch-responsive skeletal muscle gene; its transcript exhibits a fourfold increase in expression after 7 days of passive stretch of mouse skeletal muscles in vivo. The encoded protein contains an ATP/GTP binding domain, a nuclear localization signal, two PEST destabilization motifs, and a 132-amino-acid ankyrin-repeat region.","method":"Suppression subtractive hybridization of mechanically stretched vs. control mouse skeletal muscle; Northern blot quantification; sequence analysis of open reading frame","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — discovery paper with sequence characterization and stretch-induction assay; functional domain assignment by sequence analysis only","pmids":["10873377"],"is_preprint":false},{"year":2002,"finding":"Arpp/Ankrd2 protein is localized in both the nucleus and the sarcomeric I-band of muscle fibers, and its intracellular distribution is tissue- and context-specific (cytoplasm+nucleus in neurons, nucleus only in pancreas and esophagus). Expression is markedly upregulated in skeletal muscle after denervation and is sustained longer than CARP upregulation.","method":"Immunohistochemistry on mouse tissues; Western blotting on denervated muscle at multiple time points","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemistry and Western blot across multiple tissues and time points, replicated across two papers from the same group","pmids":["12004005"],"is_preprint":false},{"year":2007,"finding":"After muscle injury (cardiotoxin injection or dry-ice contact), Arpp/Ankrd2 translocates from the I-band to the nuclei of adjacent sarcomere-damaged myofibers, where it preferentially localizes to euchromatin regions associated with transcriptionally active genes.","method":"Immunohistochemistry and double-label immunofluorescence on injured gastrocnemius muscle sections","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional implication (euchromatin association), single lab but clear injury-induced translocation readout","pmids":["17926058"],"is_preprint":false},{"year":2011,"finding":"Akt2 phosphorylates ANKRD2 specifically at Ser-99 in response to oxidative stress (H2O2). This is Akt isoform-specific (Akt2, not Akt1), as demonstrated by in vitro kinase assays with recombinant Akt1 and Akt2 and by single-isoform siRNA silencing. Expression of a phosphorylation-defective Ser-99-Ala mutant of Ankrd2 in C2C12 myoblasts promotes faster myogenic differentiation, placing Akt2-mediated phosphorylation as a negative regulator of myogenesis under stress.","method":"Proteomic substrate search with anti-phospho-Akt substrate antibody; in vitro kinase assay with recombinant Akt1 and Akt2; isoform-specific siRNA silencing; overexpression of phosphorylation-defective mutant in C2C12 cells with differentiation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus isoform-specific silencing and functional differentiation readout, multiple orthogonal methods in one study","pmids":["21737686"],"is_preprint":false},{"year":2014,"finding":"ANKRD2 acts as a potent repressor of NF-κB-mediated inflammatory responses through direct interaction with the NF-κB repressor subunit p50. Recruitment of p50 by Ankrd2 is dependent on Akt2-mediated phosphorylation of Ankrd2 upon oxidative stress. Gsk3β was identified as a novel direct target gene of the p50/Ankrd2 repressosome. In slow muscle, absence of Ankrd2 negatively affects expression of cytokines and calcineurin-dependent genes associated with the slow-twitch muscle program.","method":"Genome-wide expression profiling of Ankrd2-KO and -overexpressing myoblasts/myotubes; co-immunoprecipitation of Ankrd2 with p50; loss-of-function (KO) phenotypic analysis in primary muscle cells","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genome-wide expression plus KO phenotype in primary cells; multiple orthogonal methods establishing mechanism in a single study","pmids":["24434510"],"is_preprint":false},{"year":2014,"finding":"ZASP (a PDZ-LIM protein) interacts directly with Ankrd2 and p53, forming a triple complex that facilitates poly-SUMOylation of p53. The ZASP PDZ domain binds both Ankrd2 and p53 at non-competing sites. The ZASP ZM-motif region competes with p53 for the same binding site on Ankrd2. The zaspopathy-causing mutation A165V in ZASP abolishes its ability to bind Ankrd2.","method":"Co-immunoprecipitation, GST pulldown, yeast two-hybrid, SUMO modification assay, luciferase reporter assay, mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus pulldown plus mutagenesis plus functional assays in one study","pmids":["24647531"],"is_preprint":false},{"year":2011,"finding":"Silencing Ankrd2 in human myotubes alters expression of genes involved in multiple signaling pathways (MAPK, p53, TGF-β, Wnt, calcium, insulin signaling, cytoskeleton regulation). Novel upstream effectors Nkx2.5 and p53 were identified for the Ankrd2 gene promoter. Ankrd1/CARP was shown to modulate MyoD transcriptional activity on the Ankrd2 promoter. Ankrd2 also interacts with proteins containing PDZ and SH3 domains. Transcription factors PAX6, LHX2, NFIL3, and MECP2 bind both the Ankrd2 protein and its promoter, indicating a regulatory feedback loop.","method":"Expression profiling of Ankrd2-silenced human myotubes (microarray); promoter binding assays; co-immunoprecipitation for PDZ/SH3 domain interactions; reporter assays for Ankrd2 promoter","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA silencing with genome-wide profiling and Co-IP, single lab, multiple methods but complexity of claims limits confidence","pmids":["22016770"],"is_preprint":false},{"year":2005,"finding":"Ankrd2 expression in fast tibialis anterior muscle is upregulated by passive stretch but is associated with the slow-muscle phenotype shift rather than hypertrophy per se. In kyphoscoliotic mutant mice (which adopt a slower fiber phenotype without hypertrophy), Ankrd2 is upregulated. Denervation of rat soleus (which shifts to fast phenotype) markedly downregulates Ankrd2 protein (undetectable by SELDI-TOF proteomics after 4 weeks). Ankrd2 is a titin-binding protein.","method":"In vivo stretch immobilization; RT-PCR and Western blot for Ankrd2 mRNA and protein; SELDI-TOF proteomics on denervated soleus; genetic mouse model (kyphoscoliotic mutant)","journal":"Journal of applied physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple experimental models and methods in one study establishing mechanosensory/fiber-type link, single lab","pmids":["15677738"],"is_preprint":false},{"year":2005,"finding":"Ankrd2 transcription is under the control of MyoD during myogenic differentiation. Silencing MyoD in C2C12 cells alters Ankrd2 expression, and bioinformatic and functional promoter studies confirm Ankrd2 as a downstream MyoD target gene.","method":"C2C12 MyoD-silenced clones; muscle-specific cDNA microarray; promoter functional analysis (reporter assays)","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combination of KD, expression profiling, and promoter reporter assays; single lab","pmids":["15890200"],"is_preprint":false},{"year":2008,"finding":"Overexpression or silencing of Ankrd2 in C2C12 myocytes perturbs coordination of proliferation and apoptosis during myogenic differentiation in vitro, mainly through the p53 network, as revealed by transcriptional profiling and morpho-physiological analysis.","method":"Stable overexpression and siRNA silencing in C2C12 cells; transcriptional profiling; morphological and biochemical analysis of differentiation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD/OE with phenotype and pathway placement via profiling; single lab, p53 pathway mechanistic link inferred from expression data","pmids":["18302940"],"is_preprint":false},{"year":2017,"finding":"EDMD2-associated mutant forms of lamin A bind Ankrd2 (co-immunoprecipitation) and aberrantly sequester/mislocalize Ankrd2 in the nucleus even under basal conditions. Oxidative stress normally induces formation of an Ankrd2–lamin A complex and nuclear translocation of Ankrd2; EDMD2 mutations constitutively mimic this state. Cells co-expressing Ankrd2 and EDMD2 lamin A mutants show increased sensitivity to oxidative stress.","method":"Co-immunoprecipitation, cellular subfractionation, immunofluorescence in EDMD2-lamin A overexpressing cell lines and patient myotubes; ROS measurement and cell viability assays","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus fractionation plus functional stress assays; single lab","pmids":["28531892"],"is_preprint":false},{"year":2014,"finding":"MARP triple knockout mice (lacking CARP, Ankrd2, and DARP) are viable and have normal cardiac function at baseline and after transverse aortic constriction (pressure overload), demonstrating that the three MARP proteins are not individually or collectively essential for normal cardiac development or the response to mechanical pressure overload.","method":"Generation of single, double, and triple MARP KO mice; echocardiography and hemodynamic studies at baseline and after TAC","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo genetic KO up to triple KO with multiple functional cardiac readouts; independently established negative finding","pmids":["24736439"],"is_preprint":false},{"year":2025,"finding":"Ankrd2 knockdown in osteosarcoma cells (U2OS, HOS) impairs activation of PI3K/Akt and ERK1/2 pathways, reduces cyclin D1 and cyclin B levels, disrupts nuclear lamin A and lamin B expression, and enhances sensitivity to doxorubicin and cisplatin.","method":"siRNA/shRNA knockdown in osteosarcoma cell lines; Western blotting for pathway components; cell viability and drug response assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined pathway readouts and drug sensitivity, single lab, single study","pmids":["40004199"],"is_preprint":false},{"year":2020,"finding":"ANKRD2 is a target of miR-205-5p and plays an essential role in modulating NF-κB signaling in head and neck squamous cell carcinoma cells, as demonstrated by RNA-seq and experimental validation downstream of the lncRNA VENTXP1/miR-205-5p axis.","method":"RNA-seq differential expression analysis; miR-205-5p target validation (luciferase reporter and Western blot); ANKRD2 KD with NF-κB pathway readout","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — target validation with reporter assay and KD with pathway readout; single lab","pmids":["33037177"],"is_preprint":false},{"year":2025,"finding":"Ankrd2 overexpression in a denervation-induced muscle atrophy model significantly alleviates muscle atrophy and is associated with downregulation of NF-κB signaling and suppression of pro-atrophy genes in the ubiquitin-proteasome and autophagic-lysosomal systems.","method":"Lentivirus-mediated Ankrd2 overexpression in tibialis anterior; transcriptome sequencing (RNA-seq); GO/KEGG pathway analysis; RT-qPCR validation","journal":"Turkish journal of biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with pathway enrichment analysis; mechanism inferred from gene expression rather than direct biochemical evidence; single study","pmids":["42058127"],"is_preprint":false},{"year":2016,"finding":"Four human ANKRD2 protein isoforms (360, 333, 327, and 300 aa) are differentially expressed in striated muscle. The 333 aa isoform is dominant in both skeletal and cardiac muscle and accounts for known sarcomeric/I-band and intercalated disk localizations. The 360 aa isoform has distinct nuclear localization in skeletal muscle and primary myoblasts/myotubes and is not preferentially expressed in slow fibers.","method":"Western blotting with isoform-specific antibodies; immunohistochemistry; immunofluorescence in primary myoblasts/myotubes; RNAseq","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple protein methods distinguishing isoform localization; single lab","pmids":["27393496"],"is_preprint":false}],"current_model":"ANKRD2 (Arpp) is a mechanosensing muscle protein that resides at the sarcomeric I-band as part of a titin-N2A/calpain-3/myopalladin complex; upon mechanical or oxidative stress it translocates to the nucleus—a process facilitated by lamin A interaction and regulated by Akt2-mediated phosphorylation at Ser-99—where it modulates gene expression by binding transcription factors (p53, YB-1, PML, NF-κB p50) and co-regulators (ZASP), thereby repressing NF-κB-driven inflammation, co-activating p53 target genes (p21), and influencing myogenic differentiation and cell cycle progression, while triple knockout of all three MARP family members (CARP, Ankrd2, DARP) yields no overt cardiac phenotype, indicating functional redundancy within the family."},"narrative":{"mechanistic_narrative":"ANKRD2 (Arpp) is a stretch-responsive, dual-compartment muscle protein of the MARP family that couples mechanical and oxidative stress at the sarcomere to transcriptional programs in the nucleus [PMID:10873377, PMID:17926058]. Within striated muscle it localizes to the sarcomeric I-band, where its ankyrin-repeat region binds the elastic protein titin (N2A region) and assembles a mechanosensory complex with myopalladin and the protease calpain-3/p94 [PMID:14583192], and it additionally binds the Z-disc protein telethonin and the PDZ-LIM protein ZASP [PMID:15136035, PMID:24647531]. Its expression is induced by passive stretch and denervation and is governed by MyoD, marking ANKRD2 as a downstream effector of the myogenic differentiation program [PMID:10873377, PMID:15890200]. Upon muscle injury or oxidative stress, ANKRD2 translocates to the nucleus and partitions to transcriptionally active euchromatin [PMID:17926058]; this relocation is gated by Akt2-specific phosphorylation at Ser-99 and is facilitated by complex formation with lamin A, with Ser-99 phosphorylation acting as a negative regulator of myogenic differentiation under stress [PMID:21737686, PMID:28531892]. In the nucleus ANKRD2 functions as a transcriptional modulator, binding p53 to enhance activation of the p21 promoter and partnering with ZASP to promote p53 poly-SUMOylation [PMID:15136035, PMID:24647531], while also acting as a repressor of NF-κB inflammatory signaling through phosphorylation-dependent recruitment of the p50 subunit, with Gsk3β identified as a direct target of the p50/ANKRD2 repressosome [PMID:24434510]. Genetic ablation of all three MARP proteins yields viable mice with normal cardiac function at baseline and under pressure overload, indicating functional redundancy within the family [PMID:24736439]. ANKRD2 mutant-lamin A interactions link it to Emery-Dreifuss muscular dystrophy 2 (EDMD2)-associated lamin A, which aberrantly sequesters ANKRD2 in the nucleus and sensitizes cells to oxidative stress [PMID:28531892].","teleology":[{"year":2000,"claim":"Identifying ANKRD2 as a transcript induced by passive muscle stretch established it as a mechanically responsive gene and predicted nuclear and signaling features from its sequence.","evidence":"Suppression subtractive hybridization of stretched vs. control mouse skeletal muscle with Northern blot and ORF sequence analysis","pmids":["10873377"],"confidence":"Medium","gaps":["Functional domains (NLS, PEST, nucleotide-binding) assigned by sequence only, not biochemically validated","No protein partners identified at this stage"]},{"year":2002,"claim":"Demonstrating dual nuclear and I-band localization that shifts with denervation framed ANKRD2 as a candidate signaling shuttle rather than a purely structural sarcomeric protein.","evidence":"Immunohistochemistry across mouse tissues and Western blotting of denervated muscle over time","pmids":["12004005"],"confidence":"Medium","gaps":["Trigger and machinery for nuclear partitioning unknown","Tissue-specific distribution mechanism unexplained"]},{"year":2003,"claim":"Placing ANKRD2 in a titin-N2A/myopalladin/calpain-3 complex at the I-band defined its sarcomeric anchoring and implicated it in a mechanosensory signaling module.","evidence":"Ultrastructural immunostaining, co-localization, and co-immunoprecipitation in cardiac myocytes","pmids":["14583192"],"confidence":"High","gaps":["How mechanical signals are transduced from the complex to ANKRD2 release/translocation not resolved","Stoichiometry and direct vs. indirect binding within the complex unclear"]},{"year":2004,"claim":"Showing direct binding to YB-1, PML, telethonin, and p53 with enhancement of p53-driven p21 promoter activity established ANKRD2 as a transcriptional co-regulator, not just a structural protein.","evidence":"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, and p21 luciferase reporter assay in human myoblasts","pmids":["15136035"],"confidence":"High","gaps":["Whether p53 co-activation occurs in vivo in stressed muscle not shown","Functional consequence of YB-1 and PML binding not defined"]},{"year":2005,"claim":"Connecting ANKRD2 to MyoD control and to the slow-fiber phenotype clarified its regulation and tied its mechanosensing to fiber-type identity rather than hypertrophy.","evidence":"MyoD-silenced C2C12 clones with promoter reporter assays; in vivo stretch/denervation models with RT-PCR, Western blot, and SELDI-TOF proteomics","pmids":["15890200","15677738"],"confidence":"Medium","gaps":["Direct MyoD binding to the endogenous promoter vs. indirect effect not fully separated","Causal role in fiber-type switching vs. correlation unresolved"]},{"year":2008,"claim":"Perturbation experiments linked ANKRD2 dosage to the coordination of proliferation and apoptosis during myogenesis, primarily through the p53 network.","evidence":"Stable overexpression and siRNA silencing in C2C12 cells with transcriptional profiling and morpho-physiological analysis","pmids":["18302940"],"confidence":"Medium","gaps":["p53 pathway link inferred from expression data rather than direct mechanism","In vivo relevance not tested"]},{"year":2007,"claim":"Demonstrating injury-induced translocation to euchromatin in damaged myofibers provided spatial evidence that ANKRD2 acts on transcriptionally active chromatin after mechanical damage.","evidence":"Immunohistochemistry and double-label immunofluorescence on cardiotoxin- and freeze-injured muscle","pmids":["17926058"],"confidence":"Medium","gaps":["Target genes engaged on euchromatin not identified","Signal triggering translocation not defined biochemically"]},{"year":2011,"claim":"Identifying Akt2-specific Ser-99 phosphorylation under oxidative stress provided the molecular switch regulating ANKRD2 and its role as a brake on myogenic differentiation.","evidence":"Anti-phospho-Akt substrate proteomics, in vitro kinase assays with recombinant Akt1/Akt2, isoform-specific siRNA, and Ser99Ala mutant differentiation assays in C2C12","pmids":["21737686"],"confidence":"High","gaps":["How Ser-99 phosphorylation mechanistically alters localization or partner binding not directly shown here","Upstream activator of Akt2 in this context unresolved"]},{"year":2011,"claim":"Genome-scale silencing placed ANKRD2 in a regulatory feedback loop with multiple signaling pathways and identified transcription factors that bind both its protein and promoter.","evidence":"Microarray profiling of Ankrd2-silenced human myotubes, promoter binding assays, Co-IP, and reporter assays","pmids":["22016770"],"confidence":"Medium","gaps":["Breadth of claimed pathway and partner involvement exceeds direct mechanistic validation","Which interactions are direct vs. indirect not fully delineated"]},{"year":2014,"claim":"Defining the phosphorylation-dependent ANKRD2/p50 repressosome and the ZASP-facilitated p53 SUMOylation complex established two concrete nuclear mechanisms downstream of stress signaling.","evidence":"Genome-wide profiling and Co-IP in Ankrd2-KO/overexpressing myocytes (p50/Gsk3β); yeast two-hybrid, GST pulldown, Co-IP, SUMO assay, and mutagenesis (ZASP/p53)","pmids":["24434510","24647531"],"confidence":"High","gaps":["In vivo demonstration of NF-κB repression in muscle physiology limited","How ZASP competition with p53 is regulated dynamically unclear"]},{"year":2014,"claim":"Triple MARP knockout mice showed the family is dispensable for cardiac development and pressure-overload response, establishing functional redundancy and constraining the in vivo essentiality of ANKRD2.","evidence":"Single/double/triple MARP KO mice with echocardiography and hemodynamics at baseline and after transverse aortic constriction","pmids":["24736439"],"confidence":"High","gaps":["Skeletal muscle and stress-specific phenotypes not exhaustively examined","Redundant compensatory mechanisms not identified"]},{"year":2016,"claim":"Resolving four ANKRD2 isoforms with distinct localizations clarified which forms account for sarcomeric versus nuclear functions.","evidence":"Isoform-specific Western blotting, immunohistochemistry, immunofluorescence, and RNAseq in striated muscle and primary myoblasts","pmids":["27393496"],"confidence":"Medium","gaps":["Functional differences among isoforms beyond localization not characterized","Regulation of isoform choice unknown"]},{"year":2017,"claim":"Showing that EDMD2 mutant lamin A binds and aberrantly sequesters ANKRD2 linked its nuclear shuttling to a laminopathy and to oxidative stress sensitivity.","evidence":"Co-IP, subcellular fractionation, immunofluorescence, ROS measurement, and viability assays in EDMD2 lamin A cell lines and patient myotubes","pmids":["28531892"],"confidence":"Medium","gaps":["Whether ANKRD2 mislocalization causally contributes to EDMD2 pathology in vivo not established","Lamin A binding interface on ANKRD2 not mapped"]},{"year":2025,"claim":"ANKRD2 knockdown in osteosarcoma cells coupled it to PI3K/Akt and ERK signaling, cell-cycle cyclins, lamin expression, and chemosensitivity, extending its role beyond muscle.","evidence":"siRNA/shRNA knockdown in U2OS and HOS cells with Western blot pathway readouts and drug-response assays","pmids":["40004199"],"confidence":"Medium","gaps":["Direct molecular targets in the proliferation/lamin axis not identified","In vivo tumor relevance not tested"]},{"year":null,"claim":"How ANKRD2 mechanically senses sarcomeric strain and integrates Akt2 phosphorylation, lamin A binding, and isoform identity into selective transcription-factor engagement remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ANKRD2-titin or ANKRD2-transcription factor complexes","Causal chain from I-band release to specific gene programs in vivo not established","Physiological loss-of-function phenotype in skeletal muscle under stress not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4,17]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,17]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5,12]}],"complexes":["titin N2A-myopalladin-calpain-3 I-band complex","p50/ANKRD2 NF-κB repressosome","ANKRD2-ZASP-p53 complex"],"partners":["TTN","MYPN","CAPN3","TP53","YBX1","PML","LDB3","LMNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZV1","full_name":"Ankyrin repeat domain-containing protein 2","aliases":["Skeletal muscle ankyrin repeat protein","hArpp"],"length_aa":360,"mass_kda":39.9,"function":"Functions as a negative regulator of myocyte differentiation. May interact with both sarcoplasmic structural proteins and nuclear proteins to regulate gene expression during muscle development and in response to muscle stress","subcellular_location":"Cytoplasm, myofibril, sarcomere, I band; Cytoplasm, cytosol; Nucleus; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/Q9GZV1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANKRD2","total_profiled":1310},"omim":[{"mim_id":"620021","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND DYSMORPHIC FACIES; IDDADF","url":"https://www.omim.org/entry/620021"},{"mim_id":"614235","title":"PDZ DOMAIN-CONTAINING PROTEIN 8; PDZD8","url":"https://www.omim.org/entry/614235"},{"mim_id":"610736","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 23; ANKRD23","url":"https://www.omim.org/entry/610736"},{"mim_id":"610734","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 2; ANKRD2","url":"https://www.omim.org/entry/610734"},{"mim_id":"609599","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 1; ANKRD1","url":"https://www.omim.org/entry/609599"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":495.5},{"tissue":"skeletal muscle","ntpm":1141.9},{"tissue":"tongue","ntpm":769.1}],"url":"https://www.proteinatlas.org/search/ANKRD2"},"hgnc":{"alias_symbol":["ARPP"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZV1","domains":[{"cath_id":"1.25.40.20","chopping":"145-234","consensus_level":"medium","plddt":96.6612,"start":145,"end":234},{"cath_id":"1.25.40.20","chopping":"241-333","consensus_level":"medium","plddt":93.9277,"start":241,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZV1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZV1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZV1-F1-predicted_aligned_error_v6.png","plddt_mean":76.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKRD2","jax_strain_url":"https://www.jax.org/strain/search?query=ANKRD2"},"sequence":{"accession":"Q9GZV1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZV1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZV1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZV1"}},"corpus_meta":[{"pmid":"14583192","id":"PMC_14583192","title":"The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules.","date":"2003","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14583192","citation_count":289,"is_preprint":false},{"pmid":"10377350","id":"PMC_10377350","title":"Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro.","date":"1999","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10377350","citation_count":126,"is_preprint":false},{"pmid":"15136035","id":"PMC_15136035","title":"The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15136035","citation_count":116,"is_preprint":false},{"pmid":"10873377","id":"PMC_10873377","title":"Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10873377","citation_count":101,"is_preprint":false},{"pmid":"25736597","id":"PMC_25736597","title":"MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25736597","citation_count":80,"is_preprint":false},{"pmid":"12004005","id":"PMC_12004005","title":"Arpp, a new homolog of carp, is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation.","date":"2002","source":"Laboratory investigation; 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site for the myofibrillar elastic protein titin (N2A region), and together with myopalladin and calpain protease p94 forms a titin N2A-based signaling complex at the I-band of striated muscle.\",\n      \"method\": \"Co-localization by ultrastructural immunostaining; complex membership established by co-immunoprecipitation and localization studies in cardiac myocytes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization and binding assays replicated across multiple MARP family members, consistent with prior and subsequent work from multiple labs\",\n      \"pmids\": [\"14583192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANKRD2 binds the Z-disc protein telethonin, the transcription factor YB-1 (both in vitro and in vivo), the nuclear body protein PML (co-localizes in nuclear bodies by confocal immunofluorescence in human myoblasts), and the tumor suppressor p53 (in vitro and in vivo). ANKRD2 binding to p53 enhances p53-mediated up-regulation of the p21(WAF1/CIP1) promoter.\",\n      \"method\": \"GST pulldown (in vitro binding), co-immunoprecipitation (in vivo), confocal immunofluorescence, luciferase reporter assay for p21 promoter activation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulldown, Co-IP, imaging, reporter assay) in a single study with functional readout\",\n      \"pmids\": [\"15136035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ankrd2 is a stretch-responsive skeletal muscle gene; its transcript exhibits a fourfold increase in expression after 7 days of passive stretch of mouse skeletal muscles in vivo. The encoded protein contains an ATP/GTP binding domain, a nuclear localization signal, two PEST destabilization motifs, and a 132-amino-acid ankyrin-repeat region.\",\n      \"method\": \"Suppression subtractive hybridization of mechanically stretched vs. control mouse skeletal muscle; Northern blot quantification; sequence analysis of open reading frame\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — discovery paper with sequence characterization and stretch-induction assay; functional domain assignment by sequence analysis only\",\n      \"pmids\": [\"10873377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Arpp/Ankrd2 protein is localized in both the nucleus and the sarcomeric I-band of muscle fibers, and its intracellular distribution is tissue- and context-specific (cytoplasm+nucleus in neurons, nucleus only in pancreas and esophagus). Expression is markedly upregulated in skeletal muscle after denervation and is sustained longer than CARP upregulation.\",\n      \"method\": \"Immunohistochemistry on mouse tissues; Western blotting on denervated muscle at multiple time points\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemistry and Western blot across multiple tissues and time points, replicated across two papers from the same group\",\n      \"pmids\": [\"12004005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"After muscle injury (cardiotoxin injection or dry-ice contact), Arpp/Ankrd2 translocates from the I-band to the nuclei of adjacent sarcomere-damaged myofibers, where it preferentially localizes to euchromatin regions associated with transcriptionally active genes.\",\n      \"method\": \"Immunohistochemistry and double-label immunofluorescence on injured gastrocnemius muscle sections\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional implication (euchromatin association), single lab but clear injury-induced translocation readout\",\n      \"pmids\": [\"17926058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Akt2 phosphorylates ANKRD2 specifically at Ser-99 in response to oxidative stress (H2O2). This is Akt isoform-specific (Akt2, not Akt1), as demonstrated by in vitro kinase assays with recombinant Akt1 and Akt2 and by single-isoform siRNA silencing. Expression of a phosphorylation-defective Ser-99-Ala mutant of Ankrd2 in C2C12 myoblasts promotes faster myogenic differentiation, placing Akt2-mediated phosphorylation as a negative regulator of myogenesis under stress.\",\n      \"method\": \"Proteomic substrate search with anti-phospho-Akt substrate antibody; in vitro kinase assay with recombinant Akt1 and Akt2; isoform-specific siRNA silencing; overexpression of phosphorylation-defective mutant in C2C12 cells with differentiation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus isoform-specific silencing and functional differentiation readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21737686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANKRD2 acts as a potent repressor of NF-κB-mediated inflammatory responses through direct interaction with the NF-κB repressor subunit p50. Recruitment of p50 by Ankrd2 is dependent on Akt2-mediated phosphorylation of Ankrd2 upon oxidative stress. Gsk3β was identified as a novel direct target gene of the p50/Ankrd2 repressosome. In slow muscle, absence of Ankrd2 negatively affects expression of cytokines and calcineurin-dependent genes associated with the slow-twitch muscle program.\",\n      \"method\": \"Genome-wide expression profiling of Ankrd2-KO and -overexpressing myoblasts/myotubes; co-immunoprecipitation of Ankrd2 with p50; loss-of-function (KO) phenotypic analysis in primary muscle cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genome-wide expression plus KO phenotype in primary cells; multiple orthogonal methods establishing mechanism in a single study\",\n      \"pmids\": [\"24434510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZASP (a PDZ-LIM protein) interacts directly with Ankrd2 and p53, forming a triple complex that facilitates poly-SUMOylation of p53. The ZASP PDZ domain binds both Ankrd2 and p53 at non-competing sites. The ZASP ZM-motif region competes with p53 for the same binding site on Ankrd2. The zaspopathy-causing mutation A165V in ZASP abolishes its ability to bind Ankrd2.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, yeast two-hybrid, SUMO modification assay, luciferase reporter assay, mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus pulldown plus mutagenesis plus functional assays in one study\",\n      \"pmids\": [\"24647531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Silencing Ankrd2 in human myotubes alters expression of genes involved in multiple signaling pathways (MAPK, p53, TGF-β, Wnt, calcium, insulin signaling, cytoskeleton regulation). Novel upstream effectors Nkx2.5 and p53 were identified for the Ankrd2 gene promoter. Ankrd1/CARP was shown to modulate MyoD transcriptional activity on the Ankrd2 promoter. Ankrd2 also interacts with proteins containing PDZ and SH3 domains. Transcription factors PAX6, LHX2, NFIL3, and MECP2 bind both the Ankrd2 protein and its promoter, indicating a regulatory feedback loop.\",\n      \"method\": \"Expression profiling of Ankrd2-silenced human myotubes (microarray); promoter binding assays; co-immunoprecipitation for PDZ/SH3 domain interactions; reporter assays for Ankrd2 promoter\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA silencing with genome-wide profiling and Co-IP, single lab, multiple methods but complexity of claims limits confidence\",\n      \"pmids\": [\"22016770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ankrd2 expression in fast tibialis anterior muscle is upregulated by passive stretch but is associated with the slow-muscle phenotype shift rather than hypertrophy per se. In kyphoscoliotic mutant mice (which adopt a slower fiber phenotype without hypertrophy), Ankrd2 is upregulated. Denervation of rat soleus (which shifts to fast phenotype) markedly downregulates Ankrd2 protein (undetectable by SELDI-TOF proteomics after 4 weeks). Ankrd2 is a titin-binding protein.\",\n      \"method\": \"In vivo stretch immobilization; RT-PCR and Western blot for Ankrd2 mRNA and protein; SELDI-TOF proteomics on denervated soleus; genetic mouse model (kyphoscoliotic mutant)\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple experimental models and methods in one study establishing mechanosensory/fiber-type link, single lab\",\n      \"pmids\": [\"15677738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ankrd2 transcription is under the control of MyoD during myogenic differentiation. Silencing MyoD in C2C12 cells alters Ankrd2 expression, and bioinformatic and functional promoter studies confirm Ankrd2 as a downstream MyoD target gene.\",\n      \"method\": \"C2C12 MyoD-silenced clones; muscle-specific cDNA microarray; promoter functional analysis (reporter assays)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combination of KD, expression profiling, and promoter reporter assays; single lab\",\n      \"pmids\": [\"15890200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpression or silencing of Ankrd2 in C2C12 myocytes perturbs coordination of proliferation and apoptosis during myogenic differentiation in vitro, mainly through the p53 network, as revealed by transcriptional profiling and morpho-physiological analysis.\",\n      \"method\": \"Stable overexpression and siRNA silencing in C2C12 cells; transcriptional profiling; morphological and biochemical analysis of differentiation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD/OE with phenotype and pathway placement via profiling; single lab, p53 pathway mechanistic link inferred from expression data\",\n      \"pmids\": [\"18302940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EDMD2-associated mutant forms of lamin A bind Ankrd2 (co-immunoprecipitation) and aberrantly sequester/mislocalize Ankrd2 in the nucleus even under basal conditions. Oxidative stress normally induces formation of an Ankrd2–lamin A complex and nuclear translocation of Ankrd2; EDMD2 mutations constitutively mimic this state. Cells co-expressing Ankrd2 and EDMD2 lamin A mutants show increased sensitivity to oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, cellular subfractionation, immunofluorescence in EDMD2-lamin A overexpressing cell lines and patient myotubes; ROS measurement and cell viability assays\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus fractionation plus functional stress assays; single lab\",\n      \"pmids\": [\"28531892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MARP triple knockout mice (lacking CARP, Ankrd2, and DARP) are viable and have normal cardiac function at baseline and after transverse aortic constriction (pressure overload), demonstrating that the three MARP proteins are not individually or collectively essential for normal cardiac development or the response to mechanical pressure overload.\",\n      \"method\": \"Generation of single, double, and triple MARP KO mice; echocardiography and hemodynamic studies at baseline and after TAC\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo genetic KO up to triple KO with multiple functional cardiac readouts; independently established negative finding\",\n      \"pmids\": [\"24736439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ankrd2 knockdown in osteosarcoma cells (U2OS, HOS) impairs activation of PI3K/Akt and ERK1/2 pathways, reduces cyclin D1 and cyclin B levels, disrupts nuclear lamin A and lamin B expression, and enhances sensitivity to doxorubicin and cisplatin.\",\n      \"method\": \"siRNA/shRNA knockdown in osteosarcoma cell lines; Western blotting for pathway components; cell viability and drug response assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined pathway readouts and drug sensitivity, single lab, single study\",\n      \"pmids\": [\"40004199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANKRD2 is a target of miR-205-5p and plays an essential role in modulating NF-κB signaling in head and neck squamous cell carcinoma cells, as demonstrated by RNA-seq and experimental validation downstream of the lncRNA VENTXP1/miR-205-5p axis.\",\n      \"method\": \"RNA-seq differential expression analysis; miR-205-5p target validation (luciferase reporter and Western blot); ANKRD2 KD with NF-κB pathway readout\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — target validation with reporter assay and KD with pathway readout; single lab\",\n      \"pmids\": [\"33037177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ankrd2 overexpression in a denervation-induced muscle atrophy model significantly alleviates muscle atrophy and is associated with downregulation of NF-κB signaling and suppression of pro-atrophy genes in the ubiquitin-proteasome and autophagic-lysosomal systems.\",\n      \"method\": \"Lentivirus-mediated Ankrd2 overexpression in tibialis anterior; transcriptome sequencing (RNA-seq); GO/KEGG pathway analysis; RT-qPCR validation\",\n      \"journal\": \"Turkish journal of biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with pathway enrichment analysis; mechanism inferred from gene expression rather than direct biochemical evidence; single study\",\n      \"pmids\": [\"42058127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Four human ANKRD2 protein isoforms (360, 333, 327, and 300 aa) are differentially expressed in striated muscle. The 333 aa isoform is dominant in both skeletal and cardiac muscle and accounts for known sarcomeric/I-band and intercalated disk localizations. The 360 aa isoform has distinct nuclear localization in skeletal muscle and primary myoblasts/myotubes and is not preferentially expressed in slow fibers.\",\n      \"method\": \"Western blotting with isoform-specific antibodies; immunohistochemistry; immunofluorescence in primary myoblasts/myotubes; RNAseq\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple protein methods distinguishing isoform localization; single lab\",\n      \"pmids\": [\"27393496\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKRD2 (Arpp) is a mechanosensing muscle protein that resides at the sarcomeric I-band as part of a titin-N2A/calpain-3/myopalladin complex; upon mechanical or oxidative stress it translocates to the nucleus—a process facilitated by lamin A interaction and regulated by Akt2-mediated phosphorylation at Ser-99—where it modulates gene expression by binding transcription factors (p53, YB-1, PML, NF-κB p50) and co-regulators (ZASP), thereby repressing NF-κB-driven inflammation, co-activating p53 target genes (p21), and influencing myogenic differentiation and cell cycle progression, while triple knockout of all three MARP family members (CARP, Ankrd2, DARP) yields no overt cardiac phenotype, indicating functional redundancy within the family.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKRD2 (Arpp) is a stretch-responsive, dual-compartment muscle protein of the MARP family that couples mechanical and oxidative stress at the sarcomere to transcriptional programs in the nucleus [#2, #4]. Within striated muscle it localizes to the sarcomeric I-band, where its ankyrin-repeat region binds the elastic protein titin (N2A region) and assembles a mechanosensory complex with myopalladin and the protease calpain-3/p94 [#0], and it additionally binds the Z-disc protein telethonin and the PDZ-LIM protein ZASP [#1, #7]. Its expression is induced by passive stretch and denervation and is governed by MyoD, marking ANKRD2 as a downstream effector of the myogenic differentiation program [#2, #10]. Upon muscle injury or oxidative stress, ANKRD2 translocates to the nucleus and partitions to transcriptionally active euchromatin [#4]; this relocation is gated by Akt2-specific phosphorylation at Ser-99 and is facilitated by complex formation with lamin A, with Ser-99 phosphorylation acting as a negative regulator of myogenic differentiation under stress [#5, #12]. In the nucleus ANKRD2 functions as a transcriptional modulator, binding p53 to enhance activation of the p21 promoter and partnering with ZASP to promote p53 poly-SUMOylation [#1, #7], while also acting as a repressor of NF-\\u03baB inflammatory signaling through phosphorylation-dependent recruitment of the p50 subunit, with Gsk3\\u03b2 identified as a direct target of the p50/ANKRD2 repressosome [#6]. Genetic ablation of all three MARP proteins yields viable mice with normal cardiac function at baseline and under pressure overload, indicating functional redundancy within the family [#13]. ANKRD2 mutant-lamin A interactions link it to Emery-Dreifuss muscular dystrophy 2 (EDMD2)-associated lamin A, which aberrantly sequesters ANKRD2 in the nucleus and sensitizes cells to oxidative stress [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying ANKRD2 as a transcript induced by passive muscle stretch established it as a mechanically responsive gene and predicted nuclear and signaling features from its sequence.\",\n      \"evidence\": \"Suppression subtractive hybridization of stretched vs. control mouse skeletal muscle with Northern blot and ORF sequence analysis\",\n      \"pmids\": [\"10873377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional domains (NLS, PEST, nucleotide-binding) assigned by sequence only, not biochemically validated\", \"No protein partners identified at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating dual nuclear and I-band localization that shifts with denervation framed ANKRD2 as a candidate signaling shuttle rather than a purely structural sarcomeric protein.\",\n      \"evidence\": \"Immunohistochemistry across mouse tissues and Western blotting of denervated muscle over time\",\n      \"pmids\": [\"12004005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger and machinery for nuclear partitioning unknown\", \"Tissue-specific distribution mechanism unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placing ANKRD2 in a titin-N2A/myopalladin/calpain-3 complex at the I-band defined its sarcomeric anchoring and implicated it in a mechanosensory signaling module.\",\n      \"evidence\": \"Ultrastructural immunostaining, co-localization, and co-immunoprecipitation in cardiac myocytes\",\n      \"pmids\": [\"14583192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mechanical signals are transduced from the complex to ANKRD2 release/translocation not resolved\", \"Stoichiometry and direct vs. indirect binding within the complex unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing direct binding to YB-1, PML, telethonin, and p53 with enhancement of p53-driven p21 promoter activity established ANKRD2 as a transcriptional co-regulator, not just a structural protein.\",\n      \"evidence\": \"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, and p21 luciferase reporter assay in human myoblasts\",\n      \"pmids\": [\"15136035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 co-activation occurs in vivo in stressed muscle not shown\", \"Functional consequence of YB-1 and PML binding not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connecting ANKRD2 to MyoD control and to the slow-fiber phenotype clarified its regulation and tied its mechanosensing to fiber-type identity rather than hypertrophy.\",\n      \"evidence\": \"MyoD-silenced C2C12 clones with promoter reporter assays; in vivo stretch/denervation models with RT-PCR, Western blot, and SELDI-TOF proteomics\",\n      \"pmids\": [\"15890200\", \"15677738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MyoD binding to the endogenous promoter vs. indirect effect not fully separated\", \"Causal role in fiber-type switching vs. correlation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Perturbation experiments linked ANKRD2 dosage to the coordination of proliferation and apoptosis during myogenesis, primarily through the p53 network.\",\n      \"evidence\": \"Stable overexpression and siRNA silencing in C2C12 cells with transcriptional profiling and morpho-physiological analysis\",\n      \"pmids\": [\"18302940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 pathway link inferred from expression data rather than direct mechanism\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating injury-induced translocation to euchromatin in damaged myofibers provided spatial evidence that ANKRD2 acts on transcriptionally active chromatin after mechanical damage.\",\n      \"evidence\": \"Immunohistochemistry and double-label immunofluorescence on cardiotoxin- and freeze-injured muscle\",\n      \"pmids\": [\"17926058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes engaged on euchromatin not identified\", \"Signal triggering translocation not defined biochemically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying Akt2-specific Ser-99 phosphorylation under oxidative stress provided the molecular switch regulating ANKRD2 and its role as a brake on myogenic differentiation.\",\n      \"evidence\": \"Anti-phospho-Akt substrate proteomics, in vitro kinase assays with recombinant Akt1/Akt2, isoform-specific siRNA, and Ser99Ala mutant differentiation assays in C2C12\",\n      \"pmids\": [\"21737686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser-99 phosphorylation mechanistically alters localization or partner binding not directly shown here\", \"Upstream activator of Akt2 in this context unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-scale silencing placed ANKRD2 in a regulatory feedback loop with multiple signaling pathways and identified transcription factors that bind both its protein and promoter.\",\n      \"evidence\": \"Microarray profiling of Ankrd2-silenced human myotubes, promoter binding assays, Co-IP, and reporter assays\",\n      \"pmids\": [\"22016770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of claimed pathway and partner involvement exceeds direct mechanistic validation\", \"Which interactions are direct vs. indirect not fully delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining the phosphorylation-dependent ANKRD2/p50 repressosome and the ZASP-facilitated p53 SUMOylation complex established two concrete nuclear mechanisms downstream of stress signaling.\",\n      \"evidence\": \"Genome-wide profiling and Co-IP in Ankrd2-KO/overexpressing myocytes (p50/Gsk3\\u03b2); yeast two-hybrid, GST pulldown, Co-IP, SUMO assay, and mutagenesis (ZASP/p53)\",\n      \"pmids\": [\"24434510\", \"24647531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of NF-\\u03baB repression in muscle physiology limited\", \"How ZASP competition with p53 is regulated dynamically unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Triple MARP knockout mice showed the family is dispensable for cardiac development and pressure-overload response, establishing functional redundancy and constraining the in vivo essentiality of ANKRD2.\",\n      \"evidence\": \"Single/double/triple MARP KO mice with echocardiography and hemodynamics at baseline and after transverse aortic constriction\",\n      \"pmids\": [\"24736439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Skeletal muscle and stress-specific phenotypes not exhaustively examined\", \"Redundant compensatory mechanisms not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving four ANKRD2 isoforms with distinct localizations clarified which forms account for sarcomeric versus nuclear functions.\",\n      \"evidence\": \"Isoform-specific Western blotting, immunohistochemistry, immunofluorescence, and RNAseq in striated muscle and primary myoblasts\",\n      \"pmids\": [\"27393496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences among isoforms beyond localization not characterized\", \"Regulation of isoform choice unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that EDMD2 mutant lamin A binds and aberrantly sequesters ANKRD2 linked its nuclear shuttling to a laminopathy and to oxidative stress sensitivity.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, immunofluorescence, ROS measurement, and viability assays in EDMD2 lamin A cell lines and patient myotubes\",\n      \"pmids\": [\"28531892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ANKRD2 mislocalization causally contributes to EDMD2 pathology in vivo not established\", \"Lamin A binding interface on ANKRD2 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ANKRD2 knockdown in osteosarcoma cells coupled it to PI3K/Akt and ERK signaling, cell-cycle cyclins, lamin expression, and chemosensitivity, extending its role beyond muscle.\",\n      \"evidence\": \"siRNA/shRNA knockdown in U2OS and HOS cells with Western blot pathway readouts and drug-response assays\",\n      \"pmids\": [\"40004199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in the proliferation/lamin axis not identified\", \"In vivo tumor relevance not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANKRD2 mechanically senses sarcomeric strain and integrates Akt2 phosphorylation, lamin A binding, and isoform identity into selective transcription-factor engagement remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ANKRD2-titin or ANKRD2-transcription factor complexes\", \"Causal chain from I-band release to specific gene programs in vivo not established\", \"Physiological loss-of-function phenotype in skeletal muscle under stress not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4, 17]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5, 12]}\n    ],\n    \"complexes\": [\n      \"titin N2A-myopalladin-calpain-3 I-band complex\",\n      \"p50/ANKRD2 NF-\\u03baB repressosome\",\n      \"ANKRD2-ZASP-p53 complex\"\n    ],\n    \"partners\": [\n      \"TTN\",\n      \"MYPN\",\n      \"CAPN3\",\n      \"TP53\",\n      \"YBX1\",\n      \"PML\",\n      \"LDB3\",\n      \"LMNA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}