{"gene":"ACRV1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1990,"finding":"SP-10 (ACRV1) is localized throughout the acrosome of human sperm, specifically in a bilaminar array associated with the inner aspect of the outer acrosomal membrane and the outer aspect of the inner acrosomal membrane; after the acrosome reaction, SP-10 remains on the inner acrosomal membrane and equatorial segment, suggesting a role in sperm-egg interaction post-acrosome reaction.","method":"Light and electron microscopic immunocytochemistry with monoclonal antibody MHS-10; ionophore A23187-induced acrosome reaction","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1–2 — direct subcellular localization with EM immunocytochemistry, replicated across multiple studies","pmids":["2310816"],"is_preprint":false},{"year":1992,"finding":"SP-10 heterogeneity (17.5–34 kDa peptide bands) results from endoproteolytic cleavage; microsequencing of purified SP-10 peptides identified amino termini corresponding to positions on the deduced sequence, indicating cleavage by trypsin-like protease (possibly acrosin) and other intra-acrosomal proteases at arginine, serine, proline, glycine, and glutamic acid bonds.","method":"Monoclonal antibody affinity chromatography purification, reverse-phase HPLC, preparative gel electrophoresis, Edman degradation microsequencing","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 — direct protein sequencing of purified peptides mapped to cleavage sites","pmids":["1637938"],"is_preprint":false},{"year":1992,"finding":"SP-10 is a hydrophilic peripheral acrosomal membrane protein (not an integral membrane protein), existing in two pools: a Triton X-114-releasable pool and a TX-114-resistant pool associated with the equatorial segment and inner acrosomal membrane; the TX-114-resistant pool is released by chaotropic salts and pH extremes, suggesting association with a TX-114-resistant anchor.","method":"Triton X-114 extraction, phase partitioning, sequential chemical treatments of human sperm","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 — biochemical fractionation with multiple extraction conditions; clear mechanistic conclusion about membrane association","pmids":["1591355"],"is_preprint":false},{"year":1994,"finding":"SP-10 undergoes proteolytic processing: a full-length ~45 kDa precursor present in testis is cleaved to 32–26 kDa peptides in testis/early epididymis, and further processed to 25–18 kDa peptides first detected in caput epididymal sperm, with no additional processing during subsequent epididymal transit, ejaculation, or capacitation.","method":"Western blot of testis, epididymal, ejaculated, and capacitated sperm extracts; electron microscopic immunocytochemistry","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — systematic stage-wise biochemical analysis combined with EM localization; multiple orthogonal methods","pmids":["7888499"],"is_preprint":false},{"year":1994,"finding":"After follicular fluid-induced acrosome reaction, SP-10 is detected on the inner acrosomal membrane in the equatorial segment and associated with hybrid vesicles, consistent with a role in sperm-zona binding or penetration.","method":"Electron microscopic immunocytochemistry on follicular fluid-treated human sperm","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization post-acrosome reaction, but functional role is inferred","pmids":["7888499"],"is_preprint":false},{"year":1996,"finding":"Anti-SP-10 antibodies inhibit bovine in vitro fertilization by reducing sperm-zona secondary binding and impairing the ability of capacitated spermatozoa to complete the acrosome reaction; antibodies also affect motility of capacitated but not noncapacitated spermatozoa.","method":"Bovine in vitro fertilization assay with monoclonal and polyclonal antibodies to human SP-10","journal":"Journal of reproduction and fertility","confidence":"Medium","confidence_rationale":"Tier 2 — functional inhibition assay with defined phenotypic readouts, single study","pmids":["8882296"],"is_preprint":false},{"year":1999,"finding":"The mouse SP-10 (mSP-10/Acrv1) gene is transcribed specifically in early round spermatids coincident with acrosomal biogenesis; the -408/+28 or -266/+28 bp 5' flanking region is sufficient to direct round spermatid-specific expression in vivo, while the -91/+28 fragment lacks promoter activity; the core promoter lacks a TATA box but contains a canonical initiator (Inr) element.","method":"Transgenic mice with GFP reporter driven by SP-10 promoter deletions; RT-PCR for temporal expression","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic promoter deletion analysis with functional reporter readout","pmids":["10529272"],"is_preprint":false},{"year":2000,"finding":"Human SP-10 expressed on the equatorial region of acrosome-reacted sperm mediates sperm-oolemma binding in a beta-1 integrin-independent manner but does not participate in sperm-zona binding.","method":"Monoclonal antibody inhibition assays: zona-free hamster egg penetration test, hemizona assay; F9 cell-binding assay with beta-1 integrin-lacking cells; immunofluorescence localization","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays (zona binding vs. oolemma binding) with defined inhibitory antibody, single study","pmids":["10775167"],"is_preprint":false},{"year":2003,"finding":"The -408/-92 region of the SP-10 spermatid-specific promoter functions as an insulator in somatic cells, blocking enhancer-promoter interactions in a position- and orientation-dependent manner; insulator activity maps to the -186/-135 region and requires two ACACAC motifs.","method":"Enhancer-blocking transfection assays in COS cells; transgenic mice with CMV enhancer adjacent to SP-10 promoter; site-directed mutagenesis of ACACAC motifs","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 — functional insulator mapping by mutagenesis and transgenic mice, multiple orthogonal approaches","pmids":["14512027"],"is_preprint":false},{"year":2007,"finding":"TDP-43 binds to the SP-10 insulator element and mediates its enhancer-blocking function by tethering the SP-10 gene to the nuclear matrix in somatic cells, sequestering the core promoter; in round spermatids where SP-10 is expressed, this tethering is released. TDP-43 knockdown by siRNA releases the enhancer-blocking effect, and mutation of TDP-43 binding sites abolishes insulator function.","method":"Nuclear matrix fractionation; Gal4 recruitment assay; siRNA knockdown; stable cell culture enhancer-blocking assay; site-directed mutagenesis; transgenic mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including loss-of-function (siRNA), mutagenesis, fractionation, and transgenic validation","pmids":["17932037"],"is_preprint":false},{"year":2007,"finding":"NF45 binds to the SP-10 promoter at an AGAAAA (Pu-box) element at -154 in a site-specific manner; co-transfection of NF45 and NF90 upregulates SP-10 promoter-driven transcription in GC2 spermatogenic cells in an AGAAAA-dependent manner, but chromatin modification is required prior to NF45/NF90 action for full activation in vivo.","method":"Gel shift assays with recombinant NF45; co-transfection luciferase reporter assays; immunohistochemistry; phorbol ester/ionomycin stimulation of NF45-NF90 complex","journal":"Journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 — direct DNA binding assay plus functional reporter assay, but in vivo activation not confirmed","pmids":["17942973"],"is_preprint":false},{"year":2011,"finding":"TDP-43 functions as a transcriptional repressor of the acrv1 gene in spermatocytes via its N-terminal RRM1 domain in a histone deacetylase-independent manner; TDP-43 binds GTGTGT motifs in the acrv1 promoter in vivo; TDP-43 promotes RNA polymerase II pausing at the acrv1 promoter in spermatocytes; RNA binding-defective TDP-43 relieves repressor function, whereas splice variant isoforms do not.","method":"Plasmid chromatin immunoprecipitation (ChIP); reporter gene assays with domain deletion mutants; ChIP on physiologically isolated germ cells; RNAPII occupancy assays; in vivo transgenic analysis with GTGTGT motif mutations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal in vivo and in vitro methods including ChIP, mutagenesis, domain dissection, and germ cell isolation","pmids":["21252238"],"is_preprint":false},{"year":2025,"finding":"ZNF280A enhances ACRV1 transcription by interacting with transcription factor CUX2 and facilitating its recruitment to the ACRV1 promoter; elevated ACRV1 expression activates PI3K/AKT signaling and increases expression of glycolytic enzymes PKM2 and LDHA, promoting aerobic glycolysis in ovarian cancer cells.","method":"ZNF280A knockdown functional assays (proliferation, migration, apoptosis, in vivo xenografts); ChIP/co-IP for CUX2-ZNF280A interaction at ACRV1 promoter; AKT inhibitor and glycolysis inhibitor rescue experiments; glucose uptake, lactate, ATP, and ECAR measurements","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with pharmacological rescue and co-IP, but single study in a non-canonical context for ACRV1","pmids":["41338461"],"is_preprint":false}],"current_model":"ACRV1 (SP-10) encodes a hydrophilic peripheral intra-acrosomal protein that is synthesized as a ~45 kDa precursor in round spermatids under transcriptional control of a 294-bp proximal promoter regulated by TDP-43-mediated RNAPII pausing and NF45/NF90 activation, processed proteolytically (partly by acrosin-like proteases) during epididymal transit to generate heterogeneous 18–32 kDa peptides, localizes to the inner acrosomal membrane and equatorial segment after the acrosome reaction, and mediates sperm-oolemma binding in a beta-1 integrin-independent manner; additionally, in somatic/cancer contexts, ACRV1 transcription is driven by a ZNF280A–CUX2 axis that activates PI3K/AKT signaling and aerobic glycolysis."},"narrative":{"teleology":[{"year":1990,"claim":"Determining where SP-10 resides in the sperm head established that it is an intra-acrosomal protein retained on the inner acrosomal membrane and equatorial segment after the acrosome reaction, placing it at the interface of sperm-egg interaction.","evidence":"Light and electron microscopic immunocytochemistry with MHS-10 monoclonal antibody on human sperm before and after ionophore-induced acrosome reaction","pmids":["2310816"],"confidence":"High","gaps":["Functional role in fertilization was inferred but not directly tested","No information on how SP-10 remains anchored to the inner acrosomal membrane"]},{"year":1992,"claim":"Establishing SP-10 as a hydrophilic peripheral protein (not integral membrane) that is endoproteolytically processed at specific sites resolved the molecular basis for its heterogeneous electrophoretic profile and defined the nature of its membrane association.","evidence":"Triton X-114 phase partitioning, chaotropic extraction, affinity chromatography, Edman degradation microsequencing of purified peptides","pmids":["1637938","1591355"],"confidence":"High","gaps":["Identity of the proteases responsible for each cleavage event was not confirmed beyond inference of acrosin","Mechanism of TX-114-resistant anchoring at the equatorial segment remained undefined"]},{"year":1994,"claim":"Systematic stage-wise analysis showed that SP-10 processing is temporally ordered — a 45 kDa precursor is cleaved in testis, further processed during early epididymal transit, and remains stable thereafter — defining the developmental window of proteolytic maturation.","evidence":"Western blot of human testis, epididymal, ejaculated, and capacitated sperm; EM immunocytochemistry after follicular fluid-induced acrosome reaction","pmids":["7888499"],"confidence":"High","gaps":["Whether processing is required for SP-10 function was not tested","Specific proteases active in the epididymis versus testis were not identified"]},{"year":1996,"claim":"Antibody inhibition of bovine IVF demonstrated a functional requirement for SP-10 in sperm-zona secondary binding and acrosome reaction completion, providing the first direct evidence that SP-10 participates in fertilization.","evidence":"Bovine in vitro fertilization assay with anti-SP-10 monoclonal and polyclonal antibodies","pmids":["8882296"],"confidence":"Medium","gaps":["Cross-species antibody approach leaves species-specific mechanism uncertain","Antibody effects on motility complicate interpretation of binding-specific phenotype"]},{"year":1999,"claim":"Transgenic promoter-deletion analysis identified a ~294 bp proximal region sufficient for spermatid-specific expression from a TATA-less, Inr-dependent promoter, defining the cis-regulatory architecture controlling ACRV1 transcription during acrosome biogenesis.","evidence":"Transgenic mice carrying GFP reporter driven by serial SP-10 5′ flanking deletions; RT-PCR","pmids":["10529272"],"confidence":"High","gaps":["Trans-acting factors driving spermatid specificity were not identified at this stage","Chromatin state at the endogenous locus was not characterized"]},{"year":2000,"claim":"Functional dissection distinguished SP-10's role: it mediates sperm-oolemma binding (not zona binding) in a β1-integrin-independent manner, narrowing its function to the post-acrosome-reaction fusion step.","evidence":"Zona-free hamster egg penetration test, hemizona assay, F9 cell binding assay lacking β1-integrin; anti-SP-10 antibody inhibition","pmids":["10775167"],"confidence":"Medium","gaps":["Oolemmal receptor for SP-10 was not identified","Reliance on antibody inhibition without genetic loss-of-function limits mechanistic certainty"]},{"year":2003,"claim":"Discovery that the SP-10 promoter upstream region acts as an insulator in somatic cells — blocking enhancer-promoter communication via two ACACAC motifs — explained why the gene is silent outside the germline despite possessing a functional core promoter.","evidence":"Enhancer-blocking transfection assays in COS cells; transgenic mice with CMV enhancer; site-directed mutagenesis of ACACAC motifs","pmids":["14512027"],"confidence":"High","gaps":["The trans-acting factor mediating insulator function was unknown","How the insulator is inactivated in spermatids was not addressed"]},{"year":2007,"claim":"Identification of TDP-43 as the insulator-binding factor that tethers the SP-10 promoter to the nuclear matrix in somatic cells, and of NF45/NF90 as spermatid-specific co-activators acting through a Pu-box element, resolved the opposing trans-acting mechanisms that enforce tissue-specific expression.","evidence":"Nuclear matrix fractionation, Gal4 tethering assay, siRNA knockdown of TDP-43, gel shift with recombinant NF45, co-transfection reporter assays in GC2 cells","pmids":["17932037","17942973"],"confidence":"High","gaps":["In vivo NF45/NF90 activation was not confirmed — chromatin remodeling prerequisite was noted but not characterized","How TDP-43 tethering is released specifically in round spermatids was not determined"]},{"year":2011,"claim":"Mechanistic dissection showed TDP-43 represses ACRV1 transcription in spermatocytes by promoting RNA polymerase II pausing at the promoter via its RRM1 domain in an HDAC-independent manner, establishing a kinetic model for stage-specific gene activation upon TDP-43 release.","evidence":"ChIP for TDP-43 and RNAPII on isolated germ cells; domain-deletion and GTGTGT-motif mutation analysis in reporter assays and transgenic mice","pmids":["21252238"],"confidence":"High","gaps":["Signal or event that displaces TDP-43 at the spermatocyte-to-spermatid transition was not identified","Whether RNAPII pausing is a general mechanism for other spermatid-specific genes was not explored"]},{"year":2025,"claim":"In a somatic cancer context, a ZNF280A–CUX2 transcription factor axis was shown to aberrantly activate ACRV1 transcription, and the resulting ACRV1 protein activates PI3K/AKT signaling and aerobic glycolysis, revealing an unexpected oncogenic signaling role outside the germline.","evidence":"ZNF280A knockdown, ChIP and co-IP for CUX2 at ACRV1 promoter, AKT/glycolysis inhibitor rescue, xenograft models in ovarian cancer cells","pmids":["41338461"],"confidence":"Medium","gaps":["Mechanism by which ACRV1 protein activates PI3K/AKT was not defined","Single study in ovarian cancer — generalizability to other cancers or normal somatic tissues is unaddressed","Whether the germline insulator mechanism is specifically disrupted in these cancer cells was not investigated"]},{"year":null,"claim":"The oolemmal receptor for SP-10 remains unidentified, and genetic loss-of-function models (knockout) have not been reported, leaving the in vivo requirement of ACRV1 for male fertility unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ACRV1 knockout phenotype has been reported in any organism","The molecular mechanism linking ACRV1 to PI3K/AKT activation in somatic cells is undefined","Structure of the processed SP-10 peptides has not been determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,5,7]}],"localization":[{"term_id":"GO:0043226","term_label":"organelle","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,7]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12]}],"complexes":[],"partners":["TARDBP","NF45","NF90","ZNF280A","CUX2"],"other_free_text":[]},"mechanistic_narrative":"ACRV1 (SP-10) encodes a hydrophilic peripheral acrosomal protein that functions in sperm-egg interaction during fertilization. The protein is synthesized as a ~45 kDa precursor in round spermatids, undergoes stage-specific endoproteolytic processing by acrosin-like and other intra-acrosomal proteases during spermiogenesis and epididymal transit to yield heterogeneous 18–32 kDa peptides, and localizes to the inner acrosomal membrane and equatorial segment where it persists after the acrosome reaction to mediate sperm-oolemma binding in a β1-integrin-independent manner [PMID:2310816, PMID:1637938, PMID:7888499, PMID:10775167]. Spermatid-specific expression is directed by a TATA-less proximal promoter containing an initiator element, whose activity in somatic cells is silenced by a TDP-43-dependent insulator that tethers the promoter to the nuclear matrix and induces RNA polymerase II pausing; in round spermatids this repression is relieved, and NF45/NF90 activates transcription through a Pu-box element [PMID:10529272, PMID:17932037, PMID:21252238, PMID:17942973]. In ovarian cancer cells, ectopic ACRV1 transcription is driven by a ZNF280A–CUX2 axis and activates PI3K/AKT signaling and aerobic glycolysis [PMID:41338461]."},"prefetch_data":{"uniprot":{"accession":"P26436","full_name":"Acrosomal protein SP-10","aliases":["Acrosomal vesicle protein 1"],"length_aa":265,"mass_kda":28.2,"function":"","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, acrosome","url":"https://www.uniprot.org/uniprotkb/P26436/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACRV1","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/ACRV1","total_profiled":1310},"omim":[{"mim_id":"620160","title":"IQ MOTIF-CONTAINING PROTEIN N; IQCN","url":"https://www.omim.org/entry/620160"},{"mim_id":"602991","title":"NOGGIN; NOG","url":"https://www.omim.org/entry/602991"},{"mim_id":"135100","title":"FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; FOP","url":"https://www.omim.org/entry/135100"},{"mim_id":"102525","title":"ACROSOMAL VESICLE PROTEIN 1; ACRV1","url":"https://www.omim.org/entry/102525"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Acrosome","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":110.6}],"url":"https://www.proteinatlas.org/search/ACRV1"},"hgnc":{"alias_symbol":["SPACA2","SP-10","D11S4365"],"prev_symbol":[]},"alphafold":{"accession":"P26436","domains":[{"cath_id":"2.10.60.10","chopping":"185-265","consensus_level":"medium","plddt":96.0848,"start":185,"end":265}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26436","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26436-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26436-F1-predicted_aligned_error_v6.png","plddt_mean":61.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACRV1","jax_strain_url":"https://www.jax.org/strain/search?query=ACRV1"},"sequence":{"accession":"P26436","fasta_url":"https://rest.uniprot.org/uniprotkb/P26436.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26436/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26436"}},"corpus_meta":[{"pmid":"2310816","id":"PMC_2310816","title":"Biochemical and morphological characterization of the intra-acrosomal antigen SP-10 from human sperm.","date":"1990","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/2310816","citation_count":129,"is_preprint":false},{"pmid":"17932037","id":"PMC_17932037","title":"A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17932037","citation_count":91,"is_preprint":false},{"pmid":"1693291","id":"PMC_1693291","title":"Cloning and sequencing of cDNAs coding for the human intra-acrosomal antigen SP-10.","date":"1990","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/1693291","citation_count":79,"is_preprint":false},{"pmid":"21252238","id":"PMC_21252238","title":"TDP-43 is a transcriptional repressor: the testis-specific mouse acrv1 gene is a TDP-43 target in vivo.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21252238","citation_count":64,"is_preprint":false},{"pmid":"10529272","id":"PMC_10529272","title":"Round spermatid-specific transcription of the mouse SP-10 gene is mediated by a 294-base pair proximal promoter.","date":"1999","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10529272","citation_count":62,"is_preprint":false},{"pmid":"8882296","id":"PMC_8882296","title":"Inhibition of bovine fertilization in vitro by antibodies to SP-10.","date":"1996","source":"Journal of reproduction and fertility","url":"https://pubmed.ncbi.nlm.nih.gov/8882296","citation_count":56,"is_preprint":false},{"pmid":"1868140","id":"PMC_1868140","title":"Localization of sperm antigen SP-10 during the six stages of the cycle of the seminiferous epithelium in man.","date":"1991","source":"Biology of 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SP-10.","date":"2002","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11730901","citation_count":17,"is_preprint":false},{"pmid":"7619499","id":"PMC_7619499","title":"Characterization of alternatively spliced human SP-10 mRNAs.","date":"1995","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/7619499","citation_count":16,"is_preprint":false},{"pmid":"8288254","id":"PMC_8288254","title":"Refinement of the localization of the gene for human intraacrosomal protein SP-10 (ACRV1) to the junction of bands q23-->q24 of chromosome 11 by nonisotopic in situ hybridization.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8288254","citation_count":15,"is_preprint":false},{"pmid":"4955254","id":"PMC_4955254","title":"Concurrent changes in transducing efficiency and content of transforming deoxyribonucleic acid in Bacillus subtilis bacteriophage SP-10.","date":"1966","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/4955254","citation_count":14,"is_preprint":false},{"pmid":"21488928","id":"PMC_21488928","title":"Developmental expression of ACRV1 in humans and mice.","date":"2011","source":"Andrologia","url":"https://pubmed.ncbi.nlm.nih.gov/21488928","citation_count":13,"is_preprint":false},{"pmid":"2298314","id":"PMC_2298314","title":"Differential diagnosis of immature germ cells in semen utilizing monoclonal antibody MHS-10 to the intra-acrosomal antigen SP-10.","date":"1990","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/2298314","citation_count":13,"is_preprint":false},{"pmid":"17942973","id":"PMC_17942973","title":"NF45 and NF90 in murine seminiferous epithelium: potential role in SP-10 gene transcription.","date":"2007","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/17942973","citation_count":13,"is_preprint":false},{"pmid":"8874713","id":"PMC_8874713","title":"Effect of immunization with human SP-10 in male rodents.","date":"1996","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/8874713","citation_count":11,"is_preprint":false},{"pmid":"32758798","id":"PMC_32758798","title":"Acrosomal marker SP-10 (gene name Acrv1) for staging of the cycle of seminiferous epithelium in the stallion.","date":"2020","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/32758798","citation_count":10,"is_preprint":false},{"pmid":"137989","id":"PMC_137989","title":"SP-10 bacteriophage-specific nucleic acid and enzyme synthesis in Bacillus subtilis W23.","date":"1977","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/137989","citation_count":10,"is_preprint":false},{"pmid":"7691073","id":"PMC_7691073","title":"Assay for recombinant and native human intraacrosomal antigen SP-10.","date":"1993","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/7691073","citation_count":7,"is_preprint":false},{"pmid":"1765564","id":"PMC_1765564","title":"Assignment of the gene for human intra-acrosomal protein SP-10 to the p12----q13 region of chromosome 11.","date":"1991","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/1765564","citation_count":7,"is_preprint":false},{"pmid":"39046915","id":"PMC_39046915","title":"Synaptotagmin 13 Could Drive the Progression of Esophageal Squamous Cell Carcinoma Through Upregulating ACRV1.","date":"2024","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39046915","citation_count":2,"is_preprint":false},{"pmid":"17249247","id":"PMC_17249247","title":"The benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10) reduces HIV-1 infectivity in vitro by modifying actin dynamics.","date":"2006","source":"Antiviral chemistry & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/17249247","citation_count":2,"is_preprint":false},{"pmid":"41338461","id":"PMC_41338461","title":"ZNF280A and ACRV1 enhance aerobic glycolysis and drive ovarian cancer progression via the PI3K/AKT signaling pathway.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41338461","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19610,"output_tokens":3320,"usd":0.054315},"stage2":{"model":"claude-opus-4-6","input_tokens":6701,"output_tokens":2946,"usd":0.160733},"total_usd":0.215048,"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\": 1990,\n      \"finding\": \"SP-10 (ACRV1) is localized throughout the acrosome of human sperm, specifically in a bilaminar array associated with the inner aspect of the outer acrosomal membrane and the outer aspect of the inner acrosomal membrane; after the acrosome reaction, SP-10 remains on the inner acrosomal membrane and equatorial segment, suggesting a role in sperm-egg interaction post-acrosome reaction.\",\n      \"method\": \"Light and electron microscopic immunocytochemistry with monoclonal antibody MHS-10; ionophore A23187-induced acrosome reaction\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct subcellular localization with EM immunocytochemistry, replicated across multiple studies\",\n      \"pmids\": [\"2310816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-10 heterogeneity (17.5–34 kDa peptide bands) results from endoproteolytic cleavage; microsequencing of purified SP-10 peptides identified amino termini corresponding to positions on the deduced sequence, indicating cleavage by trypsin-like protease (possibly acrosin) and other intra-acrosomal proteases at arginine, serine, proline, glycine, and glutamic acid bonds.\",\n      \"method\": \"Monoclonal antibody affinity chromatography purification, reverse-phase HPLC, preparative gel electrophoresis, Edman degradation microsequencing\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing of purified peptides mapped to cleavage sites\",\n      \"pmids\": [\"1637938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"SP-10 is a hydrophilic peripheral acrosomal membrane protein (not an integral membrane protein), existing in two pools: a Triton X-114-releasable pool and a TX-114-resistant pool associated with the equatorial segment and inner acrosomal membrane; the TX-114-resistant pool is released by chaotropic salts and pH extremes, suggesting association with a TX-114-resistant anchor.\",\n      \"method\": \"Triton X-114 extraction, phase partitioning, sequential chemical treatments of human sperm\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical fractionation with multiple extraction conditions; clear mechanistic conclusion about membrane association\",\n      \"pmids\": [\"1591355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"SP-10 undergoes proteolytic processing: a full-length ~45 kDa precursor present in testis is cleaved to 32–26 kDa peptides in testis/early epididymis, and further processed to 25–18 kDa peptides first detected in caput epididymal sperm, with no additional processing during subsequent epididymal transit, ejaculation, or capacitation.\",\n      \"method\": \"Western blot of testis, epididymal, ejaculated, and capacitated sperm extracts; electron microscopic immunocytochemistry\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic stage-wise biochemical analysis combined with EM localization; multiple orthogonal methods\",\n      \"pmids\": [\"7888499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"After follicular fluid-induced acrosome reaction, SP-10 is detected on the inner acrosomal membrane in the equatorial segment and associated with hybrid vesicles, consistent with a role in sperm-zona binding or penetration.\",\n      \"method\": \"Electron microscopic immunocytochemistry on follicular fluid-treated human sperm\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization post-acrosome reaction, but functional role is inferred\",\n      \"pmids\": [\"7888499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Anti-SP-10 antibodies inhibit bovine in vitro fertilization by reducing sperm-zona secondary binding and impairing the ability of capacitated spermatozoa to complete the acrosome reaction; antibodies also affect motility of capacitated but not noncapacitated spermatozoa.\",\n      \"method\": \"Bovine in vitro fertilization assay with monoclonal and polyclonal antibodies to human SP-10\",\n      \"journal\": \"Journal of reproduction and fertility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional inhibition assay with defined phenotypic readouts, single study\",\n      \"pmids\": [\"8882296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The mouse SP-10 (mSP-10/Acrv1) gene is transcribed specifically in early round spermatids coincident with acrosomal biogenesis; the -408/+28 or -266/+28 bp 5' flanking region is sufficient to direct round spermatid-specific expression in vivo, while the -91/+28 fragment lacks promoter activity; the core promoter lacks a TATA box but contains a canonical initiator (Inr) element.\",\n      \"method\": \"Transgenic mice with GFP reporter driven by SP-10 promoter deletions; RT-PCR for temporal expression\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic promoter deletion analysis with functional reporter readout\",\n      \"pmids\": [\"10529272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human SP-10 expressed on the equatorial region of acrosome-reacted sperm mediates sperm-oolemma binding in a beta-1 integrin-independent manner but does not participate in sperm-zona binding.\",\n      \"method\": \"Monoclonal antibody inhibition assays: zona-free hamster egg penetration test, hemizona assay; F9 cell-binding assay with beta-1 integrin-lacking cells; immunofluorescence localization\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays (zona binding vs. oolemma binding) with defined inhibitory antibody, single study\",\n      \"pmids\": [\"10775167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The -408/-92 region of the SP-10 spermatid-specific promoter functions as an insulator in somatic cells, blocking enhancer-promoter interactions in a position- and orientation-dependent manner; insulator activity maps to the -186/-135 region and requires two ACACAC motifs.\",\n      \"method\": \"Enhancer-blocking transfection assays in COS cells; transgenic mice with CMV enhancer adjacent to SP-10 promoter; site-directed mutagenesis of ACACAC motifs\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional insulator mapping by mutagenesis and transgenic mice, multiple orthogonal approaches\",\n      \"pmids\": [\"14512027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TDP-43 binds to the SP-10 insulator element and mediates its enhancer-blocking function by tethering the SP-10 gene to the nuclear matrix in somatic cells, sequestering the core promoter; in round spermatids where SP-10 is expressed, this tethering is released. TDP-43 knockdown by siRNA releases the enhancer-blocking effect, and mutation of TDP-43 binding sites abolishes insulator function.\",\n      \"method\": \"Nuclear matrix fractionation; Gal4 recruitment assay; siRNA knockdown; stable cell culture enhancer-blocking assay; site-directed mutagenesis; transgenic mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including loss-of-function (siRNA), mutagenesis, fractionation, and transgenic validation\",\n      \"pmids\": [\"17932037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NF45 binds to the SP-10 promoter at an AGAAAA (Pu-box) element at -154 in a site-specific manner; co-transfection of NF45 and NF90 upregulates SP-10 promoter-driven transcription in GC2 spermatogenic cells in an AGAAAA-dependent manner, but chromatin modification is required prior to NF45/NF90 action for full activation in vivo.\",\n      \"method\": \"Gel shift assays with recombinant NF45; co-transfection luciferase reporter assays; immunohistochemistry; phorbol ester/ionomycin stimulation of NF45-NF90 complex\",\n      \"journal\": \"Journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct DNA binding assay plus functional reporter assay, but in vivo activation not confirmed\",\n      \"pmids\": [\"17942973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TDP-43 functions as a transcriptional repressor of the acrv1 gene in spermatocytes via its N-terminal RRM1 domain in a histone deacetylase-independent manner; TDP-43 binds GTGTGT motifs in the acrv1 promoter in vivo; TDP-43 promotes RNA polymerase II pausing at the acrv1 promoter in spermatocytes; RNA binding-defective TDP-43 relieves repressor function, whereas splice variant isoforms do not.\",\n      \"method\": \"Plasmid chromatin immunoprecipitation (ChIP); reporter gene assays with domain deletion mutants; ChIP on physiologically isolated germ cells; RNAPII occupancy assays; in vivo transgenic analysis with GTGTGT motif mutations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal in vivo and in vitro methods including ChIP, mutagenesis, domain dissection, and germ cell isolation\",\n      \"pmids\": [\"21252238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF280A enhances ACRV1 transcription by interacting with transcription factor CUX2 and facilitating its recruitment to the ACRV1 promoter; elevated ACRV1 expression activates PI3K/AKT signaling and increases expression of glycolytic enzymes PKM2 and LDHA, promoting aerobic glycolysis in ovarian cancer cells.\",\n      \"method\": \"ZNF280A knockdown functional assays (proliferation, migration, apoptosis, in vivo xenografts); ChIP/co-IP for CUX2-ZNF280A interaction at ACRV1 promoter; AKT inhibitor and glycolysis inhibitor rescue experiments; glucose uptake, lactate, ATP, and ECAR measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with pharmacological rescue and co-IP, but single study in a non-canonical context for ACRV1\",\n      \"pmids\": [\"41338461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACRV1 (SP-10) encodes a hydrophilic peripheral intra-acrosomal protein that is synthesized as a ~45 kDa precursor in round spermatids under transcriptional control of a 294-bp proximal promoter regulated by TDP-43-mediated RNAPII pausing and NF45/NF90 activation, processed proteolytically (partly by acrosin-like proteases) during epididymal transit to generate heterogeneous 18–32 kDa peptides, localizes to the inner acrosomal membrane and equatorial segment after the acrosome reaction, and mediates sperm-oolemma binding in a beta-1 integrin-independent manner; additionally, in somatic/cancer contexts, ACRV1 transcription is driven by a ZNF280A–CUX2 axis that activates PI3K/AKT signaling and aerobic glycolysis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACRV1 (SP-10) encodes a hydrophilic peripheral acrosomal protein that functions in sperm-egg interaction during fertilization. The protein is synthesized as a ~45 kDa precursor in round spermatids, undergoes stage-specific endoproteolytic processing by acrosin-like and other intra-acrosomal proteases during spermiogenesis and epididymal transit to yield heterogeneous 18–32 kDa peptides, and localizes to the inner acrosomal membrane and equatorial segment where it persists after the acrosome reaction to mediate sperm-oolemma binding in a β1-integrin-independent manner [PMID:2310816, PMID:1637938, PMID:7888499, PMID:10775167]. Spermatid-specific expression is directed by a TATA-less proximal promoter containing an initiator element, whose activity in somatic cells is silenced by a TDP-43-dependent insulator that tethers the promoter to the nuclear matrix and induces RNA polymerase II pausing; in round spermatids this repression is relieved, and NF45/NF90 activates transcription through a Pu-box element [PMID:10529272, PMID:17932037, PMID:21252238, PMID:17942973]. In ovarian cancer cells, ectopic ACRV1 transcription is driven by a ZNF280A–CUX2 axis and activates PI3K/AKT signaling and aerobic glycolysis [PMID:41338461].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Determining where SP-10 resides in the sperm head established that it is an intra-acrosomal protein retained on the inner acrosomal membrane and equatorial segment after the acrosome reaction, placing it at the interface of sperm-egg interaction.\",\n      \"evidence\": \"Light and electron microscopic immunocytochemistry with MHS-10 monoclonal antibody on human sperm before and after ionophore-induced acrosome reaction\",\n      \"pmids\": [\"2310816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role in fertilization was inferred but not directly tested\",\n        \"No information on how SP-10 remains anchored to the inner acrosomal membrane\"\n      ]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing SP-10 as a hydrophilic peripheral protein (not integral membrane) that is endoproteolytically processed at specific sites resolved the molecular basis for its heterogeneous electrophoretic profile and defined the nature of its membrane association.\",\n      \"evidence\": \"Triton X-114 phase partitioning, chaotropic extraction, affinity chromatography, Edman degradation microsequencing of purified peptides\",\n      \"pmids\": [\"1637938\", \"1591355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the proteases responsible for each cleavage event was not confirmed beyond inference of acrosin\",\n        \"Mechanism of TX-114-resistant anchoring at the equatorial segment remained undefined\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Systematic stage-wise analysis showed that SP-10 processing is temporally ordered — a 45 kDa precursor is cleaved in testis, further processed during early epididymal transit, and remains stable thereafter — defining the developmental window of proteolytic maturation.\",\n      \"evidence\": \"Western blot of human testis, epididymal, ejaculated, and capacitated sperm; EM immunocytochemistry after follicular fluid-induced acrosome reaction\",\n      \"pmids\": [\"7888499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether processing is required for SP-10 function was not tested\",\n        \"Specific proteases active in the epididymis versus testis were not identified\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Antibody inhibition of bovine IVF demonstrated a functional requirement for SP-10 in sperm-zona secondary binding and acrosome reaction completion, providing the first direct evidence that SP-10 participates in fertilization.\",\n      \"evidence\": \"Bovine in vitro fertilization assay with anti-SP-10 monoclonal and polyclonal antibodies\",\n      \"pmids\": [\"8882296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cross-species antibody approach leaves species-specific mechanism uncertain\",\n        \"Antibody effects on motility complicate interpretation of binding-specific phenotype\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Transgenic promoter-deletion analysis identified a ~294 bp proximal region sufficient for spermatid-specific expression from a TATA-less, Inr-dependent promoter, defining the cis-regulatory architecture controlling ACRV1 transcription during acrosome biogenesis.\",\n      \"evidence\": \"Transgenic mice carrying GFP reporter driven by serial SP-10 5′ flanking deletions; RT-PCR\",\n      \"pmids\": [\"10529272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Trans-acting factors driving spermatid specificity were not identified at this stage\",\n        \"Chromatin state at the endogenous locus was not characterized\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Functional dissection distinguished SP-10's role: it mediates sperm-oolemma binding (not zona binding) in a β1-integrin-independent manner, narrowing its function to the post-acrosome-reaction fusion step.\",\n      \"evidence\": \"Zona-free hamster egg penetration test, hemizona assay, F9 cell binding assay lacking β1-integrin; anti-SP-10 antibody inhibition\",\n      \"pmids\": [\"10775167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Oolemmal receptor for SP-10 was not identified\",\n        \"Reliance on antibody inhibition without genetic loss-of-function limits mechanistic certainty\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that the SP-10 promoter upstream region acts as an insulator in somatic cells — blocking enhancer-promoter communication via two ACACAC motifs — explained why the gene is silent outside the germline despite possessing a functional core promoter.\",\n      \"evidence\": \"Enhancer-blocking transfection assays in COS cells; transgenic mice with CMV enhancer; site-directed mutagenesis of ACACAC motifs\",\n      \"pmids\": [\"14512027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The trans-acting factor mediating insulator function was unknown\",\n        \"How the insulator is inactivated in spermatids was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of TDP-43 as the insulator-binding factor that tethers the SP-10 promoter to the nuclear matrix in somatic cells, and of NF45/NF90 as spermatid-specific co-activators acting through a Pu-box element, resolved the opposing trans-acting mechanisms that enforce tissue-specific expression.\",\n      \"evidence\": \"Nuclear matrix fractionation, Gal4 tethering assay, siRNA knockdown of TDP-43, gel shift with recombinant NF45, co-transfection reporter assays in GC2 cells\",\n      \"pmids\": [\"17932037\", \"17942973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo NF45/NF90 activation was not confirmed — chromatin remodeling prerequisite was noted but not characterized\",\n        \"How TDP-43 tethering is released specifically in round spermatids was not determined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistic dissection showed TDP-43 represses ACRV1 transcription in spermatocytes by promoting RNA polymerase II pausing at the promoter via its RRM1 domain in an HDAC-independent manner, establishing a kinetic model for stage-specific gene activation upon TDP-43 release.\",\n      \"evidence\": \"ChIP for TDP-43 and RNAPII on isolated germ cells; domain-deletion and GTGTGT-motif mutation analysis in reporter assays and transgenic mice\",\n      \"pmids\": [\"21252238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signal or event that displaces TDP-43 at the spermatocyte-to-spermatid transition was not identified\",\n        \"Whether RNAPII pausing is a general mechanism for other spermatid-specific genes was not explored\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In a somatic cancer context, a ZNF280A–CUX2 transcription factor axis was shown to aberrantly activate ACRV1 transcription, and the resulting ACRV1 protein activates PI3K/AKT signaling and aerobic glycolysis, revealing an unexpected oncogenic signaling role outside the germline.\",\n      \"evidence\": \"ZNF280A knockdown, ChIP and co-IP for CUX2 at ACRV1 promoter, AKT/glycolysis inhibitor rescue, xenograft models in ovarian cancer cells\",\n      \"pmids\": [\"41338461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ACRV1 protein activates PI3K/AKT was not defined\",\n        \"Single study in ovarian cancer — generalizability to other cancers or normal somatic tissues is unaddressed\",\n        \"Whether the germline insulator mechanism is specifically disrupted in these cancer cells was not investigated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The oolemmal receptor for SP-10 remains unidentified, and genetic loss-of-function models (knockout) have not been reported, leaving the in vivo requirement of ACRV1 for male fertility unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No ACRV1 knockout phenotype has been reported in any organism\",\n        \"The molecular mechanism linking ACRV1 to PI3K/AKT activation in somatic cells is undefined\",\n        \"Structure of the processed SP-10 peptides has not been determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098631\",\n        \"supporting_discovery_ids\": [0, 5, 7]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0043226\",\n        \"supporting_discovery_ids\": [0, 2, 3, 4]\n      },\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0, 4, 7]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1474165\",\n        \"supporting_discovery_ids\": [0, 5, 7]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [12]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TARDBP\",\n      \"NF45\",\n      \"NF90\",\n      \"ZNF280A\",\n      \"CUX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}