{"gene":"TEX14","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2006,"finding":"TEX14 localizes to germ cell intercellular bridges and is required for their formation; in Tex14-/- mice, intercellular bridges are absent by electron microscopy and immunofluorescence, and spermatogenesis arrests before completion of the first meiotic division.","method":"Targeted gene knockout in mice, electron microscopy, immunofluorescence localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and developmental phenotype, multiple orthogonal methods (EM + IF), replicated across subsequent studies","pmids":["16549803"],"is_preprint":false},{"year":2008,"finding":"TEX14 is an essential component of both male and female embryonic germ cell intercellular bridges; KIF23 (MKLP1) was identified as a component of intercellular bridges during spermatogenesis and in embryonic germ cells, and intercellular bridges are absent between germ cells of Tex14-null mice.","method":"Tex14 knockout mice, electron microscopy, KIF23 immunofluorescence","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined phenotype, multiple orthogonal methods (EM + IF), identifies KIF23 as a bridge component","pmids":["19020301"],"is_preprint":false},{"year":2010,"finding":"TEX14 interacts with CEP55 via a conserved GPPX3Y motif; this interaction competitively blocks ALIX and TSG101 from binding CEP55 at the midbody, thereby preventing abscission and stabilizing the intercellular bridge. CEP55 was identified as a stable component of the intercellular bridge by biochemical enrichment of male germ cell intercellular bridges.","method":"Biochemical enrichment of intercellular bridges, co-immunoprecipitation, competitive binding assays, localization studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical enrichment, co-IP, competitive binding), replicated in structural study","pmids":["20176808"],"is_preprint":false},{"year":2012,"finding":"TEX14 is recruited to kinetochores by Plk1 in a Cdk1-dependent manner during early mitosis; exclusion of TEX14 from kinetochores impairs outer kinetochore component localization, kinetochore-microtubule attachment, chromosome congression, and spindle assembly checkpoint function. Plk1 phosphorylation of TEX14 during metaphase promotes APC/C(Cdc20)-mediated TEX14 degradation, and inhibition of this phosphorylation causes retention of TEX14 at kinetochores and delayed metaphase-to-anaphase transition.","method":"Kinase assays, loss-of-function (knockdown/exclusion), phosphorylation site mutagenesis, live-cell imaging, chromosome segregation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including mutagenesis, kinase assay, epistasis with Plk1 and APC/C, single lab","pmids":["22405274"],"is_preprint":false},{"year":2003,"finding":"TEX14 encodes a 1450-amino-acid protein containing three ankyrin repeats, a protein kinase domain, and a leucine zipper dimerization motif; mRNA is expressed specifically in the testis with highest levels in pachytene, diplotene, and meiotically dividing spermatocytes.","method":"Sequence analysis, Northern blot, in situ hybridization, 5'-RACE","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence characterization and expression mapping, no functional assay, but well-defined domain architecture","pmids":["12711554"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of the CEP55-EABR domain bound to TEX14 peptide revealed that TEX14 interacts with CEP55 via an AxGPPx3YxPP motif (Ala793, Gly795, Pro796, Pro797, Tyr801, Pro803, Pro804); TEX14 competitively prevents ALIX recruitment to CEP55-EABR. High affinity and low dissociation rate of TEX14 for CEP55, together with increased local concentration, cooperatively prevent ALIX from recruiting ESCRT complexes to the midbody.","method":"X-ray crystallography, binding assays (affinity/kinetics), chimeric peptide functional characterization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by multiple biochemical methods, confirms and extends mechanism from PMID 20176808","pmids":["26392564"],"is_preprint":false},{"year":2011,"finding":"A 51 bp insertion within exon 27 of porcine Tex14 causes differential splicing, a premature stop codon, loss of TEX14 protein expression (confirmed by Western blot), and spermatogenic arrest, demonstrating TEX14 is required for spermatogenesis in pigs.","method":"Genome-wide SNP scan, candidate gene sequencing, RT-PCR, Western blot, testis histology","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural loss-of-function mutation with protein loss confirmed by Western blot, single species/lab","pmids":["22136159"],"is_preprint":false},{"year":2019,"finding":"DAZL (deleted in azoospermia-like), a germ cell RNA-binding protein, regulates TEX14 at the translational level via the TEX14 3'UTR, without altering Tex14 mRNA levels; demonstrated by 3'UTR-luciferase reporter assays. In Dazl hypomorph ovaries, TEX14 protein foci were reduced ~59% with no change in mRNA, linking DAZL-dependent translation of TEX14 to intercellular bridge formation and primordial follicle assembly.","method":"3'UTR-luciferase reporter assay, siRNA knockdown (Dazl hypomorph), immunostaining, RT-qPCR","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus protein/mRNA dissociation in knockdown model, single lab","pmids":["31659914"],"is_preprint":false},{"year":2025,"finding":"Partial peptides of TEX14 containing the GPPX3Y motif are sufficient to inhibit proliferation and induce apoptosis in cancer cells; the length and amino acid variation surrounding the GPPX3Y motif modulate this activity.","method":"Cell proliferation assays, apoptosis assays with TEX14 partial peptides in cancer cell lines","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined peptide activity in cell-based assays, single lab, single study","pmids":["41219627"],"is_preprint":false},{"year":2025,"finding":"Compound heterozygous loss-of-function mutations in TEX14 (p.S268C and p.R341*) disrupt TEX14 synthesis, leading to meiotic arrest at the pachytene stage and impaired intercellular bridge assembly in human testes.","method":"Exome/Sanger sequencing, Western blot (protein loss), immunofluorescence (ICB assembly), testis histology","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variant with functional protein-level and histological validation, single lab","pmids":["40492599"],"is_preprint":false},{"year":2026,"finding":"Loss-of-function TEX14 frameshift variants cause complete loss of TEX14 protein in the testis, failure of intercellular bridge formation, and spermatogenic arrest at the zygotene stage in both a mouse knock-in model and in the testes of a patient carrying the analogous variant. Mass spectrometry of purified ICBs showed ICB-associated proteins are predominantly involved in RNA processing and ribonucleoprotein complex biogenesis.","method":"Exome sequencing, mouse knock-in model, Western blot, immunofluorescence, histology, mass spectrometry of purified ICBs","journal":"Andrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, mouse model plus human correlate, mass spectrometry of purified bridges","pmids":["41603674"],"is_preprint":false}],"current_model":"TEX14 is a testis-enriched protein that localizes to the midbody/intercellular bridge region during germ cell cytokinesis, where it binds the CEP55-EABR domain via a high-affinity AxGPPx3YxPP motif to competitively exclude ALIX and TSG101, thereby blocking ESCRT-mediated abscission and stabilizing the permanent intercellular bridges essential for spermatogenesis; in somatic mitotic cells, TEX14 is additionally recruited to kinetochores by Plk1 in a Cdk1-dependent manner to support kinetochore-microtubule attachment and spindle assembly checkpoint signaling, and is subsequently degraded by APC/C(Cdc20) upon Plk1 phosphorylation; TEX14 translation is regulated post-transcriptionally by the RNA-binding protein DAZL in oogenic germ cells."},"narrative":{"mechanistic_narrative":"TEX14 is a testis-enriched protein that builds and stabilizes the permanent germ cell intercellular bridges (ICBs) required for spermatogenesis, and its loss abolishes ICBs and arrests germ cell development before completion of meiosis [PMID:16549803, PMID:19020301]. The molecular basis of bridge stabilization is competitive occupancy of the abscission machinery: TEX14 binds the CEP55-EABR domain through a conserved AxGPPx3YxPP motif with high affinity and a low dissociation rate, thereby excluding ALIX and TSG101 and preventing ESCRT-mediated recruitment that would otherwise complete cytokinetic abscission [PMID:20176808, PMID:26392564]. Beyond germ cells, TEX14 acts in somatic mitosis: it is recruited to kinetochores by Plk1 in a Cdk1-dependent manner to support kinetochore-microtubule attachment, chromosome congression, and spindle assembly checkpoint signaling, after which Plk1 phosphorylation triggers APC/C(Cdc20)-mediated degradation to permit the metaphase-to-anaphase transition [PMID:22405274]. TEX14 expression is controlled post-transcriptionally, with the germ cell RNA-binding protein DAZL promoting TEX14 translation via its 3'UTR to drive ICB formation and primordial follicle assembly [PMID:31659914]. Loss-of-function TEX14 variants cause spermatogenic arrest with failed ICB assembly in humans, recapitulated in mouse models [PMID:40492599, PMID:41603674].","teleology":[{"year":2003,"claim":"Before any function was known, defining the protein's domain architecture and expression pattern established TEX14 as a testis-specific, meiosis-associated multidomain protein worth functional dissection.","evidence":"Sequence analysis, Northern blot, and in situ hybridization of the TEX14 transcript","pmids":["12711554"],"confidence":"Medium","gaps":["No functional role assigned","Kinase domain catalytic activity not tested","No protein localization data"]},{"year":2006,"claim":"The central question of what TEX14 does in germ cells was answered by knockout, showing it is required to build intercellular bridges and for progression through meiosis.","evidence":"Targeted gene knockout in mice with EM and immunofluorescence","pmids":["16549803"],"confidence":"High","gaps":["Molecular mechanism of bridge formation not defined","Binding partners unknown","Does not address somatic roles"]},{"year":2008,"claim":"Extending the role beyond the testis, TEX14 was shown to be essential for both male and female embryonic germ cell bridges, and KIF23 was identified as a bridge component, placing TEX14 within a defined cytokinetic protein context.","evidence":"Tex14 knockout mice, EM, and KIF23 immunofluorescence","pmids":["19020301"],"confidence":"High","gaps":["Direct TEX14-KIF23 interaction not demonstrated","Mechanism linking TEX14 to bridge stabilization still unknown"]},{"year":2010,"claim":"The mechanism of permanent bridge stabilization was established: TEX14 binds CEP55 via a GPPX3Y motif and competitively excludes the ESCRT adaptors ALIX and TSG101, explaining how abscission is blocked.","evidence":"Biochemical enrichment of intercellular bridges, co-IP, and competitive binding assays","pmids":["20176808"],"confidence":"High","gaps":["Structural basis of competition not resolved","Affinity/kinetics not quantified","Does not address mitotic kinetochore function"]},{"year":2011,"claim":"A natural porcine loss-of-function mutation confirmed that TEX14 is required for spermatogenesis across mammals, generalizing the mouse phenotype.","evidence":"SNP scan, candidate gene sequencing, RT-PCR, Western blot, and testis histology in pigs","pmids":["22136159"],"confidence":"Medium","gaps":["Single species and lab","Mechanism of arrest not dissected","Bridge-specific defect not directly imaged"]},{"year":2012,"claim":"A distinct somatic function was uncovered, showing TEX14 is a Plk1- and Cdk1-regulated kinetochore factor supporting microtubule attachment and the spindle checkpoint, then degraded by APC/C(Cdc20) to allow anaphase.","evidence":"Kinase assays, loss-of-function, phospho-site mutagenesis, live-cell imaging, and chromosome segregation assays","pmids":["22405274"],"confidence":"High","gaps":["Single lab","Relationship between mitotic and germ cell roles unclear","Direct kinetochore-binding interface not mapped"]},{"year":2015,"claim":"The competitive exclusion mechanism was given atomic resolution, defining the AxGPPx3YxPP residues and showing high affinity, slow off-rate, and local concentration cooperatively block ALIX/ESCRT recruitment.","evidence":"X-ray crystallography of CEP55-EABR bound to TEX14 peptide with binding kinetics and chimeric peptide assays","pmids":["26392564"],"confidence":"High","gaps":["Full-length TEX14 structure not determined","In vivo dynamics of competition not measured"]},{"year":2019,"claim":"How TEX14 levels are set in germ cells was addressed by showing DAZL drives TEX14 translation via its 3'UTR without changing mRNA, linking RNA-binding control to bridge formation and follicle assembly.","evidence":"3'UTR-luciferase reporter, Dazl hypomorph immunostaining, and RT-qPCR","pmids":["31659914"],"confidence":"Medium","gaps":["Single lab","Direct DAZL binding to TEX14 3'UTR not mapped","Mechanism of translational activation unresolved"]},{"year":2025,"claim":"TEX14 loss-of-function was confirmed as a cause of human germ cell failure, with biallelic variants disrupting protein synthesis and ICB assembly and arresting meiosis.","evidence":"Exome/Sanger sequencing, Western blot, immunofluorescence, and testis histology in patients","pmids":["40492599"],"confidence":"Medium","gaps":["Single lab","Limited patient numbers","Variant-specific mechanism not isolated from general loss"]},{"year":2025,"claim":"The CEP55-binding motif was repurposed as a tool, showing GPPX3Y-containing TEX14 peptides inhibit proliferation and induce apoptosis in cancer cells, indicating the motif is biologically active out of context.","evidence":"Proliferation and apoptosis assays with TEX14 partial peptides in cancer cell lines","pmids":["41219627"],"confidence":"Medium","gaps":["Single study/lab","Endogenous TEX14 role in cancer not established","Mechanism of apoptosis induction not defined"]},{"year":2026,"claim":"A mouse knock-in plus matching patient confirmed frameshift TEX14 variants ablate protein and bridge formation, and ICB proteomics revealed enrichment of RNA-processing and RNP biogenesis factors, hinting at a broader bridge cargo function.","evidence":"Exome sequencing, mouse knock-in, Western blot, IF, histology, and mass spectrometry of purified ICBs","pmids":["41603674"],"confidence":"High","gaps":["Functional role of bridge-associated RNA machinery not tested","Mechanism connecting TEX14 to RNP transport unknown"]},{"year":null,"claim":"How TEX14's mitotic kinetochore activity, its germ cell bridge-stabilizing role, and the RNA-processing cargo of intercellular bridges are mechanistically integrated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking somatic and germ cell functions","Function of TEX14 kinase domain untested","Role of ICB-associated RNP machinery undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["intercellular bridge","kinetochore"],"partners":["CEP55","KIF23","PLK1","DAZL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWB6","full_name":"Inactive serine/threonine-protein kinase TEX14","aliases":["Protein kinase-like protein SgK307","Sugen kinase 307","Testis-expressed sequence 14","Testis-expressed sequence 14 protein"],"length_aa":1497,"mass_kda":167.9,"function":"Required both for the formation of intercellular bridges during meiosis and for kinetochore-microtubule attachment during mitosis. Intercellular bridges are evolutionarily conserved structures that connect differentiating germ cells and are required for spermatogenesis and male fertility. Acts by promoting the conversion of midbodies into intercellular bridges via its interaction with CEP55: interaction with CEP55 inhibits the interaction between CEP55 and PDCD6IP/ALIX and TSG101, blocking cell abscission and leading to transform midbodies into intercellular bridges. Also plays a role during mitosis: recruited to kinetochores by PLK1 during early mitosis and regulates the maturation of the outer kinetochores and microtubule attachment. Has no protein kinase activity in vitro (By similarity)","subcellular_location":"Cytoplasm; Midbody; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q8IWB6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEX14","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEX14","total_profiled":1310},"omim":[{"mim_id":"621038","title":"RNA-BINDING MOTIF PROTEIN 44; RBM44","url":"https://www.omim.org/entry/621038"},{"mim_id":"617707","title":"SPERMATOGENIC FAILURE 23; SPGF23","url":"https://www.omim.org/entry/617707"},{"mim_id":"610000","title":"CENTROSOMAL PROTEIN, 55-KD; CEP55","url":"https://www.omim.org/entry/610000"},{"mim_id":"605792","title":"TESTIS-EXPRESSED GENE 14; TEX14","url":"https://www.omim.org/entry/605792"},{"mim_id":"605064","title":"KINESIN FAMILY MEMBER 23; KIF23","url":"https://www.omim.org/entry/605064"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":25.2}],"url":"https://www.proteinatlas.org/search/TEX14"},"hgnc":{"alias_symbol":["CT113","SgK307"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWB6","domains":[{"cath_id":"1.25.40.20","chopping":"12-176","consensus_level":"medium","plddt":86.5654,"start":12,"end":176}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWB6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWB6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWB6-F1-predicted_aligned_error_v6.png","plddt_mean":50.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEX14","jax_strain_url":"https://www.jax.org/strain/search?query=TEX14"},"sequence":{"accession":"Q8IWB6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWB6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWB6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWB6"}},"corpus_meta":[{"pmid":"16549803","id":"PMC_16549803","title":"TEX14 is essential for intercellular bridges and fertility in male mice.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16549803","citation_count":227,"is_preprint":false},{"pmid":"19020301","id":"PMC_19020301","title":"Mouse TEX14 is required for embryonic germ cell intercellular bridges but not female fertility.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/19020301","citation_count":89,"is_preprint":false},{"pmid":"20176808","id":"PMC_20176808","title":"TEX14 interacts with CEP55 to block cell abscission.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20176808","citation_count":70,"is_preprint":false},{"pmid":"22405274","id":"PMC_22405274","title":"Tex14, a Plk1-regulated protein, is required for kinetochore-microtubule attachment and regulation of the spindle assembly checkpoint.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22405274","citation_count":43,"is_preprint":false},{"pmid":"12711554","id":"PMC_12711554","title":"Sequence and expression of testis-expressed gene 14 (Tex14): a gene encoding a protein kinase preferentially expressed during spermatogenesis.","date":"2003","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/12711554","citation_count":33,"is_preprint":false},{"pmid":"29932616","id":"PMC_29932616","title":"Expression analysis of genes encoding TEX11, TEX12, TEX14 and TEX15 in testis tissues of men with non-obstructive azoospermia.","date":"2018","source":"JBRA assisted reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29932616","citation_count":27,"is_preprint":false},{"pmid":"26392564","id":"PMC_26392564","title":"Structural and biochemical insights into the role of testis-expressed gene 14 (TEX14) in forming the stable intercellular bridges of germ cells.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26392564","citation_count":27,"is_preprint":false},{"pmid":"34156079","id":"PMC_34156079","title":"Altered germline cyst formation and oogenesis in Tex14 mutant mice.","date":"2021","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/34156079","citation_count":24,"is_preprint":false},{"pmid":"22136159","id":"PMC_22136159","title":"An exonic insertion within Tex14 gene causes spermatogenic arrest in pigs.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22136159","citation_count":22,"is_preprint":false},{"pmid":"31659914","id":"PMC_31659914","title":"Dazl determines primordial follicle formation through the translational regulation of Tex14.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31659914","citation_count":13,"is_preprint":false},{"pmid":"32438343","id":"PMC_32438343","title":"Spermatogonial asynchrony in Tex14 mutant mice lacking intercellular bridges.","date":"2020","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32438343","citation_count":10,"is_preprint":false},{"pmid":"39188605","id":"PMC_39188605","title":"Correlation between TEX14 and ADAM17 expressions in colorectal cancer tissues of elderly patients and neoplasm staging, invasion, and metastasis.","date":"2024","source":"World journal of clinical cases","url":"https://pubmed.ncbi.nlm.nih.gov/39188605","citation_count":3,"is_preprint":false},{"pmid":"40492599","id":"PMC_40492599","title":"A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40492599","citation_count":1,"is_preprint":false},{"pmid":"37409705","id":"PMC_37409705","title":"Inhibition mechanism of testis-expressed gene 14 (TEX14) in cytokinetic abscission: Well-tempered metadynamics simulation studies.","date":"2023","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/37409705","citation_count":0,"is_preprint":false},{"pmid":"41603674","id":"PMC_41603674","title":"Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice.","date":"2026","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/41603674","citation_count":0,"is_preprint":false},{"pmid":"41219627","id":"PMC_41219627","title":"Partial TEX14 peptides inhibit proliferation of cancer cells and have potential as anti-tumour agents.","date":"2025","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/41219627","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10022,"output_tokens":2786,"usd":0.035928,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10041,"output_tokens":3392,"usd":0.067502,"stage2_stop_reason":"end_turn"},"total_usd":0.10343,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"TEX14 localizes to germ cell intercellular bridges and is required for their formation; in Tex14-/- mice, intercellular bridges are absent by electron microscopy and immunofluorescence, and spermatogenesis arrests before completion of the first meiotic division.\",\n      \"method\": \"Targeted gene knockout in mice, electron microscopy, immunofluorescence localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and developmental phenotype, multiple orthogonal methods (EM + IF), replicated across subsequent studies\",\n      \"pmids\": [\"16549803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TEX14 is an essential component of both male and female embryonic germ cell intercellular bridges; KIF23 (MKLP1) was identified as a component of intercellular bridges during spermatogenesis and in embryonic germ cells, and intercellular bridges are absent between germ cells of Tex14-null mice.\",\n      \"method\": \"Tex14 knockout mice, electron microscopy, KIF23 immunofluorescence\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined phenotype, multiple orthogonal methods (EM + IF), identifies KIF23 as a bridge component\",\n      \"pmids\": [\"19020301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TEX14 interacts with CEP55 via a conserved GPPX3Y motif; this interaction competitively blocks ALIX and TSG101 from binding CEP55 at the midbody, thereby preventing abscission and stabilizing the intercellular bridge. CEP55 was identified as a stable component of the intercellular bridge by biochemical enrichment of male germ cell intercellular bridges.\",\n      \"method\": \"Biochemical enrichment of intercellular bridges, co-immunoprecipitation, competitive binding assays, localization studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical enrichment, co-IP, competitive binding), replicated in structural study\",\n      \"pmids\": [\"20176808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TEX14 is recruited to kinetochores by Plk1 in a Cdk1-dependent manner during early mitosis; exclusion of TEX14 from kinetochores impairs outer kinetochore component localization, kinetochore-microtubule attachment, chromosome congression, and spindle assembly checkpoint function. Plk1 phosphorylation of TEX14 during metaphase promotes APC/C(Cdc20)-mediated TEX14 degradation, and inhibition of this phosphorylation causes retention of TEX14 at kinetochores and delayed metaphase-to-anaphase transition.\",\n      \"method\": \"Kinase assays, loss-of-function (knockdown/exclusion), phosphorylation site mutagenesis, live-cell imaging, chromosome segregation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including mutagenesis, kinase assay, epistasis with Plk1 and APC/C, single lab\",\n      \"pmids\": [\"22405274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TEX14 encodes a 1450-amino-acid protein containing three ankyrin repeats, a protein kinase domain, and a leucine zipper dimerization motif; mRNA is expressed specifically in the testis with highest levels in pachytene, diplotene, and meiotically dividing spermatocytes.\",\n      \"method\": \"Sequence analysis, Northern blot, in situ hybridization, 5'-RACE\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence characterization and expression mapping, no functional assay, but well-defined domain architecture\",\n      \"pmids\": [\"12711554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the CEP55-EABR domain bound to TEX14 peptide revealed that TEX14 interacts with CEP55 via an AxGPPx3YxPP motif (Ala793, Gly795, Pro796, Pro797, Tyr801, Pro803, Pro804); TEX14 competitively prevents ALIX recruitment to CEP55-EABR. High affinity and low dissociation rate of TEX14 for CEP55, together with increased local concentration, cooperatively prevent ALIX from recruiting ESCRT complexes to the midbody.\",\n      \"method\": \"X-ray crystallography, binding assays (affinity/kinetics), chimeric peptide functional characterization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by multiple biochemical methods, confirms and extends mechanism from PMID 20176808\",\n      \"pmids\": [\"26392564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A 51 bp insertion within exon 27 of porcine Tex14 causes differential splicing, a premature stop codon, loss of TEX14 protein expression (confirmed by Western blot), and spermatogenic arrest, demonstrating TEX14 is required for spermatogenesis in pigs.\",\n      \"method\": \"Genome-wide SNP scan, candidate gene sequencing, RT-PCR, Western blot, testis histology\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural loss-of-function mutation with protein loss confirmed by Western blot, single species/lab\",\n      \"pmids\": [\"22136159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DAZL (deleted in azoospermia-like), a germ cell RNA-binding protein, regulates TEX14 at the translational level via the TEX14 3'UTR, without altering Tex14 mRNA levels; demonstrated by 3'UTR-luciferase reporter assays. In Dazl hypomorph ovaries, TEX14 protein foci were reduced ~59% with no change in mRNA, linking DAZL-dependent translation of TEX14 to intercellular bridge formation and primordial follicle assembly.\",\n      \"method\": \"3'UTR-luciferase reporter assay, siRNA knockdown (Dazl hypomorph), immunostaining, RT-qPCR\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus protein/mRNA dissociation in knockdown model, single lab\",\n      \"pmids\": [\"31659914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Partial peptides of TEX14 containing the GPPX3Y motif are sufficient to inhibit proliferation and induce apoptosis in cancer cells; the length and amino acid variation surrounding the GPPX3Y motif modulate this activity.\",\n      \"method\": \"Cell proliferation assays, apoptosis assays with TEX14 partial peptides in cancer cell lines\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined peptide activity in cell-based assays, single lab, single study\",\n      \"pmids\": [\"41219627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound heterozygous loss-of-function mutations in TEX14 (p.S268C and p.R341*) disrupt TEX14 synthesis, leading to meiotic arrest at the pachytene stage and impaired intercellular bridge assembly in human testes.\",\n      \"method\": \"Exome/Sanger sequencing, Western blot (protein loss), immunofluorescence (ICB assembly), testis histology\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variant with functional protein-level and histological validation, single lab\",\n      \"pmids\": [\"40492599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss-of-function TEX14 frameshift variants cause complete loss of TEX14 protein in the testis, failure of intercellular bridge formation, and spermatogenic arrest at the zygotene stage in both a mouse knock-in model and in the testes of a patient carrying the analogous variant. Mass spectrometry of purified ICBs showed ICB-associated proteins are predominantly involved in RNA processing and ribonucleoprotein complex biogenesis.\",\n      \"method\": \"Exome sequencing, mouse knock-in model, Western blot, immunofluorescence, histology, mass spectrometry of purified ICBs\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, mouse model plus human correlate, mass spectrometry of purified bridges\",\n      \"pmids\": [\"41603674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEX14 is a testis-enriched protein that localizes to the midbody/intercellular bridge region during germ cell cytokinesis, where it binds the CEP55-EABR domain via a high-affinity AxGPPx3YxPP motif to competitively exclude ALIX and TSG101, thereby blocking ESCRT-mediated abscission and stabilizing the permanent intercellular bridges essential for spermatogenesis; in somatic mitotic cells, TEX14 is additionally recruited to kinetochores by Plk1 in a Cdk1-dependent manner to support kinetochore-microtubule attachment and spindle assembly checkpoint signaling, and is subsequently degraded by APC/C(Cdc20) upon Plk1 phosphorylation; TEX14 translation is regulated post-transcriptionally by the RNA-binding protein DAZL in oogenic germ cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEX14 is a testis-enriched protein that builds and stabilizes the permanent germ cell intercellular bridges (ICBs) required for spermatogenesis, and its loss abolishes ICBs and arrests germ cell development before completion of meiosis [#0, #1]. The molecular basis of bridge stabilization is competitive occupancy of the abscission machinery: TEX14 binds the CEP55-EABR domain through a conserved AxGPPx3YxPP motif with high affinity and a low dissociation rate, thereby excluding ALIX and TSG101 and preventing ESCRT-mediated recruitment that would otherwise complete cytokinetic abscission [#2, #5]. Beyond germ cells, TEX14 acts in somatic mitosis: it is recruited to kinetochores by Plk1 in a Cdk1-dependent manner to support kinetochore-microtubule attachment, chromosome congression, and spindle assembly checkpoint signaling, after which Plk1 phosphorylation triggers APC/C(Cdc20)-mediated degradation to permit the metaphase-to-anaphase transition [#3]. TEX14 expression is controlled post-transcriptionally, with the germ cell RNA-binding protein DAZL promoting TEX14 translation via its 3'UTR to drive ICB formation and primordial follicle assembly [#7]. Loss-of-function TEX14 variants cause spermatogenic arrest with failed ICB assembly in humans, recapitulated in mouse models [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Before any function was known, defining the protein's domain architecture and expression pattern established TEX14 as a testis-specific, meiosis-associated multidomain protein worth functional dissection.\",\n      \"evidence\": \"Sequence analysis, Northern blot, and in situ hybridization of the TEX14 transcript\",\n      \"pmids\": [\"12711554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role assigned\", \"Kinase domain catalytic activity not tested\", \"No protein localization data\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The central question of what TEX14 does in germ cells was answered by knockout, showing it is required to build intercellular bridges and for progression through meiosis.\",\n      \"evidence\": \"Targeted gene knockout in mice with EM and immunofluorescence\",\n      \"pmids\": [\"16549803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of bridge formation not defined\", \"Binding partners unknown\", \"Does not address somatic roles\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extending the role beyond the testis, TEX14 was shown to be essential for both male and female embryonic germ cell bridges, and KIF23 was identified as a bridge component, placing TEX14 within a defined cytokinetic protein context.\",\n      \"evidence\": \"Tex14 knockout mice, EM, and KIF23 immunofluorescence\",\n      \"pmids\": [\"19020301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TEX14-KIF23 interaction not demonstrated\", \"Mechanism linking TEX14 to bridge stabilization still unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The mechanism of permanent bridge stabilization was established: TEX14 binds CEP55 via a GPPX3Y motif and competitively excludes the ESCRT adaptors ALIX and TSG101, explaining how abscission is blocked.\",\n      \"evidence\": \"Biochemical enrichment of intercellular bridges, co-IP, and competitive binding assays\",\n      \"pmids\": [\"20176808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of competition not resolved\", \"Affinity/kinetics not quantified\", \"Does not address mitotic kinetochore function\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A natural porcine loss-of-function mutation confirmed that TEX14 is required for spermatogenesis across mammals, generalizing the mouse phenotype.\",\n      \"evidence\": \"SNP scan, candidate gene sequencing, RT-PCR, Western blot, and testis histology in pigs\",\n      \"pmids\": [\"22136159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single species and lab\", \"Mechanism of arrest not dissected\", \"Bridge-specific defect not directly imaged\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A distinct somatic function was uncovered, showing TEX14 is a Plk1- and Cdk1-regulated kinetochore factor supporting microtubule attachment and the spindle checkpoint, then degraded by APC/C(Cdc20) to allow anaphase.\",\n      \"evidence\": \"Kinase assays, loss-of-function, phospho-site mutagenesis, live-cell imaging, and chromosome segregation assays\",\n      \"pmids\": [\"22405274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Relationship between mitotic and germ cell roles unclear\", \"Direct kinetochore-binding interface not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The competitive exclusion mechanism was given atomic resolution, defining the AxGPPx3YxPP residues and showing high affinity, slow off-rate, and local concentration cooperatively block ALIX/ESCRT recruitment.\",\n      \"evidence\": \"X-ray crystallography of CEP55-EABR bound to TEX14 peptide with binding kinetics and chimeric peptide assays\",\n      \"pmids\": [\"26392564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length TEX14 structure not determined\", \"In vivo dynamics of competition not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How TEX14 levels are set in germ cells was addressed by showing DAZL drives TEX14 translation via its 3'UTR without changing mRNA, linking RNA-binding control to bridge formation and follicle assembly.\",\n      \"evidence\": \"3'UTR-luciferase reporter, Dazl hypomorph immunostaining, and RT-qPCR\",\n      \"pmids\": [\"31659914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct DAZL binding to TEX14 3'UTR not mapped\", \"Mechanism of translational activation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TEX14 loss-of-function was confirmed as a cause of human germ cell failure, with biallelic variants disrupting protein synthesis and ICB assembly and arresting meiosis.\",\n      \"evidence\": \"Exome/Sanger sequencing, Western blot, immunofluorescence, and testis histology in patients\",\n      \"pmids\": [\"40492599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Limited patient numbers\", \"Variant-specific mechanism not isolated from general loss\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The CEP55-binding motif was repurposed as a tool, showing GPPX3Y-containing TEX14 peptides inhibit proliferation and induce apoptosis in cancer cells, indicating the motif is biologically active out of context.\",\n      \"evidence\": \"Proliferation and apoptosis assays with TEX14 partial peptides in cancer cell lines\",\n      \"pmids\": [\"41219627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study/lab\", \"Endogenous TEX14 role in cancer not established\", \"Mechanism of apoptosis induction not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A mouse knock-in plus matching patient confirmed frameshift TEX14 variants ablate protein and bridge formation, and ICB proteomics revealed enrichment of RNA-processing and RNP biogenesis factors, hinting at a broader bridge cargo function.\",\n      \"evidence\": \"Exome sequencing, mouse knock-in, Western blot, IF, histology, and mass spectrometry of purified ICBs\",\n      \"pmids\": [\"41603674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of bridge-associated RNA machinery not tested\", \"Mechanism connecting TEX14 to RNP transport unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEX14's mitotic kinetochore activity, its germ cell bridge-stabilizing role, and the RNA-processing cargo of intercellular bridges are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking somatic and germ cell functions\", \"Function of TEX14 kinase domain untested\", \"Role of ICB-associated RNP machinery undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"intercellular bridge\", \"kinetochore\"],\n    \"partners\": [\"CEP55\", \"KIF23\", \"PLK1\", \"DAZL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}