{"gene":"TEP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1997,"finding":"TEP1 (identical to PTEN/MMAC1) possesses intrinsic protein tyrosine phosphatase activity, demonstrated by in vitro phosphatase assays using the PTP signature motif. The protein is localized to the cytoplasm by immunofluorescence and shares homology with tensin and auxilin.","method":"In vitro phosphatase assay, immunofluorescence","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic activity directly demonstrated with PTP motif, cytoplasmic localization confirmed by immunofluorescence, single lab but two orthogonal methods","pmids":["9187108"],"is_preprint":false},{"year":1997,"finding":"TLP1/TEP1 encodes a protein component of rat telomerase; anti-TLP1 antibody immunoprecipitated telomerase activity, and the protein was co-purified with telomerase through extensive purification steps. The p240 form is post-translationally modified to the p230 form in vivo, and p230 is the dominant form in telomerase-positive cells.","method":"Immunoprecipitation, co-purification, pulse-chase experiment","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-purification plus immunoprecipitation of enzymatic activity, pulse-chase establishing PTM, replicated across multiple purification steps","pmids":["9118230"],"is_preprint":false},{"year":1998,"finding":"PTEN/MMAC1/TEP1 suppresses glioblastoma cell growth by blocking G1 cell cycle progression, correlating with increased p27(KIP1) and decreased G1 CDK activities. PTEN expression inhibits Akt/PKB, and this effect on p27 and the cell cycle can be mimicked by PI3-kinase inhibitor LY294002, placing PTEN upstream of PI3K/Akt/p27.","method":"Cell cycle analysis, Western blotting, kinase assay, pharmacological inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotype plus pharmacological epistasis, single lab with multiple orthogonal methods","pmids":["9860981"],"is_preprint":false},{"year":1999,"finding":"TEP1 is a component of the vault ribonucleoprotein particle (the 240 kDa vault protein); vaults purified with TEP1 present have no detectable telomerase activity. Using a yeast three-hybrid assay, several human vault RNAs interact with TEP1 in a sequence-specific manner.","method":"Partial cDNA identification, vault purification, telomerase activity assay (TRAP), yeast three-hybrid assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical co-purification, functional TRAP assay, yeast three-hybrid RNA binding; multiple orthogonal methods in one study","pmids":["10551828"],"is_preprint":false},{"year":2000,"finding":"mTep1-deficient mice are viable with normal telomerase activity, normal telomere length across seven generations, and no reactivation of telomerase in normally telomerase-negative tissues. TEP1 is thus dispensable for telomerase function in vivo. TEP1 also specifically binds vault RNA (vRNA), establishing it as an RNA-binding protein not restricted to the telomerase complex.","method":"Knockout mouse (mTep1−/−), TRAP assay, telomere length analysis (FISH), RNA binding","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — clean in vivo knockout with comprehensive telomere/telomerase readouts across multiple tissues and seven generations","pmids":["11027287"],"is_preprint":false},{"year":2001,"finding":"In mTep1−/− mice, vault particles appear structurally intact but show reduced cap density by cryo-EM 3D reconstruction. Critically, vault RNA is completely absent from purified vaults and is destabilized (reduced levels) in the absence of TEP1, establishing TEP1 as required for stable association of vault RNA with the vault particle.","method":"Cryo-electron microscopy, 3D reconstruction, vault purification, RNA quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural cryo-EM plus biochemical co-purification and RNA stability measurement in a genetic knockout model","pmids":["11149928"],"is_preprint":false},{"year":2000,"finding":"Specific hTERT deletions that retain interaction with telomerase RNA and TEP1 are completely inactive for telomerase polymerization in vitro and in vivo, demonstrating that TEP1 binding and RNA binding can be functionally uncoupled from catalysis. The amino-terminus of hTERT is required for primer elongation but not for RNA or TEP1 binding.","method":"In vitro reconstitution of telomerase activity, deletion mutagenesis, in vivo assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution combined with systematic mutagenesis and in vivo validation in one rigorous study","pmids":["11029039"],"is_preprint":false},{"year":2000,"finding":"PTEN/TEP1 inhibits H-Ras–induced transformation and anchorage-independent growth in NIH3T3 cells by suppressing the PI3K-dependent (but not MAPK) signaling cascade. C-terminal truncation mutants show that anti-transformation activity correlates with ability to dephosphorylate inositol-(1,3,4,5)-tetrakisphosphate in vitro and to suppress Akt kinase activity in cells.","method":"NIH3T3 transformation assay, soft-agar growth, in vitro phosphatase assay, Akt kinase activity measurement, deletion mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro lipid phosphatase assay plus cellular epistasis experiments with mutagenesis panel, multiple orthogonal methods","pmids":["10698513"],"is_preprint":false},{"year":2004,"finding":"Anopheles gambiae TEP1 (complement-like protein) binds to and mediates killing of Plasmodium berghei midgut stages. dsRNA knockdown of TEP1 completely abolishes melanotic refractoriness in a refractory mosquito strain and increases parasite numbers in susceptible mosquitoes.","method":"dsRNA knockdown (RNAi), parasite counting, melanization assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean RNAi loss-of-function with quantitative parasitological phenotype, published in high-impact venue, founding mechanistic study replicated by multiple subsequent labs","pmids":["15006349"],"is_preprint":false},{"year":2005,"finding":"The Tetrahymena p80 homology region (amino acids 1–871) of TEP1 is necessary and sufficient for interaction with both telomerase RNA and vault RNA in yeast three-hybrid assays, and for targeting TEP1 to the vault particle. Recombinant TEP1 RNA-binding domain directly binds RNA (EMSA), and vault RNA competes with telomerase RNA for this domain.","method":"Yeast three-hybrid assay, electrophoretic mobility shift assay (EMSA), deletion mutagenesis, vault targeting assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro direct binding (EMSA) combined with yeast three-hybrid and mutagenesis, multiple orthogonal methods in one study","pmids":["15701761"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of Anopheles gambiae TEP1 isoform TEP1r reveals an overall fold resembling complement factor C3 but with repositioned domains that stabilize the inactive (thioester-intact) conformation in the absence of the anaphylotoxin domain. Structural differences between TEP1r and TEP1s alleles map to the TED-MG8 interface protecting the thioester bond.","method":"X-ray crystallography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination providing molecular mechanism; single lab but high-resolution structural data","pmids":["17606907"],"is_preprint":false},{"year":2009,"finding":"LRIM1 and APL1 leucine-rich repeat proteins are required for binding of TEP1 to Plasmodium parasites. RNAi silencing of LRIM1 or APL1 causes deposition of TEP1 on mosquito tissues, depleting circulating TEP1 and preventing its binding to parasites. LRIM1 and APL1 stabilize each other and stabilize circulating TEP1.","method":"RNAi knockdown, hemolymph immunoblot, parasite binding assay","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic RNAi dissection with biochemical binding readout, independently supported by multiple subsequent structural studies","pmids":["19286136"],"is_preprint":false},{"year":2011,"finding":"The coiled-coil domain of the LRIM1/APL1C complex is the binding site for mature (cleaved) TEP1. Key cysteine residues form the intermolecular disulfide bond of the LRIM1/APL1C heterodimer. The complex also interacts with mature forms of TEP3 and two other TEP proteins via the same coiled-coil domain.","method":"Cell culture expression of allele mutants, co-immunoprecipitation, disulfide-bond mutagenesis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis panel with Co-IP readout, multiple alleles and constructs tested","pmids":["21533217"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of full-length TEP1*S1 allele shows flexibility in MG1-MG6 domains relative to TEP1*R1. Amino acid differences localize to the TED-MG8 interface protecting the thioester; cleaved TEP1*S1 is significantly more susceptible to thioester hydrolysis than TEP1*R1. The LRIM1/APL1C complex stabilizes the thioester in cleaved TEP1*S1.","method":"X-ray crystallography, thioester hydrolysis assay, biochemical complex formation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional biochemical assay of thioester stability, single lab but two orthogonal methods","pmids":["23055931"],"is_preprint":false},{"year":2014,"finding":"CLIPA2 (clip domain serine protease homolog) negatively regulates TEP1 consumption during systemic infections by localizing to microbial surfaces in a TEP1-dependent manner and inhibiting the putative TEP1 convertase that cleaves full-length TEP1-F into active TEP1cut. CLIPA2 silencing triggers exacerbated TEP1-mediated immunity.","method":"RNAi knockdown, hemolymph immunoblot (TEP1 cleavage assay), infection phenotype scoring","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via RNAi with biochemical TEP1 processing readout; convertase identity inferred indirectly","pmids":["25012124"],"is_preprint":false},{"year":2019,"finding":"Cleaved TEP1 forms a soluble complex with the LRIM1/APL1C heterodimer through the coiled-coil domain of LRIM1/APL1C. Complex formation requires a conformational change in the TED-MG8 domain interface of TEP1 induced by cleavage; disulfide-stabilized TEP1 (TED-MG8 locked) does not interact with LRIM1/APL1C, establishing that TED-MG8 separation is prerequisite for complex formation.","method":"Engineered disulfide mutagenesis, co-immunoprecipitation, biochemical stability assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structure-guided mutagenesis (disulfide engineering) with functional binding readout; mechanistically rigorous single-lab study","pmids":["31237887"],"is_preprint":false},{"year":2000,"finding":"The S. cerevisiae TEP1 ortholog (YNL128w) functions in the phosphatidylinositol pathway: tep1 diploids are resistant to the PI3-kinase inhibitor wortmannin and to lithium. A common human PTEN tumor mutation introduced at the analogous yeast position produces a non-functional Tep1p. TEP1 is required for normal dityrosine deposition on spore walls during sporulation.","method":"Yeast deletion genetics, drug resistance assay, sporulation phenotype analysis, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with pharmacological readout plus mutagenesis; yeast ortholog model with direct functional validation","pmids":["11070083"],"is_preprint":false},{"year":2006,"finding":"PARP-1 knockdown by siRNA in HeLa cells reduces poly(ADP-ribosyl)ation of hTERT and decreases TEP1/TP1 protein expression, correlating with reduced telomerase activity. This establishes PARP-1 as a regulator of TEP1 expression/function in the telomerase complex.","method":"siRNA knockdown, TRAP assay, Western blot, immunoprecipitation of poly(ADP-ribosyl)ated proteins","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach; mechanistic link to TEP1 is indirect (expression change, not direct modification of TEP1)","pmids":["17141279"],"is_preprint":false},{"year":2019,"finding":"TEP1, TEP3, and TEP4 in Anopheles gambiae are positive regulators of periostial hemocyte aggregation at the heart ostia during bacterial infection. RNAi knockdown of TEP1 reduced periostial hemocyte numbers, bacterial accumulation, and melanin deposition at periostial regions, without affecting non-periostial sessile hemocytes.","method":"RNAi knockdown, intravital imaging, bacterial burden quantification, melanization scoring","journal":"Insect biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi loss-of-function with multiple quantitative phenotypic readouts; functional integration of immune and circulatory systems established","pmids":["30690067"],"is_preprint":false},{"year":2017,"finding":"TEP1 is secreted and circulates in the mosquito hemolymph; its activated cleaved form binds and eliminates malaria parasites. The fat body is the main site of TEP1 expression by GFP reporter assay. Transgenic TEP1r rescues loss-of-function TEP1 mutations but does not increase parasite resistance in the presence of a susceptible wild-type allele.","method":"GFP reporter transgene, transgenic rescue, hemolymph immunoblot, parasite counting","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization via reporter transgene plus transgenic rescue genetics; single lab","pmids":["28095489"],"is_preprint":false}],"current_model":"TEP1 (human/mammalian) is a dual-function ribonucleoprotein component: it is an integral structural subunit of the vault particle required for vault RNA stability and recruitment, and it associates with telomerase (binding both telomerase RNA and hTERT) but is dispensable for telomerase catalytic activity and telomere length maintenance in vivo; its p80-homology domain directly binds vault and telomerase RNAs and is sufficient for vault targeting. In mosquitoes, the orthologous Anopheles gambiae TEP1 is a complement C3-like thioester-containing protein that circulates in the hemolymph as an inactive form, undergoes protease-dependent cleavage to expose a reactive thioester, and—stabilized by the LRIM1/APL1C leucine-rich repeat heterodimer via their coiled-coil domain—binds and kills Plasmodium parasites through lysis and melanization."},"narrative":{"mechanistic_narrative":"The TEP1 timeline resolves into two internally coherent but biologically distinct proteins linked by a shared gene symbol, reflecting a symbol collision across species and historical nomenclature. In mammals, TEP1/TLP1 is a dual-function RNA-binding protein: it co-purifies with telomerase and binds telomerase RNA, but it is dispensable for telomerase catalytic activity and telomere length maintenance in vivo [PMID:9118230, PMID:11027287, PMID:11029039], and it is independently a structural subunit of the vault ribonucleoprotein particle where it is required for stable association and recruitment of vault RNA [PMID:10551828, PMID:11149928]. A single Tetrahymena p80-homology RNA-binding domain (residues 1–871) directly binds both telomerase RNA and vault RNA in competition, and is necessary and sufficient to target TEP1 to vaults [PMID:15701761]. A second cluster of mammalian findings instead describes PTEN/MMAC1, a cytoplasmic protein tyrosine and inositol-phosphate phosphatase that antagonizes PI3K/Akt signaling, raises p27(KIP1), arrests cells in G1, and suppresses Ras-induced transformation [PMID:9187108, PMID:9860981, PMID:10698513]; this PTEN-associated work uses the TEP1 alias and a yeast ortholog acting in the phosphatidylinositol pathway [PMID:11070083]. In mosquitoes (Anopheles gambiae), TEP1 is an entirely separate complement C3-like thioester-containing protein of the innate immune system that circulates in the hemolymph, is secreted by the fat body, and after protease-dependent cleavage binds and kills Plasmodium parasites by lysis and melanization [PMID:15006349, PMID:28095489]. Mosquito TEP1 is held in its inactive thioester-intact conformation by a TED-MG8 domain interface [PMID:17606907, PMID:23055931]; cleavage drives TED-MG8 separation, which is prerequisite for binding the LRIM1/APL1C leucine-rich-repeat heterodimer through its coiled-coil domain, and this complex stabilizes the reactive cleaved form and delivers it to parasite surfaces [PMID:19286136, PMID:21533217, PMID:31237887]. Upstream, a CLIPA2 clip-domain protease homolog restrains TEP1 convertase activity to limit TEP1 consumption [PMID:25012124], and TEP1 also promotes periostial hemocyte aggregation during bacterial infection [PMID:30690067]. Because these clusters describe unrelated proteins, the molecular_activity and pathway slots below are populated separately and the narrative should not be read as one protein.","teleology":[{"year":1997,"claim":"Two independent identifications established the symbol's ambiguity: one assigned TEP1 to a cytoplasmic tyrosine phosphatase (PTEN/MMAC1), the other to a co-purifying protein subunit of telomerase.","evidence":"In vitro phosphatase assay and immunofluorescence (PTEN); anti-TLP1 immunoprecipitation of telomerase activity and co-purification with pulse-chase PTM analysis (rat telomerase)","pmids":["9187108","9118230"],"confidence":"High","gaps":["The two 1997 findings describe unrelated proteins sharing a symbol","Whether TEP1 contributes catalytically to telomerase was not addressed"]},{"year":1998,"claim":"PTEN/MMAC1/TEP1 was placed in a defined growth-suppressive signaling cascade, answering how it controls proliferation.","evidence":"Cell cycle analysis, Western blot, kinase assay and pharmacological inhibition in glioblastoma cells","pmids":["9860981"],"confidence":"High","gaps":["Concerns the PTEN protein, not the telomerase/vault TEP1","Direct phosphatase substrate in cells inferred via epistasis"]},{"year":1999,"claim":"TEP1 was shown to be a bona fide vault particle component that binds vault RNAs sequence-specifically, separating its RNA-binding role from telomerase catalysis.","evidence":"Vault purification, TRAP activity assay, yeast three-hybrid RNA-binding assay","pmids":["10551828"],"confidence":"High","gaps":["Functional consequence of TEP1–vault RNA binding not yet established","Structural basis of recruitment unresolved"]},{"year":2000,"claim":"A knockout and reconstitution work resolved that TEP1 is dispensable for telomerase catalysis in vivo and that TEP1/RNA binding is uncoupled from polymerization.","evidence":"mTep1−/− mice with TRAP and telomere FISH across seven generations; hTERT deletion mutagenesis with in vitro reconstitution","pmids":["11027287","11029039"],"confidence":"High","gaps":["Why telomerase retains TEP1 if catalytically dispensable is unexplained","TEP1's non-telomerase RNA role pointed toward vaults but not yet mechanistically dissected"]},{"year":2000,"claim":"Structure-function and ortholog studies tied the PTEN-associated TEP1 alias to lipid-phosphatase activity and an evolutionarily conserved phosphatidylinositol pathway role.","evidence":"NIH3T3 transformation/soft-agar assays with phosphatase and Akt readouts; S. cerevisiae deletion genetics with wortmannin/lithium resistance and sporulation phenotype","pmids":["10698513","11070083"],"confidence":"High","gaps":["Yeast ortholog evidence is Medium-confidence","These findings concern PTEN, distinct from telomerase/vault TEP1"]},{"year":2001,"claim":"The vault role was made mechanistic: TEP1 is required for stable association of vault RNA with the particle and for normal cap structure.","evidence":"Cryo-EM 3D reconstruction, vault purification and RNA quantification in mTep1−/− mice","pmids":["11149928"],"confidence":"High","gaps":["Functional consequence of vault RNA loss for cells unresolved","Whether reduced cap density alters vault cargo handling unknown"]},{"year":2004,"claim":"A wholly distinct mosquito TEP1 was established as a complement-like effector that binds and kills malaria parasites, founding the innate-immunity branch.","evidence":"dsRNA knockdown with parasite counting and melanization assays in Anopheles gambiae","pmids":["15006349"],"confidence":"High","gaps":["Activation mechanism and required cofactors not yet defined","Mechanism of parasite killing (lysis vs melanization) not separated"]},{"year":2005,"claim":"The mammalian TEP1 RNA-binding determinant was mapped to a single p80-homology domain sufficient for both telomerase RNA and vault RNA binding and for vault targeting.","evidence":"Yeast three-hybrid, EMSA direct binding, deletion mutagenesis, vault targeting assay","pmids":["15701761"],"confidence":"High","gaps":["Structural basis of RNA specificity not solved","How a single domain partitions between telomerase and vaults in cells unresolved"]},{"year":2007,"claim":"Crystallography defined how mosquito TEP1 maintains an inactive thioester-intact conformation and how allelic variation maps to thioester protection.","evidence":"X-ray crystallography of TEP1r isoform","pmids":["17606907"],"confidence":"High","gaps":["Conformational transition upon activation not captured","In vivo trigger for thioester exposure not defined here"]},{"year":2009,"claim":"The LRIM1/APL1 LRR proteins were shown to stabilize circulating TEP1 and enable its binding to parasites, explaining how the effector is kept available in hemolymph.","evidence":"RNAi silencing with hemolymph immunoblot and parasite binding assay","pmids":["19286136"],"confidence":"High","gaps":["Molecular interface of stabilization not yet defined","Whether stabilization acts on full-length or cleaved TEP1 unresolved"]},{"year":2011,"claim":"The LRIM1/APL1C coiled-coil domain was identified as the docking site for mature cleaved TEP1, generalizing the interaction to multiple TEP proteins.","evidence":"Allele-mutant expression, co-immunoprecipitation, disulfide-bond mutagenesis","pmids":["21533217"],"confidence":"High","gaps":["Stoichiometry of the in vivo complex not determined","Functional consequence of binding other TEPs not characterized"]},{"year":2012,"claim":"Full-length structure plus biochemistry linked allelic susceptibility to thioester hydrolysis and showed LRIM1/APL1C stabilizes the reactive cleaved form.","evidence":"X-ray crystallography of TEP1*S1, thioester hydrolysis assay, complex formation","pmids":["23055931"],"confidence":"High","gaps":["Dynamics of MG1-MG6 flexibility in solution not resolved","How stabilization translates to parasite-surface deposition not shown here"]},{"year":2014,"claim":"A regulatory layer was added: CLIPA2 restrains TEP1 convertase activity to limit TEP1 consumption during infection.","evidence":"RNAi knockdown with hemolymph TEP1 cleavage immunoblot and infection scoring","pmids":["25012124"],"confidence":"Medium","gaps":["Convertase identity inferred indirectly, not isolated","Direct CLIPA2–convertase interaction not demonstrated"]},{"year":2017,"claim":"The source and secretion of mosquito TEP1 were localized, establishing the fat body as the main expression site and confirming hemolymph circulation of the active cleaved form.","evidence":"GFP reporter transgene, transgenic rescue, hemolymph immunoblot, parasite counting","pmids":["28095489"],"confidence":"Medium","gaps":["Single-lab reporter localization","Allele dominance behavior not mechanistically explained"]},{"year":2019,"claim":"The activation logic was completed for mosquito TEP1 and extended to a new effector role: TED-MG8 separation upon cleavage is prerequisite for LRIM1/APL1C binding, and TEP1 also drives periostial hemocyte aggregation in bacterial infection.","evidence":"Engineered disulfide mutagenesis with Co-IP (activation); RNAi with intravital imaging and bacterial/melanin quantification (periostial role)","pmids":["31237887","30690067"],"confidence":"High","gaps":["How TED-MG8 separation is structurally coupled to coiled-coil binding not solved","Mechanism by which TEP1 recruits hemocytes to ostia unknown"]},{"year":null,"claim":"It remains unresolved how the mammalian TEP1 RNA-binding subunit functions biologically given its dispensability for telomerase, and what cellular role vault RNA recruitment serves.","evidence":"No timeline discovery assigns a downstream cellular function to mammalian TEP1's vault/telomerase RNA binding","pmids":[],"confidence":"Low","gaps":["No cellular phenotype tied to TEP1 vault RNA recruitment","No structural model of the TEP1 RNA-binding domain–RNA complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,11,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7]}],"complexes":["vault ribonucleoprotein particle","telomerase","LRIM1/APL1C heterodimer complex"],"partners":["HTERT","LRIM1","APL1C","TEP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99973","full_name":"Telomerase protein component 1","aliases":["Telomerase-associated protein 1","Telomerase protein 1","p240","p80 telomerase homolog"],"length_aa":2627,"mass_kda":290.5,"function":"Component of the telomerase ribonucleoprotein complex that is essential for the replication of chromosome termini (PubMed:19179534). Also a component of the ribonucleoprotein vaults particle, a multi-subunit structure involved in nucleo-cytoplasmic transport (By similarity). Responsible for the localizing and stabilizing vault RNA (vRNA) association in the vault ribonucleoprotein particle. Binds to TERC (By similarity)","subcellular_location":"Nucleus; Chromosome, telomere","url":"https://www.uniprot.org/uniprotkb/Q99973/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEP1","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/TEP1","total_profiled":1310},"omim":[{"mim_id":"612697","title":"VAULT RNA 1-3; VTRNA1-3","url":"https://www.omim.org/entry/612697"},{"mim_id":"612696","title":"VAULT RNA 1-2; VTRNA1-2","url":"https://www.omim.org/entry/612696"},{"mim_id":"612695","title":"VAULT RNA 1-1; VTRNA1-1","url":"https://www.omim.org/entry/612695"},{"mim_id":"605088","title":"MAJOR VAULT PROTEIN; MVP","url":"https://www.omim.org/entry/605088"},{"mim_id":"601728","title":"PHOSPHATASE AND TENSIN HOMOLOG; PTEN","url":"https://www.omim.org/entry/601728"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEP1"},"hgnc":{"alias_symbol":["TP1","TLP1","VAULT2","p240","TROVE1"],"prev_symbol":[]},"alphafold":{"accession":"Q99973","domains":[{"cath_id":"-","chopping":"498-605_613-672","consensus_level":"medium","plddt":73.8859,"start":498,"end":672},{"cath_id":"3.40.50.410","chopping":"673-755_768-837","consensus_level":"medium","plddt":67.2407,"start":673,"end":837},{"cath_id":"-","chopping":"907-1113","consensus_level":"high","plddt":80.0303,"start":907,"end":1113},{"cath_id":"3.40.50.300","chopping":"1140-1320","consensus_level":"high","plddt":80.3812,"start":1140,"end":1320},{"cath_id":"-","chopping":"1341-1385","consensus_level":"high","plddt":82.0633,"start":1341,"end":1385},{"cath_id":"2.130.10.10","chopping":"1984-2146","consensus_level":"medium","plddt":80.8646,"start":1984,"end":2146},{"cath_id":"2.130.10.10","chopping":"2457-2498_2542-2627","consensus_level":"medium","plddt":67.7326,"start":2457,"end":2627},{"cath_id":"1.25.40","chopping":"237-383_438-451","consensus_level":"high","plddt":75.7936,"start":237,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99973","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99973-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99973-F1-predicted_aligned_error_v6.png","plddt_mean":67.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEP1","jax_strain_url":"https://www.jax.org/strain/search?query=TEP1"},"sequence":{"accession":"Q99973","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99973.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99973/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99973"}},"corpus_meta":[{"pmid":"9187108","id":"PMC_9187108","title":"TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9187108","citation_count":792,"is_preprint":false},{"pmid":"15006349","id":"PMC_15006349","title":"Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15006349","citation_count":488,"is_preprint":false},{"pmid":"9860981","id":"PMC_9860981","title":"PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9860981","citation_count":425,"is_preprint":false},{"pmid":"9118230","id":"PMC_9118230","title":"TLP1: a gene encoding a protein component of mammalian 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parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/20599985","citation_count":3,"is_preprint":false},{"pmid":"12549040","id":"PMC_12549040","title":"[Mutation analysis of the tumor suppressor gene PTEN/MMAC1/TEP1 in human hepatocellular carcinoma].","date":"2000","source":"Shi yan sheng wu xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/12549040","citation_count":2,"is_preprint":false},{"pmid":"6603885","id":"PMC_6603885","title":"Effect of treatment with thymustimulin (Tp-1) on T and B cells in lymphoproliferative disorders.","date":"1983","source":"Blut","url":"https://pubmed.ncbi.nlm.nih.gov/6603885","citation_count":2,"is_preprint":false},{"pmid":"6977207","id":"PMC_6977207","title":"Enhancement by TP-1, a thymic extract, of pokeweed mitogen-induced differentiation of B cells from normal subjects but not of those from patients with systemic lupus erythematosus.","date":"1982","source":"Thymus","url":"https://pubmed.ncbi.nlm.nih.gov/6977207","citation_count":2,"is_preprint":false},{"pmid":"41169373","id":"PMC_41169373","title":"Comparative immunological roles of TEP1 in Anopheles gambiae and Biomphalaria glabrata: implications for malaria and schistosomiasis control.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41169373","citation_count":1,"is_preprint":false},{"pmid":"2974021","id":"PMC_2974021","title":"In vitro effect of TP-1 (a calf thymic extract) on suppressor T-cell function of patients with autoimmune chronic active hepatitis.","date":"1988","source":"International journal of immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2974021","citation_count":1,"is_preprint":false},{"pmid":"36277369","id":"PMC_36277369","title":"Evaluation of genotoxicity of SUNACTIVE Zn-P240 in vitro and in vivo.","date":"2022","source":"Toxicological research","url":"https://pubmed.ncbi.nlm.nih.gov/36277369","citation_count":0,"is_preprint":false},{"pmid":"39383173","id":"PMC_39383173","title":"Genotype distribution and allele frequency of thioester-containing protein 1(Tep1) and its effect on development of Plasmodium oocyst in populations of Anopheles arabiensis in Ethiopia.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39383173","citation_count":0,"is_preprint":false},{"pmid":"40604488","id":"PMC_40604488","title":"M6A Methylase METTL3-mediated downregulation of TEP1 mRNA stability attenuates PDGF-BB-induced HASMC remodeling and inflammation via macrophage polarization.","date":"2025","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40604488","citation_count":0,"is_preprint":false},{"pmid":"12948410","id":"PMC_12948410","title":"[Correlation between the PTEN/MMAC1/TEP1 expression and cell proliferation and apoptosis in human renal cell carcinoma (RCC)].","date":"2003","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12948410","citation_count":0,"is_preprint":false},{"pmid":"12133453","id":"PMC_12133453","title":"[The expression of human telomerase-associated protein hTERT and TEP1 in cord blood stem/progenitor cells and its significance].","date":"2002","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/12133453","citation_count":0,"is_preprint":false},{"pmid":"21823319","id":"PMC_21823319","title":"[Function of TEP1 gene during Plasmodium yoelii infection in Anopheles dirus].","date":"2011","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21823319","citation_count":0,"is_preprint":false},{"pmid":"34242707","id":"PMC_34242707","title":"Evaluation of 28-day repeated oral dose toxicity of SUNACTIVE Zn-P240 in rats.","date":"2021","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/34242707","citation_count":0,"is_preprint":false},{"pmid":"20066988","id":"PMC_20066988","title":"[Correlation of Anopheles TEP1 gene with melanization induced by nitroquine].","date":"2009","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20066988","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49262,"output_tokens":4887,"usd":0.110546,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13094,"output_tokens":4702,"usd":0.09151,"stage2_stop_reason":"end_turn"},"total_usd":0.202056,"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\": 1997,\n      \"finding\": \"TEP1 (identical to PTEN/MMAC1) possesses intrinsic protein tyrosine phosphatase activity, demonstrated by in vitro phosphatase assays using the PTP signature motif. The protein is localized to the cytoplasm by immunofluorescence and shares homology with tensin and auxilin.\",\n      \"method\": \"In vitro phosphatase assay, immunofluorescence\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic activity directly demonstrated with PTP motif, cytoplasmic localization confirmed by immunofluorescence, single lab but two orthogonal methods\",\n      \"pmids\": [\"9187108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TLP1/TEP1 encodes a protein component of rat telomerase; anti-TLP1 antibody immunoprecipitated telomerase activity, and the protein was co-purified with telomerase through extensive purification steps. The p240 form is post-translationally modified to the p230 form in vivo, and p230 is the dominant form in telomerase-positive cells.\",\n      \"method\": \"Immunoprecipitation, co-purification, pulse-chase experiment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-purification plus immunoprecipitation of enzymatic activity, pulse-chase establishing PTM, replicated across multiple purification steps\",\n      \"pmids\": [\"9118230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PTEN/MMAC1/TEP1 suppresses glioblastoma cell growth by blocking G1 cell cycle progression, correlating with increased p27(KIP1) and decreased G1 CDK activities. PTEN expression inhibits Akt/PKB, and this effect on p27 and the cell cycle can be mimicked by PI3-kinase inhibitor LY294002, placing PTEN upstream of PI3K/Akt/p27.\",\n      \"method\": \"Cell cycle analysis, Western blotting, kinase assay, pharmacological inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotype plus pharmacological epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9860981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TEP1 is a component of the vault ribonucleoprotein particle (the 240 kDa vault protein); vaults purified with TEP1 present have no detectable telomerase activity. Using a yeast three-hybrid assay, several human vault RNAs interact with TEP1 in a sequence-specific manner.\",\n      \"method\": \"Partial cDNA identification, vault purification, telomerase activity assay (TRAP), yeast three-hybrid assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical co-purification, functional TRAP assay, yeast three-hybrid RNA binding; multiple orthogonal methods in one study\",\n      \"pmids\": [\"10551828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"mTep1-deficient mice are viable with normal telomerase activity, normal telomere length across seven generations, and no reactivation of telomerase in normally telomerase-negative tissues. TEP1 is thus dispensable for telomerase function in vivo. TEP1 also specifically binds vault RNA (vRNA), establishing it as an RNA-binding protein not restricted to the telomerase complex.\",\n      \"method\": \"Knockout mouse (mTep1−/−), TRAP assay, telomere length analysis (FISH), RNA binding\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — clean in vivo knockout with comprehensive telomere/telomerase readouts across multiple tissues and seven generations\",\n      \"pmids\": [\"11027287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In mTep1−/− mice, vault particles appear structurally intact but show reduced cap density by cryo-EM 3D reconstruction. Critically, vault RNA is completely absent from purified vaults and is destabilized (reduced levels) in the absence of TEP1, establishing TEP1 as required for stable association of vault RNA with the vault particle.\",\n      \"method\": \"Cryo-electron microscopy, 3D reconstruction, vault purification, RNA quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural cryo-EM plus biochemical co-purification and RNA stability measurement in a genetic knockout model\",\n      \"pmids\": [\"11149928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Specific hTERT deletions that retain interaction with telomerase RNA and TEP1 are completely inactive for telomerase polymerization in vitro and in vivo, demonstrating that TEP1 binding and RNA binding can be functionally uncoupled from catalysis. The amino-terminus of hTERT is required for primer elongation but not for RNA or TEP1 binding.\",\n      \"method\": \"In vitro reconstitution of telomerase activity, deletion mutagenesis, in vivo assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution combined with systematic mutagenesis and in vivo validation in one rigorous study\",\n      \"pmids\": [\"11029039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTEN/TEP1 inhibits H-Ras–induced transformation and anchorage-independent growth in NIH3T3 cells by suppressing the PI3K-dependent (but not MAPK) signaling cascade. C-terminal truncation mutants show that anti-transformation activity correlates with ability to dephosphorylate inositol-(1,3,4,5)-tetrakisphosphate in vitro and to suppress Akt kinase activity in cells.\",\n      \"method\": \"NIH3T3 transformation assay, soft-agar growth, in vitro phosphatase assay, Akt kinase activity measurement, deletion mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro lipid phosphatase assay plus cellular epistasis experiments with mutagenesis panel, multiple orthogonal methods\",\n      \"pmids\": [\"10698513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Anopheles gambiae TEP1 (complement-like protein) binds to and mediates killing of Plasmodium berghei midgut stages. dsRNA knockdown of TEP1 completely abolishes melanotic refractoriness in a refractory mosquito strain and increases parasite numbers in susceptible mosquitoes.\",\n      \"method\": \"dsRNA knockdown (RNAi), parasite counting, melanization assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean RNAi loss-of-function with quantitative parasitological phenotype, published in high-impact venue, founding mechanistic study replicated by multiple subsequent labs\",\n      \"pmids\": [\"15006349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Tetrahymena p80 homology region (amino acids 1–871) of TEP1 is necessary and sufficient for interaction with both telomerase RNA and vault RNA in yeast three-hybrid assays, and for targeting TEP1 to the vault particle. Recombinant TEP1 RNA-binding domain directly binds RNA (EMSA), and vault RNA competes with telomerase RNA for this domain.\",\n      \"method\": \"Yeast three-hybrid assay, electrophoretic mobility shift assay (EMSA), deletion mutagenesis, vault targeting assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro direct binding (EMSA) combined with yeast three-hybrid and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15701761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of Anopheles gambiae TEP1 isoform TEP1r reveals an overall fold resembling complement factor C3 but with repositioned domains that stabilize the inactive (thioester-intact) conformation in the absence of the anaphylotoxin domain. Structural differences between TEP1r and TEP1s alleles map to the TED-MG8 interface protecting the thioester bond.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination providing molecular mechanism; single lab but high-resolution structural data\",\n      \"pmids\": [\"17606907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LRIM1 and APL1 leucine-rich repeat proteins are required for binding of TEP1 to Plasmodium parasites. RNAi silencing of LRIM1 or APL1 causes deposition of TEP1 on mosquito tissues, depleting circulating TEP1 and preventing its binding to parasites. LRIM1 and APL1 stabilize each other and stabilize circulating TEP1.\",\n      \"method\": \"RNAi knockdown, hemolymph immunoblot, parasite binding assay\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic RNAi dissection with biochemical binding readout, independently supported by multiple subsequent structural studies\",\n      \"pmids\": [\"19286136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The coiled-coil domain of the LRIM1/APL1C complex is the binding site for mature (cleaved) TEP1. Key cysteine residues form the intermolecular disulfide bond of the LRIM1/APL1C heterodimer. The complex also interacts with mature forms of TEP3 and two other TEP proteins via the same coiled-coil domain.\",\n      \"method\": \"Cell culture expression of allele mutants, co-immunoprecipitation, disulfide-bond mutagenesis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis panel with Co-IP readout, multiple alleles and constructs tested\",\n      \"pmids\": [\"21533217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of full-length TEP1*S1 allele shows flexibility in MG1-MG6 domains relative to TEP1*R1. Amino acid differences localize to the TED-MG8 interface protecting the thioester; cleaved TEP1*S1 is significantly more susceptible to thioester hydrolysis than TEP1*R1. The LRIM1/APL1C complex stabilizes the thioester in cleaved TEP1*S1.\",\n      \"method\": \"X-ray crystallography, thioester hydrolysis assay, biochemical complex formation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional biochemical assay of thioester stability, single lab but two orthogonal methods\",\n      \"pmids\": [\"23055931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CLIPA2 (clip domain serine protease homolog) negatively regulates TEP1 consumption during systemic infections by localizing to microbial surfaces in a TEP1-dependent manner and inhibiting the putative TEP1 convertase that cleaves full-length TEP1-F into active TEP1cut. CLIPA2 silencing triggers exacerbated TEP1-mediated immunity.\",\n      \"method\": \"RNAi knockdown, hemolymph immunoblot (TEP1 cleavage assay), infection phenotype scoring\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via RNAi with biochemical TEP1 processing readout; convertase identity inferred indirectly\",\n      \"pmids\": [\"25012124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cleaved TEP1 forms a soluble complex with the LRIM1/APL1C heterodimer through the coiled-coil domain of LRIM1/APL1C. Complex formation requires a conformational change in the TED-MG8 domain interface of TEP1 induced by cleavage; disulfide-stabilized TEP1 (TED-MG8 locked) does not interact with LRIM1/APL1C, establishing that TED-MG8 separation is prerequisite for complex formation.\",\n      \"method\": \"Engineered disulfide mutagenesis, co-immunoprecipitation, biochemical stability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-guided mutagenesis (disulfide engineering) with functional binding readout; mechanistically rigorous single-lab study\",\n      \"pmids\": [\"31237887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The S. cerevisiae TEP1 ortholog (YNL128w) functions in the phosphatidylinositol pathway: tep1 diploids are resistant to the PI3-kinase inhibitor wortmannin and to lithium. A common human PTEN tumor mutation introduced at the analogous yeast position produces a non-functional Tep1p. TEP1 is required for normal dityrosine deposition on spore walls during sporulation.\",\n      \"method\": \"Yeast deletion genetics, drug resistance assay, sporulation phenotype analysis, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with pharmacological readout plus mutagenesis; yeast ortholog model with direct functional validation\",\n      \"pmids\": [\"11070083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PARP-1 knockdown by siRNA in HeLa cells reduces poly(ADP-ribosyl)ation of hTERT and decreases TEP1/TP1 protein expression, correlating with reduced telomerase activity. This establishes PARP-1 as a regulator of TEP1 expression/function in the telomerase complex.\",\n      \"method\": \"siRNA knockdown, TRAP assay, Western blot, immunoprecipitation of poly(ADP-ribosyl)ated proteins\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach; mechanistic link to TEP1 is indirect (expression change, not direct modification of TEP1)\",\n      \"pmids\": [\"17141279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEP1, TEP3, and TEP4 in Anopheles gambiae are positive regulators of periostial hemocyte aggregation at the heart ostia during bacterial infection. RNAi knockdown of TEP1 reduced periostial hemocyte numbers, bacterial accumulation, and melanin deposition at periostial regions, without affecting non-periostial sessile hemocytes.\",\n      \"method\": \"RNAi knockdown, intravital imaging, bacterial burden quantification, melanization scoring\",\n      \"journal\": \"Insect biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi loss-of-function with multiple quantitative phenotypic readouts; functional integration of immune and circulatory systems established\",\n      \"pmids\": [\"30690067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TEP1 is secreted and circulates in the mosquito hemolymph; its activated cleaved form binds and eliminates malaria parasites. The fat body is the main site of TEP1 expression by GFP reporter assay. Transgenic TEP1r rescues loss-of-function TEP1 mutations but does not increase parasite resistance in the presence of a susceptible wild-type allele.\",\n      \"method\": \"GFP reporter transgene, transgenic rescue, hemolymph immunoblot, parasite counting\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization via reporter transgene plus transgenic rescue genetics; single lab\",\n      \"pmids\": [\"28095489\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEP1 (human/mammalian) is a dual-function ribonucleoprotein component: it is an integral structural subunit of the vault particle required for vault RNA stability and recruitment, and it associates with telomerase (binding both telomerase RNA and hTERT) but is dispensable for telomerase catalytic activity and telomere length maintenance in vivo; its p80-homology domain directly binds vault and telomerase RNAs and is sufficient for vault targeting. In mosquitoes, the orthologous Anopheles gambiae TEP1 is a complement C3-like thioester-containing protein that circulates in the hemolymph as an inactive form, undergoes protease-dependent cleavage to expose a reactive thioester, and—stabilized by the LRIM1/APL1C leucine-rich repeat heterodimer via their coiled-coil domain—binds and kills Plasmodium parasites through lysis and melanization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The TEP1 timeline resolves into two internally coherent but biologically distinct proteins linked by a shared gene symbol, reflecting a symbol collision across species and historical nomenclature. In mammals, TEP1/TLP1 is a dual-function RNA-binding protein: it co-purifies with telomerase and binds telomerase RNA, but it is dispensable for telomerase catalytic activity and telomere length maintenance in vivo [#1, #4, #6], and it is independently a structural subunit of the vault ribonucleoprotein particle where it is required for stable association and recruitment of vault RNA [#3, #5]. A single Tetrahymena p80-homology RNA-binding domain (residues 1–871) directly binds both telomerase RNA and vault RNA in competition, and is necessary and sufficient to target TEP1 to vaults [#9]. A second cluster of mammalian findings instead describes PTEN/MMAC1, a cytoplasmic protein tyrosine and inositol-phosphate phosphatase that antagonizes PI3K/Akt signaling, raises p27(KIP1), arrests cells in G1, and suppresses Ras-induced transformation [#0, #2, #7]; this PTEN-associated work uses the TEP1 alias and a yeast ortholog acting in the phosphatidylinositol pathway [#16]. In mosquitoes (Anopheles gambiae), TEP1 is an entirely separate complement C3-like thioester-containing protein of the innate immune system that circulates in the hemolymph, is secreted by the fat body, and after protease-dependent cleavage binds and kills Plasmodium parasites by lysis and melanization [#8, #19]. Mosquito TEP1 is held in its inactive thioester-intact conformation by a TED-MG8 domain interface [#10, #13]; cleavage drives TED-MG8 separation, which is prerequisite for binding the LRIM1/APL1C leucine-rich-repeat heterodimer through its coiled-coil domain, and this complex stabilizes the reactive cleaved form and delivers it to parasite surfaces [#11, #12, #15]. Upstream, a CLIPA2 clip-domain protease homolog restrains TEP1 convertase activity to limit TEP1 consumption [#14], and TEP1 also promotes periostial hemocyte aggregation during bacterial infection [#18]. Because these clusters describe unrelated proteins, the molecular_activity and pathway slots below are populated separately and the narrative should not be read as one protein.\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Two independent identifications established the symbol's ambiguity: one assigned TEP1 to a cytoplasmic tyrosine phosphatase (PTEN/MMAC1), the other to a co-purifying protein subunit of telomerase.\",\n      \"evidence\": \"In vitro phosphatase assay and immunofluorescence (PTEN); anti-TLP1 immunoprecipitation of telomerase activity and co-purification with pulse-chase PTM analysis (rat telomerase)\",\n      \"pmids\": [\"9187108\", \"9118230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The two 1997 findings describe unrelated proteins sharing a symbol\", \"Whether TEP1 contributes catalytically to telomerase was not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"PTEN/MMAC1/TEP1 was placed in a defined growth-suppressive signaling cascade, answering how it controls proliferation.\",\n      \"evidence\": \"Cell cycle analysis, Western blot, kinase assay and pharmacological inhibition in glioblastoma cells\",\n      \"pmids\": [\"9860981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Concerns the PTEN protein, not the telomerase/vault TEP1\", \"Direct phosphatase substrate in cells inferred via epistasis\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"TEP1 was shown to be a bona fide vault particle component that binds vault RNAs sequence-specifically, separating its RNA-binding role from telomerase catalysis.\",\n      \"evidence\": \"Vault purification, TRAP activity assay, yeast three-hybrid RNA-binding assay\",\n      \"pmids\": [\"10551828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of TEP1–vault RNA binding not yet established\", \"Structural basis of recruitment unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"A knockout and reconstitution work resolved that TEP1 is dispensable for telomerase catalysis in vivo and that TEP1/RNA binding is uncoupled from polymerization.\",\n      \"evidence\": \"mTep1−/− mice with TRAP and telomere FISH across seven generations; hTERT deletion mutagenesis with in vitro reconstitution\",\n      \"pmids\": [\"11027287\", \"11029039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why telomerase retains TEP1 if catalytically dispensable is unexplained\", \"TEP1's non-telomerase RNA role pointed toward vaults but not yet mechanistically dissected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Structure-function and ortholog studies tied the PTEN-associated TEP1 alias to lipid-phosphatase activity and an evolutionarily conserved phosphatidylinositol pathway role.\",\n      \"evidence\": \"NIH3T3 transformation/soft-agar assays with phosphatase and Akt readouts; S. cerevisiae deletion genetics with wortmannin/lithium resistance and sporulation phenotype\",\n      \"pmids\": [\"10698513\", \"11070083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast ortholog evidence is Medium-confidence\", \"These findings concern PTEN, distinct from telomerase/vault TEP1\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The vault role was made mechanistic: TEP1 is required for stable association of vault RNA with the particle and for normal cap structure.\",\n      \"evidence\": \"Cryo-EM 3D reconstruction, vault purification and RNA quantification in mTep1−/− mice\",\n      \"pmids\": [\"11149928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of vault RNA loss for cells unresolved\", \"Whether reduced cap density alters vault cargo handling unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A wholly distinct mosquito TEP1 was established as a complement-like effector that binds and kills malaria parasites, founding the innate-immunity branch.\",\n      \"evidence\": \"dsRNA knockdown with parasite counting and melanization assays in Anopheles gambiae\",\n      \"pmids\": [\"15006349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation mechanism and required cofactors not yet defined\", \"Mechanism of parasite killing (lysis vs melanization) not separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The mammalian TEP1 RNA-binding determinant was mapped to a single p80-homology domain sufficient for both telomerase RNA and vault RNA binding and for vault targeting.\",\n      \"evidence\": \"Yeast three-hybrid, EMSA direct binding, deletion mutagenesis, vault targeting assay\",\n      \"pmids\": [\"15701761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RNA specificity not solved\", \"How a single domain partitions between telomerase and vaults in cells unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystallography defined how mosquito TEP1 maintains an inactive thioester-intact conformation and how allelic variation maps to thioester protection.\",\n      \"evidence\": \"X-ray crystallography of TEP1r isoform\",\n      \"pmids\": [\"17606907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transition upon activation not captured\", \"In vivo trigger for thioester exposure not defined here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The LRIM1/APL1 LRR proteins were shown to stabilize circulating TEP1 and enable its binding to parasites, explaining how the effector is kept available in hemolymph.\",\n      \"evidence\": \"RNAi silencing with hemolymph immunoblot and parasite binding assay\",\n      \"pmids\": [\"19286136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface of stabilization not yet defined\", \"Whether stabilization acts on full-length or cleaved TEP1 unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The LRIM1/APL1C coiled-coil domain was identified as the docking site for mature cleaved TEP1, generalizing the interaction to multiple TEP proteins.\",\n      \"evidence\": \"Allele-mutant expression, co-immunoprecipitation, disulfide-bond mutagenesis\",\n      \"pmids\": [\"21533217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the in vivo complex not determined\", \"Functional consequence of binding other TEPs not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Full-length structure plus biochemistry linked allelic susceptibility to thioester hydrolysis and showed LRIM1/APL1C stabilizes the reactive cleaved form.\",\n      \"evidence\": \"X-ray crystallography of TEP1*S1, thioester hydrolysis assay, complex formation\",\n      \"pmids\": [\"23055931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of MG1-MG6 flexibility in solution not resolved\", \"How stabilization translates to parasite-surface deposition not shown here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A regulatory layer was added: CLIPA2 restrains TEP1 convertase activity to limit TEP1 consumption during infection.\",\n      \"evidence\": \"RNAi knockdown with hemolymph TEP1 cleavage immunoblot and infection scoring\",\n      \"pmids\": [\"25012124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Convertase identity inferred indirectly, not isolated\", \"Direct CLIPA2–convertase interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The source and secretion of mosquito TEP1 were localized, establishing the fat body as the main expression site and confirming hemolymph circulation of the active cleaved form.\",\n      \"evidence\": \"GFP reporter transgene, transgenic rescue, hemolymph immunoblot, parasite counting\",\n      \"pmids\": [\"28095489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reporter localization\", \"Allele dominance behavior not mechanistically explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The activation logic was completed for mosquito TEP1 and extended to a new effector role: TED-MG8 separation upon cleavage is prerequisite for LRIM1/APL1C binding, and TEP1 also drives periostial hemocyte aggregation in bacterial infection.\",\n      \"evidence\": \"Engineered disulfide mutagenesis with Co-IP (activation); RNAi with intravital imaging and bacterial/melanin quantification (periostial role)\",\n      \"pmids\": [\"31237887\", \"30690067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TED-MG8 separation is structurally coupled to coiled-coil binding not solved\", \"Mechanism by which TEP1 recruits hemocytes to ostia unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the mammalian TEP1 RNA-binding subunit functions biologically given its dispensability for telomerase, and what cellular role vault RNA recruitment serves.\",\n      \"evidence\": \"No timeline discovery assigns a downstream cellular function to mammalian TEP1's vault/telomerase RNA binding\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cellular phenotype tied to TEP1 vault RNA recruitment\", \"No structural model of the TEP1 RNA-binding domain–RNA complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 11, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [\n      \"vault ribonucleoprotein particle\",\n      \"telomerase\",\n      \"LRIM1/APL1C heterodimer complex\"\n    ],\n    \"partners\": [\n      \"hTERT\",\n      \"LRIM1\",\n      \"APL1C\",\n      \"TEP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}