ETV6 (TEL) is an ETS-family transcription factor that recognizes ETS cis-regulatory DNA sites and regulates RNA polymerase II transcription. Its ETS domain mediates sequence recognition, while its pointed/SAM domain supports protein association. Nuclear ETV6 represses transcription and associates with corepressors including HDAC9/MITR and L3MBTL1; L3MBTL1 can strengthen ETV6-dependent reporter repression through their SAM/SPM domains. ETV6 also has context-dependent positive regulatory effects, including increased Fli1 expression in mouse lymphoid cells. It participates in hematopoietic regulation, and pathogenic germline variants cause familial thrombocytopenia with predisposition to hematologic malignancy. Alternative translation initiation produces M1 and M43 forms. Pathological ETV6 fusions with receptor tyrosine kinases are distinct from the native transcription factor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:10514502 TEL is a sequence-specific transcriptional repressor. | ACCEPT | Summary: Human ETV6 directly represses RNA polymerase II reporter transcription. Reason: The actual human TEL experiments in PMID:10514502 show dose-dependent repression of an EBS-containing reporter in HeLa cells, with little effect on the minimal promoter control (Figure 1). Human TEL also represses a mouse Fli1 promoter reporter, and mutation of its ETS-binding site abolishes repression (Figure 5). Thus the raw mouse Fli1 input identifier denotes the tested target promoter, not a mouse ETV6 construct. The M1 construct carries M43A to prevent internal initiation; M1 and M43 are separately tested, rather than presumed equivalent in every function. Supporting Evidence: |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:10514502 TEL is a sequence-specific transcriptional repressor. | ACCEPT | Summary: ETV6 repression depends on its DNA-targeting and regulatory domains. Reason: PMID:10514502 tests human TEL deletion and domain-substitution constructs in HeLa reporter assays. B-domain loss impairs repression, an EBV EB1 oligomerization segment can restore repression, and distinct central repression domains are mapped (Figures 4β6). The EBS-mutant Fli1 reporter establishes sequence-dependent regulation. These are experimental human TEL constructs and chimeras, not additional natural products. The positive repressor role does not imply that ETV6 is repressive in every cell and promoter context. Supporting Evidence: |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin is consistent with the classified DNA-bound transcription-factor role. Reason: The actual author-hosted TFClass hierarchy places human ETV6 at 3.5.2.6.1 within the cited ETS family 3.5.2. This is an inferred classification-based location, not a target-specific ChIP assay. Independent human ETV6 experiments establish sequence-specific DNA binding (PMID:9018121, Methods and Figure 6) and EBS-dependent transcriptional repression (PMID:10514502, Figures 1 and 5). These support the DNA-associated nuclear transcription-factor context represented by this ISA assertion. Neither the classification nor those experiments resolve equal chromatin occupancy of all current transcript models. Propagation Review Root cause: NO FAILURE CORE Sources checked: tfclass:3.5.2 SUPPORTS TRANSFER Actual target membership recovered; chromatin localization remains inferred from the transcription-factor role rather than a newly claimed ChIP measurement. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:9018121 The TEL gene products: nuclear phosphoproteins with DNA bind... | MODIFY | Summary: Specify ETV6 recognition of an RNA polymerase II cis-regulatory ETS site. Reason: PMID:9018121 directly demonstrates sequence-specific binding of human TEL expressed in Sf9 cells to a synthetic EBS probe: wild-type competitor and TEL antibodies distinguish binding from a GG-to-CC mutant competitor (Figure 6). Independently, PMID:10514502 couples human TEL to an EBS-dependent Fli1 promoter reporter (Figure 5), establishing the cis-regulatory context appropriate for GO:0000978. The original synthetic-probe experiment is not described as native promoter occupancy or chromatin immunoprecipitation. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000117 | MODIFY | Summary: The valid regulatory-DNA rule can be specified to cis-regulatory DNA binding. Reason: Current ARBA00028973 disjunct 24 (zero-based) requires FunFam 1.10.150.50:FF:000030 and Craniata. Both match the official human target record and lineage; the rule actually outputs GO:0000977. The more specific existing term GO:0000978 fits the EBS-containing cis-regulatory promoters used in the human TEL reporter assays (PMID:10514502, Figures 1 and 5), supported by human TEL EMSA specificity in PMID:9018121. This is a biological specificity refinement, not a failed-rule or wrong-family claim. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00028973 SUPPORTS TRANSFER Exact current condition set and target FunFam/taxon match recovered; a specific existing cis-regulatory descendant is supported. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved cis-regulatory sequence recognition is supported by mouse and human experiments. Reason: The source resolves to mouse Etv6/P97360 and its Ensembl translation ENSMUSP00000079818. Current mouse GOA identifies IDA PMID:17606295: BALB/c splenic nuclear extracts bind the Fli1 EBS2 probe with an anti-Tel supershift and sequence-competition controls (Methods, EMSA; Figure 4B). The native extract is mouse; the separate pcDNA3 Tel expression plasmid has no accession/species statement in the inspected Methods. Human TEL independently shows EBS-specific binding and cis-promoter repression in PMID:9018121 and PMID:10514502. Thus the conserved binding role is supported without calling the mouse experiment human or equating all natural products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P97360 SUPPORTS TRANSFER Actual mouse IDA source and native-extract assay verified; independent human DNA experiments support conservation. ensembl:ENSMUSP00000079818 SUPPORTS TRANSFER Official mouse translation lookup and UniProt cross-reference recovered; the protein is distinct from human P41212. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | MODIFY | Summary: Specify the established human sequence-specific repressor activity. Reason: The actual PTHR11849 v19 human leaf PTN002483834 descends from PTN000218930; its ungapped MSA exactly matches the canonical 452-residue sequence. The four positive target-path IBD records are recovered with no NOT record. Human P41212 in WITH/FROM is valid descendant experimental evidence, not circular support. Human TEL represses EBS-driven reporters and a mouse Fli1 promoter reporter in HeLa cells, with sequence-mutant controls (PMID:10514502, Figures 1 and 5). GO:0001227 captures that established activity more precisely than the broad transcription-factor term. This does not assert universal repression: the separate contextual activator annotations are retained at indices 10 and 41 from the mouse T-cell evidence in PMID:17606295. The tested M1 and M43 constructs both repress the tested reporter; other transcript-derived products are not assumed equivalent. The replacement selects the principal experimentally demonstrated human repressor facet, rather than claiming that this sign exhausts all ETV6 activity. The separately retained activator context is supported by mouse lymphoid experiments with an unversioned Tel insert; it is neither discarded nor promoted to an independently established native-human core activity. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000218930 SUPPORTS TRANSFER The source placement/classification is valid; independent human experiments support the more specific repressor facet while contextual activation remains separately retained. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000117 | MODIFY | Summary: Specify the established human sequence-specific repressor activity. Reason: Current ARBA00029016 disjunct 41 (zero-based) requires FunFam 1.10.150.50:FF:000030, which is present in the official P41212 record; its output is the imported PolII transcription-factor term. Human TEL represses EBS-driven reporters and a mouse Fli1 promoter reporter in HeLa cells, with sequence-mutant controls (PMID:10514502, Figures 1 and 5). GO:0001227 captures that established activity more precisely than the broad transcription-factor term. This does not assert universal repression: the separate contextual activator annotations are retained at indices 10 and 41 from the mouse T-cell evidence in PMID:17606295. The tested M1 and M43 constructs both repress the tested reporter; other transcript-derived products are not assumed equivalent. The replacement selects the principal experimentally demonstrated human repressor facet, rather than claiming that this sign exhausts all ETV6 activity. The separately retained activator context is supported by mouse lymphoid experiments with an unversioned Tel insert; it is neither discarded nor promoted to an independently established native-human core activity. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00029016 SUPPORTS TRANSFER The source placement/classification is valid; independent human experiments support the more specific repressor facet while contextual activation remains separately retained. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | MODIFY | Summary: Specify the established human sequence-specific repressor activity. Reason: The actual TFClass hierarchy places ETV6 at 3.5.2.6.1 within ETS family 3.5.2. Membership is verified rather than inferred from a similar family name. Human TEL represses EBS-driven reporters and a mouse Fli1 promoter reporter in HeLa cells, with sequence-mutant controls (PMID:10514502, Figures 1 and 5). GO:0001227 captures that established activity more precisely than the broad transcription-factor term. This does not assert universal repression: the separate contextual activator annotations are retained at indices 10 and 41 from the mouse T-cell evidence in PMID:17606295. The tested M1 and M43 constructs both repress the tested reporter; other transcript-derived products are not assumed equivalent. The replacement selects the principal experimentally demonstrated human repressor facet, rather than claiming that this sign exhausts all ETV6 activity. The separately retained activator context is supported by mouse lymphoid experiments with an unversioned Tel insert; it is neither discarded nor promoted to an independently established native-human core activity. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: tfclass:3.5.2 SUPPORTS TRANSFER The source placement/classification is valid; independent human experiments support the more specific repressor facet while contextual activation remains separately retained. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:10514502 TEL is a sequence-specific transcriptional repressor. | ACCEPT | Summary: ETV6 has directly established DNA-binding transcription repressor activity. Reason: Human TEL represses EBS-containing RNA polymerase II reporters, including a Fli1 promoter reporter whose response depends on an intact ETS-binding site (PMID:10514502, Figures 1 and 5). DNA targeting, oligomerization and repression-domain perturbations support the functional linkage. M1 and M43 show repression in the tested reporter comparison, but this is not a universal equivalence claim. Activation reported in other cellular contexts does not negate the measured repressor activity. Supporting Evidence: |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TEL has context-dependent transcriptional activator evidence. Reason: Current mouse P97360 GOA traces this transfer to IDA PMID:17606295. In that original, native BALB/c splenic nuclear extracts show Tel-specific binding to Fli1 EBS2 (Figure 4B), and pcDNA3 Tel overexpression increases endogenous Fli1 mRNA in mouse S1A T cells relative to empty vector (Figure 5; Methods, RNA isolation and real-time RT-PCR). The expression insert accession/species is not stated, so the T-cell host is not used to assign its sequence. This is positive contextual regulatory evidence and is not refuted by ETV6 being a repressor in other settings. Human TEL represses an Fli1 promoter reporter in HeLa cells in PMID:10514502, illustrating the assay-context distinction. Retain the conserved activation facet as non-core, without claiming a universal activator role, direct human FLI1 induction, or equivalent activity of every natural product. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P97360 SUPPORTS TRANSFER Actual positive mouse-cell regulatory source recovered; conserved contextual interpretation retains the unresolved expression-insert identity. ensembl:ENSMUSP00000079818 SUPPORTS TRANSFER Official donor identity verified; not reinterpreted as a human assay. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Specify the regulatory sequence recognition underlying the broad DNA-binding transfer. Reason: The source mouse translation maps to P97360. Its current broad DNA-binding IDA cites PMID:12527908, whose complete original Methods were not accessible; the verified publisher abstract is positive and is not rejected. Independent primary evidence resolves the narrower binding role: native mouse Tel recognizes Fli1 EBS2 in PMID:17606295 Figure 4B, and human TEL binds an ETS oligonucleotide with core-sequence controls in PMID:9018121 Figure 6 and regulates EBS-dependent cis-promoter reporters in PMID:10514502. Refine to the already-present GO:0000978 without pretending that the inaccessible 2003 experiment or its exact construct was inspected. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:P97360 SUPPORTS TRANSFER Positive mouse source identity is recovered; independent mouse/human experiments establish regulatory sequence specificity. ensembl:ENSMUSP00000079818 SUPPORTS TRANSFER Official mouse donor translation identity recovered; no all-product equivalence. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | Summary: Specify the established human sequence-specific repressor activity. Reason: The aggregate source includes mouse P97360/ENSMUSP00000079818 and actual human IPR000418 ETS-domain/IPR046328 ETS-family matches. These support a DNA-binding transcription factor, not by themselves its transcriptional sign. Human TEL represses EBS-driven reporters and a mouse Fli1 promoter reporter in HeLa cells, with sequence-mutant controls (PMID:10514502, Figures 1 and 5). GO:0001227 captures that established activity more precisely than the broad transcription-factor term. This does not assert universal repression: the separate contextual activator annotations are retained at indices 10 and 41 from the mouse T-cell evidence in PMID:17606295. The tested M1 and M43 constructs both repress the tested reporter; other transcript-derived products are not assumed equivalent. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR046328 SUPPORTS TRANSFER The source placement/classification is valid; independent human experiments support the more specific repressor facet while contextual activation remains separately retained. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:7761424 Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in... | MODIFY | Summary: Refine broad transcription-factor activity to the experimentally established ETV6 repressor activity. Reason: The PMID:7761424 original body was not recovered beyond its abstract and scanned-article landing page; its fusion-focused title is not evidence that the native transcription-factor annotation is wrong. Independent actual human TEL originals establish sequence-specific ETS-site binding (PMID:9018121) and EBS-dependent repression in HeLa cells (PMID:10514502). GO:0001227 describes that demonstrated principal activity more precisely than the imported broad term. This refinement does not transfer TELβAML1 fusion properties to native ETV6 or exclude contextual activation. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0005515 protein binding | IPI PMID:12590135 The histone deacetylase 9 gene encodes multiple protein isof... | MODIFY | Summary: Specify binding to the HDAC9/MITR transcription-corepressor product class. Reason: The actual PMID:12590135 original shows TEL binding to HDAC9 variants, including the catalytic-domain-lacking HDAC9ΞCD/MITR form, by GST pull-down with reticulocyte-translated TEL and by coexpression/co-immunoprecipitation (Figure 6). The imported Q9UKV0-3 is independently identified by UniProt as MITR/HDRP, a catalytically inactive transcriptional repressor. This supports GO:0001222 rather than generic protein binding or an assertion that the partner supplies intrinsic deacetylase catalysis. The historical 593-residue ΞCD description is not asserted to be sequence-identical to the current 590-residue Q9UKV0-3 model; endogenous C-terminal-antibody co-IP does not specifically identify ΞCD. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The screened ETV6 association with Q96HA8 is supported without an established core mechanism. Reason: Actual archived HI-II-14 PSI records pair human ETV6 ORF 11407 with partner ORF 4786 in screen(s) 2, with array, pooling and validated two-hybrid records. PMID:25416956 describes human ORFs screened in yeast and sequence-confirmed pairwise retesting. This supports retention under the campaign supported-binding policy. Orthogonal validation of a study-wide subset is not attributed to this specific pair, and neither native complex membership nor equivalence of the archived ORF to every current product is inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The screened ETV6 association with Q9BXS5 is supported without an established core mechanism. Reason: Actual archived HI-II-14 PSI records pair human ETV6 ORF 11407 with partner ORF 206 in screen(s) 1 and 2, with array, pooling and validated two-hybrid records. PMID:25416956 describes human ORFs screened in yeast and sequence-confirmed pairwise retesting. This supports retention under the campaign supported-binding policy. Orthogonal validation of a study-wide subset is not attributed to this specific pair, and neither native complex membership nor equivalence of the archived ORF to every current product is inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: Retain the experimentally curated ETV6 association with the AXIN1 alternative product. Reason: The actual PMID:26871637 main Methods describe pairwise yeast two-hybrid testing of human alternative ORFs. Current IntAct records IM-25013-5015, IM-25013-593 and IM-25013-2701 explicitly pair A0A0S2Z4M1 with P41212, with pooling, validated and array methods, respectively; they cite Supplementary Table S2B and preserve human proteins tested in yeast. UniProt identifies A0A0S2Z4M1 as an AXIN1 fragment record. The original workbook could not be recovered, so exact clone-sequence equivalence is not asserted. The positive curated partner-specific result is retained without assigning an ETV6 Wnt-pathway function or replacing the imported partner accession. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: ETV6βPIN1 binary association is supported by HuRI. Reason: The actual HuRI PSI records pair human ETV6 ORF 11407 and PIN1 ORF 4406 in screen 1, with array, pooling and validated two-hybrid records. Human proteins are tested in yeast; PMID:32296183 describes sequence-confirmed pairwise retesting. This supports the imported binding assertion, while neither PIN1-catalyzed isomerization of ETV6 nor a specific shared regulatory mechanism is established by this screen. Native complex stoichiometry and all-product equivalence are not inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | KEEP AS NON CORE | Summary: ETV6 binding to NRF2 is supported by targeted interaction assays. Reason: PMID:32911434 Supplementary Table S1 row 20 explicitly records ETV6 as Y2H-positive with NRF2; Table S2 lists the mCherry-ETV6 and FL-V5-ETV6 constructs. The actual main Results also report reduced apparent ETV6βNRF2 affinity in KEAP1-knockout versus wild-type cells in the cellular DULIP assay. These results support association, without treating a cell-based readout as purified-protein affinity or assigning every study-wide validation assay to this pair. An ETV6 antioxidant-response function is not inferred from binding alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: PIN1 affinity purification supports an ETV6-containing association in human 293T cells. Reason: The actual BioPlex 3.0 293T interaction table records PIN1 (Q13526; gene 5300) as bait and ETV6 (P41212; gene 2120) as prey, with a high-confidence interaction call. The original Methods use C-terminal FLAG-HA-tagged human ORFeome baits, anti-HA affinity purification and mass spectrometry. This is complex-level association rather than proof of a purified binary interaction or PIN1 catalytic action on ETV6. The absence of this edge from the separately captured HCT116 table is not generalized into an interaction-negative conclusion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: The human U2OS interaction network independently supports ETV6βPIN1 association. Reason: The actual PMID:40205054 AP-MS network contains the ETV6βPIN1 edge linking human gene identifiers 2120 and 5300. Original Methods use C-terminal HA-Flag human ORFeome baits, U2OS cell lysates and anti-HA purification followed by mass spectrometry. Both nodes are designated baits in the network, but that does not by itself establish reciprocal pull-downs for this pair. Imaging, SEC-MS, structural prediction and functional assays performed elsewhere in the multimodal study are not attributed to this specific edge. Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Native ETV6 is a nuclear protein. Reason: The actual nucleus IBD at PTN000218930 is ancestral to human leaf PTN002483834, whose 452-residue alignment is exact. No target-path NOT record was found. Independent human RAJI immunofluorescence in PMID:9018121 Figure 3 shows nuclear signal overlapping DAPI, lost with specific antigen competition and absent in Reh controls. HPA000264 additionally reports nucleoli and cytosol in three human cell lines; these signals do not justify replacing every nuclear context by nucleoplasm or nucleolus. Retain the broader nuclear location that covers the experimentally observed native context. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000218930 SUPPORTS TRANSFER Exact target ancestry and nucleus IBD recovered; independent human endogenous localization corroborates the transfer. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The nucleus vocabulary mapping is supported by endogenous human localization. Reason: The official human record contains SL-0191, and the current UniProt location vocabulary maps it to nucleus. PMID:9018121 Figure 3 independently localizes endogenous human TEL in RAJI nuclei with DAPI overlap and antigen-competition/negative-cell controls. The HPA nucleolar and cytosolic patterns are distinct additional cellular contexts, not proof that the general native nuclear annotation is incorrect or that all products share a subnuclear distribution. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER Actual target location and vocabulary mapping agree with the independent endogenous human experiment. Supporting Evidence: |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703430 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703430 β 9703378 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703430 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703432 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703432 β 9703359 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703432 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703433 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703433 β 9703345 β 9703315 reaches ETV6(1-301)-FLT3(574-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703433 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703434 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703434 β 9703358 β 9703356 β 9703378 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703434 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703435 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703435 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703435 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703437 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703437 β 9703409 β 9703354 β 9697944 reaches ETV6(1-384)-FLT3(569-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703437 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703438 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703438 β 9703426 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703438 file:human/ETV6/ETV6-source-guide.md |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9703441 | REMOVE | Summary: This cytosol annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9703441 β 9703425 β 9703349 β 9703378 β 9703372 β 9703353 β 9703305 reaches ETV6(1-336)insGCS-p-6Y-FLT3(573-993) fusion [cytosol], a disease fusion with an ETV6 segment and inserted FLT3 sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is cytosol, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9703441 file:human/ETV6/ETV6-source-guide.md |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9673760 | REMOVE | Summary: This plasma membrane annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9673760 β 9673677 β 9673893 reaches ETV6(1-154)-PDGFRB(527-1106) fusion [plasma membrane], a disease fusion with an ETV6 segment and inserted PDGFR sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is plasma membrane, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9673760 file:human/ETV6/ETV6-source-guide.md |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9673761 | REMOVE | Summary: This plasma membrane annotation belongs to an ETV6-containing disease fusion. Reason: One representative source participant route 9673761 β 9673678 β 9673914 β 9673893 reaches ETV6(1-154)-PDGFRB(527-1106) fusion [plasma membrane], a disease fusion with an ETV6 segment and inserted PDGFR sequence. The target referenceEntity 54508/P41212 legitimately anchors the ETV6 portion; it is not a native full-length ETV6 participant. Its own compartment is plasma membrane, so the source localization is correct for the fusion but was projected to the wrong reviewed product. Remove this source-specific native-product assertion, not the valid Reactome reaction or fusion localization. Independent HPA000264 cytosolic/nucleolar staining is separately positive and does not repair this source attribution. No replacement fusion accession or corrected fusion sequence is invented. Supporting Evidence: Reactome:R-HSA-9673761 file:human/ETV6/ETV6-source-guide.md |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | MODIFY | Summary: Specify the RNA polymerase II transcriptional context. Reason: Actual human IPR000418 matches the ETS DNA-binding domain and its current mapping includes broad transcriptional regulation. Human TEL sequence-dependent promoter repression in PMID:10514502 and contextual Fli1 induction in PMID:17606295 both concern RNA polymerase II transcription. Refine the broad process to the already-present GO:0006357. The unsigned replacement preserves both regulatory directions instead of asserting repression in every cell or reinterpreting a domain match as an enzyme assay. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR000418 SUPPORTS TRANSFER Actual target domain/mapping recovered; the primary assays support the specific polymerase context. Proposed replacements: regulation of transcription by RNA polymerase II |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ETV6 regulates RNA polymerase II transcription. Reason: The actual GO:0006357 IBD is on the human target path, with exact 452-residue MSA and no NOT. The target self-WITH is legitimate descendant experimental support. Human EBS-dependent repression is directly demonstrated in PMID:10514502, while the mouse T-cell work in PMID:17606295 demonstrates a positive regulatory context. The unsigned process is appropriate across these contexts; it does not mean that the protein activates and represses the same target under identical conditions or that every natural product has been assayed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000218930 SUPPORTS TRANSFER Actual source placement/mapping is valid and the target transcriptional role is independently supported. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000002 | ACCEPT | Summary: ETV6 regulates RNA polymerase II transcription. Reason: The actual human ETS-family match IPR046328 carries the imported PolII-regulation mapping. Human EBS-dependent repression is directly demonstrated in PMID:10514502, while the mouse T-cell work in PMID:17606295 demonstrates a positive regulatory context. The unsigned process is appropriate across these contexts; it does not mean that the protein activates and represses the same target under identical conditions or that every natural product has been assayed. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR046328 SUPPORTS TRANSFER Actual source placement/mapping is valid and the target transcriptional role is independently supported. |
| GO:0019904 protein domain specific binding | IPI PMID:12588862 The human L(3)MBT polycomb group protein is a transcriptiona... | MODIFY | Summary: Specify ETV6 binding to the transcription corepressor L3MBTL1. Reason: PMID:12588862 provides endogenous human U2OS nuclear TELβL3MBTL1 co-immunoprecipitation (Figure 4), domain-dependent association in transfected human 293T cells and GST-TEL pull-down of reticulocyte-translated L3MBTL1 (Figure 5). TEL SAM and L3MBTL1 SPM regions are required in those assays. Human L3MBTL1 also strengthens TEL repression in reporter experiments in mouse NIH3T3 cells, including a rat stromelysin-1 promoter reporter (Figure 6). GO:0001222 captures the partner function more precisely than domain-specific binding. This does not assert purified two-protein reconstitution, native chromatin occupancy or membership in every Polycomb complex. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Differentiation is a retained contextual consequence of the transcriptional regulator. Reason: The actual differentiation IBD at PTN000218930 is ancestral to the exact human ETV6 leaf, with no target-path NOT. This is a phylogenetic functional judgment, not a vote based on donor count; human self-WITH is valid descendant support. ETV6 has an experimentally established sequence-specific transcriptional regulatory role, and the verified PMID:12527908 abstract reports altered erythroid differentiation with TEL expression/deletion constructs in mouse erythroleukemia cells. Its complete Methods and exact construct identity remain unavailable; this limited access is not used to reject the positive source. Retain the broad conserved differentiation context as non-core, without assigning a particular human lineage, claiming every differentiation program, or manufacturing a new process assertion. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000218930 SUPPORTS TRANSFER Actual source-to-target membership/conditions verified; contextual developmental role retained without specific lineage expansion. |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Differentiation is a retained contextual consequence of the transcriptional regulator. Reason: Current ARBA00027429 disjunct 215 (zero-based) requires FunFam 1.10.10.10:FF:000176 and 1.10.150.50:FF:000030; both are explicitly present in the official human record. The rule outputs cell differentiation. ETV6 has an experimentally established sequence-specific transcriptional regulatory role, and the verified PMID:12527908 abstract reports altered erythroid differentiation with TEL expression/deletion constructs in mouse erythroleukemia cells. Its complete Methods and exact construct identity remain unavailable; this limited access is not used to reject the positive source. Retain the broad conserved differentiation context as non-core, without assigning a particular human lineage, claiming every differentiation program, or manufacturing a new process assertion. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027429 SUPPORTS TRANSFER Actual source-to-target membership/conditions verified; contextual developmental role retained without specific lineage expansion. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | MODIFY | Summary: Specify the established cis-regulatory DNA-binding facet. Reason: Actual IPR000418 and IPR003118 match the human ETS and pointed/SAM regions. The ETS domain supports sequence recognition; the pointed domain mediates oligomerization and is not independently treated as a DNA-binding active site. Human EBS-specific EMSA in PMID:9018121 and sequence-dependent cis-promoter reporter effects in PMID:10514502 support the already-present GO:0000978. The broad sequence-specific DNA-binding assertion is therefore retained in a more informative regulatory context, without asserting that every matched domain separately contacts DNA. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR000418 SUPPORTS TRANSFER Actual ETS-domain match supports sequence recognition. InterPro:IPR003118 SUPPORTS TRANSFER Actual pointed-domain match supports the architecture of a DNA-regulatory protein; it is not by itself evidence of direct DNA contact. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive PolII regulation is retained in the demonstrated lymphocyte context. Reason: Current mouse P97360 GOA traces this transfer to IDA PMID:17606295. In that original, native BALB/c splenic nuclear extracts show Tel-specific binding to Fli1 EBS2 (Figure 4B), and pcDNA3 Tel overexpression increases endogenous Fli1 mRNA in mouse S1A T cells relative to empty vector (Figure 5; Methods, RNA isolation and real-time RT-PCR). The expression insert accession/species is not stated, so the T-cell host is not used to assign its sequence. This is positive contextual regulatory evidence and is not refuted by ETV6 being a repressor in other settings. Human TEL represses an Fli1 promoter reporter in HeLa cells in PMID:10514502, illustrating the assay-context distinction. Retain the conserved activation facet as non-core, without claiming a universal activator role, direct human FLI1 induction, or equivalent activity of every natural product. The raw transfer preserves has_input NCBI_Gene:14247 (mouse Fli1); that context is not rewritten as human FLI1. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P97360 SUPPORTS TRANSFER Actual positive mouse regulatory source and Fli1 extension are recovered; no universal sign or human-assay substitution. ensembl:ENSMUSP00000079818 SUPPORTS TRANSFER Actual donor identity verified with the expression-insert limit kept explicit. |
| GO:0071425 hematopoietic stem cell proliferation | IMP PMID:25581430 Germline ETV6 mutations in familial thrombocytopenia and hem... | KEEP AS NON CORE | Summary: ETV6 has a supported contextual role in hematopoietic stem/progenitor population expansion. Reason: PMID:25581430 tests human ETV6 variants in umbilical-cord CD34-positive hematopoietic stem/progenitor cells under expansion conditions (Figure 5a; cell-culture and proliferation Methods). Mutant-expressing cultures show reduced viable-cell expansion relative to wild-type and empty-vector controls, without reported increased apoptosis. This is a positive hematopoietic proliferative phenotype consistent with the curated term, retained as non-core downstream transcriptional regulation. The mixed CD34-positive population and viable-cell counts do not separately resolve long-term stem-cell self-renewal or establish a direct cell-cycle catalytic activity; the recombinant ETS-domain binding assay is a separate experiment. Supporting Evidence: |
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Download this section (compressed HTML)Q: How do endogenous M1, M43 and the independently annotated ETV6 transcript products differ in abundance, DNA occupancy and corepressor use?
Q: Which cis-regulatory elements and cofactors determine whether ETV6 represses transcription or increases Fli1 expression, and is the positive mouse lymphoid context reproduced by endogenous human ETV6?
Q: Do HDAC9/MITR and L3MBTL1 act with ETV6 at the same endogenous loci or in distinct repression contexts?
Q: Does the HPA000264 cytosolic signal represent endogenous native ETV6 in the tested human cell lines, which natural translation products contribute, and can genetic controls or orthogonal fractionation establish their localization despite the antibody's additional western bands? The positive HPA observation is distinct from the disease-fusion compartments underlying the removed Reactome projections.
Experiment: Combine translation-initiation profiling and product-resolved proteomics in human hematopoietic cells with matched-expression rescue of individually sequence-verified ETV6 products. Measure nascent transcription, DNA occupancy and corepressor association while distinguishing engineered M1(M43A) from native M1 and preserving the separate RefSeq product models.
Hypothesis: Alternative initiation or transcript structure changes regulatory interactions in a cell-context-dependent manner rather than making all natural products functionally equivalent.
Type: Product-resolved expression and matched functional rescue
Experiment: Compare endogenous ETV6 perturbation in human and mouse lymphoid cells with Fli1 promoter reporters carrying intact or mutated ETS sites, nascent-RNA measurements and ETV6/cofactor occupancy. Test matched promoter and cellular contexts before assigning a species difference or general activating mechanism.
Hypothesis: The transcriptional sign depends on the promoter and cellular cofactor environment, rather than an invariant activating or repressing action at every target.
Type: Context-dependent transcription and cis-element analysis
Experiment: Acute depletion and rescue of HDAC9/MITR or L3MBTL1, individually and together, followed by ETV6 occupancy and nascent-transcription measurements can test their contributions at endogenous targets. Include sequence-verified interaction-domain mutants, expression controls and DNA-binding controls to distinguish loss of recruitment from loss of ETV6 stability or occupancy.
Hypothesis: Different corepressors contribute to overlapping but nonidentical ETV6 target programs; the existing pairwise and reporter evidence does not require one constitutive complex.
Type: Corepressor perturbation with occupancy and transcription readouts
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