id: Q96C92 gene_symbol: ENTR1 product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ENTR1 (endosome-associated trafficking regulator 1; formerly SDCCAG3, serologically defined colon cancer antigen 3) is a 435-residue cytoplasmic protein with a disordered N-terminal half and a C-terminal coiled-coil (ENTR1 family, Pfam PF29363). It has no known enzymatic activity and acts as an endosome-associated scaffold/adaptor in membrane-receptor sorting. ENTR1 resides mainly on early and recycling endosomes, where it associates with the retromer core subunit VPS35 and with the FERM domain of the tyrosine phosphatase PTPN13, and binds the Arf GAP GIT1 and the coiled-coil protein dysbindin. In human cells its depletion alters the surface levels of endocytosed receptors in a cargo-specific way: SNX27-retromer cargo GLUT1 is lost from the surface, whereas the death receptor Fas accumulates at the surface because its sorting into intraluminal vesicles and delivery to lysosomes is delayed; ENTR1 is itself cleaved by caspases during Fas-induced apoptosis. During cell division ENTR1 accumulates at the midbody, and both its over- and under-expression produce multinucleate cells. ENTR1 also localizes to the centrosome and the basal body of primary cilia through its N-terminal 100 residues, which bind the intraflagellar transport protein IFT88; it is required for normal cilium number and length and for ciliary targeting of polycystin-2. existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23108400 qualifier: enables supporting_entities: - UniProtKB:Q12923 review: summary: Interaction of ENTR1 with the FERM domain of PTPN13 (Q12923), shown in the PTPN13/GIT1 cytokinesis paper. action: REMOVE reason: >- The interaction with PTPN13 is well supported and functionally relevant (it is required for ENTR1 regulation of Fas surface levels, PMID:31308371), but bare GO:0005515 protein binding carries no functional information. Removed under the protein-binding policy; this does not dispute the interaction. ENTR1 has no characterised molecular activity that would justify a more specific MF term from this evidence alone. supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 forms a complex with PTPN13, a protein tyrosine phosphatase known to be involved in the regulation of cytokinesis - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23108400 qualifier: enables supporting_entities: - UniProtKB:Q9Y2X7 review: summary: Direct interaction of the ENTR1 N-terminus with the Arf GAP GIT1 (Q9Y2X7). action: REMOVE reason: >- The GIT1 interaction is real (UniProt records it as direct), but GO:0005515 is uninformative. Removed under the protein-binding policy; the interaction itself is not disputed. supported_by: - reference_id: PMID:23108400 supporting_text: we show interaction of SDCCAG3 with the Arf GTPase activating protein GIT1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25278552 qualifier: enables supporting_entities: - UniProtKB:Q96QK1 review: summary: ENTR1 (SDCCAG3) identified in the SILAC VPS35 (Q96QK1) interactome and validated by GFP-trap pulldown. action: REMOVE reason: >- Association with retromer VPS35 underlies the retromer colocalization and endocytic recycling annotations, which are reviewed separately. Bare protein binding is uninformative and is removed under the protein-binding policy; the interaction is not disputed. supported_by: - reference_id: PMID:25278552 supporting_text: These proteins were VARP (>100-fold enriched, 46 quantified peptides), ANKRD50 (>100-fold enriched, seven quantified peptides) and SDCCAG3 (>100-fold enriched, five quantified peptides). - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27767179 qualifier: enables supporting_entities: - UniProtKB:Q13099 review: summary: The ENTR1 N-terminus (residues 1-100) binds a TPR-repeat region of IFT88 (Q13099) in yeast two-hybrid and GST pulldown assays. action: REMOVE reason: >- The IFT88 interaction is mechanistically relevant to ciliogenesis, but GO:0005515 is uninformative and no specific MF term (e.g. an adaptor activity) is demonstrated by these binding data. Removed under the protein-binding policy; the interaction is not disputed. supported_by: - reference_id: PMID:27767179 supporting_text: Mapping experiments revealed that the N-terminus of SDCCAG3 mediates this interaction by binding to a region within IFT88 comprising several tetratricopeptide (TRP) repeats. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27812135 qualifier: enables supporting_entities: - UniProtKB:Q9HC29 review: summary: ENTR1 (SDCCAG3) identified as a NOD2 (Q9HC29) interacting protein by yeast two-hybrid, co-immunoprecipitation and BRET in a NOD2 interactor screen. action: REMOVE reason: >- Screen-derived interaction with overexpressed NOD2; no functional consequence for ENTR1 was established in this paper. Bare protein binding is uninformative and is removed under the protein-binding policy; the interaction itself is not disputed. supported_by: - reference_id: PMID:27812135 supporting_text: In summary of these interactions studies, 6 NIPs were confirmed by coimmunoprecipitation and BRET (RICK, ANKHD1, LDOC1, SDCCAG3, TRIM41, and PPP1R12C) - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0086 review: summary: UniProt subcellular-location mapping to cytoplasm. action: TOO_GENERAL reason: >- True but uninformative: ENTR1 is a peripheral cytoplasmic protein, and its experimentally established locations (early endosome, recycling endosome, centrosome, ciliary basal body, midbody), all accepted in this review, already entail cytoplasm. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:A2AIW0 review: summary: Cytoplasm transferred by sequence similarity from mouse Entr1 (A2AIW0). action: TOO_GENERAL reason: >- Mouse Entr1 is the one-to-one ortholog (although PANTHER places it in PTHR31259:SF3 and human in SF6, cytoplasmic localization is not a subfamily-specific property). The term is correct but is entailed by the specific endosomal, centrosomal and midbody locations established directly for human ENTR1, so it adds no information. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0005768 label: endosome evidence_type: IDA original_reference_id: PMID:25278552 qualifier: located_in review: summary: Endogenous ENTR1 (SDCCAG3) colocalizes with VPS35 on retromer-decorated endosomes in HeLa cells. action: ACCEPT reason: >- Direct immunofluorescence of endogenous protein. The endosome subtype was not specified in this experiment, so the general term is as precise as this paper allows; the early and recycling endosome rows from PMID:23108400 give the finer picture. Endosome association is the defining feature of the protein. supported_by: - reference_id: PMID:25278552 supporting_text: immunofluorescence analysis established that endogenous SDCCAG3 and RME-8, and a transiently expressed myc-tagged VARP, were associated with retromer-decorated endosomes - term: id: GO:0005768 label: endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0101 review: summary: UniProt subcellular-location mapping to endosome, derived from the curated location PMID:25278552. action: ACCEPT reason: Consistent with the IDA row for the same term; endosomal localization is well established in human cells. supported_by: - reference_id: PMID:25278552 supporting_text: immunofluorescence analysis established that endogenous SDCCAG3 and RME-8, and a transiently expressed myc-tagged VARP, were associated with retromer-decorated endosomes - term: id: GO:0005769 label: early endosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002039065 - UniProtKB:Q96C92 review: summary: PAINT propagation from node PTN002039065, for which human ENTR1 is the experimental donor. action: ACCEPT reason: >- Human ENTR1 itself carries the IDA for early endosome, and its presence in the WITH/FROM is the expected marker that the node is grounded on this gene's experimental data. The IBA adds the curator's judgement that the localization is ancestral within the ENTR1 clade. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:23108400 qualifier: located_in review: summary: ENTR1 localizes primarily to the early/recycling endosomal compartment. action: ACCEPT reason: >- Direct localization data (cached text is abstract-only; the curator saw the full paper). Corroborated by the later finding that internalized Fas co-localizes with ENTR1- and PTPN13-positive endosomes and accumulates in EEA1-positive endosomes after ENTR1 depletion (PMID:31308371). supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - reference_id: PMID:31308371 supporting_text: Internalised Fas co-localises with ENTR1 and PTPN13 positive endosomes. - term: id: GO:0005769 label: early endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0094 review: summary: UniProt subcellular-location mapping to early endosome. action: ACCEPT reason: Consistent with the IDA and IBA rows for this term. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0005813 label: centrosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002039065 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN002039065, grounded on the human ENTR1 centrosome IDA. action: ACCEPT reason: >- Human ENTR1 is the experimental donor; centrosomal localization is shown for endogenous ENTR1 in HeLa and IMCD3 cells, and the target appearing in WITH/FROM is expected. supported_by: - reference_id: PMID:27767179 supporting_text: Both proteins were co-localizing at centrosomes as demonstrated by the presence of the centrosomal marker protein pericentrin (PCNT) - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:27767179 qualifier: located_in review: summary: Endogenous ENTR1 colocalizes with EGFP-IFT88 and pericentrin at centrosomes in HeLa cells, and with gamma-tubulin in IMCD3 cells, independently of IFT88. action: ACCEPT reason: Direct immunofluorescence of the endogenous protein in human cells, with antibody specificity validated by siRNA. supported_by: - reference_id: PMID:27767179 supporting_text: Both proteins were co-localizing at centrosomes as demonstrated by the presence of the centrosomal marker protein pericentrin (PCNT) - reference_id: PMID:27767179 supporting_text: Thus we concluded that IFT88 is not necessary for SDCCAG3 recruitment to centrosomes - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0048 review: summary: UniProt subcellular-location mapping to centrosome. action: ACCEPT reason: Consistent with the IDA and IBA rows for this term. supported_by: - reference_id: PMID:27767179 supporting_text: Both proteins were co-localizing at centrosomes as demonstrated by the presence of the centrosomal marker protein pericentrin (PCNT) - term: id: GO:0030496 label: midbody evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002039065 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN002039065, grounded on human ENTR1 midbody localization. action: ACCEPT reason: >- Human ENTR1 is the donor. Midbody recruitment was independently reproduced with exogenous SDCCAG3 in HeLa cells (PMID:27373827), where it depended on the Arf6-binding C-terminus. supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. - reference_id: PMID:27373827 supporting_text: full-length SDCCAG3, but not a mutant lacking the ability to interact with Arf6, is recruited to the midbody during cytokinesis when expressed exogenously in HeLa cells - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:23108400 qualifier: located_in review: summary: ENTR1 accumulates strongly at the midbody during cytokinesis, colocalizing with PTPN13. action: ACCEPT reason: Direct localization data, reproduced in a second laboratory (PMID:27373827). supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. - term: id: GO:0030496 label: midbody evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0469 review: summary: UniProt subcellular-location mapping to midbody. action: ACCEPT reason: Consistent with the IDA and IBA rows for this term. supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. - term: id: GO:0030904 label: retromer complex evidence_type: IDA original_reference_id: PMID:25278552 qualifier: colocalizes_with review: summary: Endogenous ENTR1 colocalizes with VPS35 on retromer-decorated endosomes and co-purifies with GFP-VPS35. action: ACCEPT reason: >- The colocalizes_with qualifier correctly records ENTR1 as a retromer-associated accessory protein rather than a retromer subunit. Supported by colocalization and by >100-fold enrichment in the VPS35 interactome. supported_by: - reference_id: PMID:25278552 supporting_text: (E) VARP, SDCCAG3 and RME-8 colocalize with VPS35. - term: id: GO:0032456 label: endocytic recycling evidence_type: IMP original_reference_id: PMID:25278552 qualifier: involved_in review: summary: siRNA depletion of ENTR1 in HeLa cells reduces surface and total GLUT1 and has minor effects on surface CD97 and TRAILR1, all SNX27-retromer cargos. action: ACCEPT reason: >- ENTR1 is a VPS35-associated endosomal protein whose loss perturbs surface levels of several SNX27-retromer recycling cargos, consistent with participation in endosome-to-plasma membrane recycling. The effects are cargo-specific and modest (GLUT1 loss did not correlate with lysosomal accumulation), and for Fas ENTR1 depletion increases recycling (PMID:31308371), so ENTR1 is better seen as a sorting regulator that influences the balance between recycling and degradative fates than as a core recycling component. Accepted as the experimentally supported process term from this study. supported_by: - reference_id: PMID:25278552 supporting_text: Suppression of SDCCAG3 led to a decrease in GLUT1 surface expression and a reduction in whole-cell levels, but this did not correlate with an obvious accumulation of GLUT1 in lysosomes - reference_id: PMID:25278552 supporting_text: For RME-8 and SDCCAG3, RNAi-mediated suppression produced minor effects on CD97 surface levels - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN002039065 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN002039065, grounded on the human ENTR1 cytokinesis data. action: ACCEPT reason: >- Human ENTR1 is the experimental donor. The PAINT curator propagated the regulatory term rather than cytokinesis itself, which matches the nature of the evidence (midbody localization plus multinucleation on altered expression). supported_by: - reference_id: PMID:23108400 supporting_text: Overexpression as well as downregulation correlates with the generation of multinucleate cells. - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IDA original_reference_id: PMID:23108400 qualifier: involved_in review: summary: Both overexpression and knockdown of ENTR1 increase multinucleate cells; ENTR1 accumulates at the midbody with PTPN13 and binds GIT1. action: ACCEPT reason: >- ENTR1 is at the midbody during abscission, forms a complex with PTPN13 and GIT1, and altering its level causes cytokinesis failure. The regulatory term is appropriately cautious; the mechanism (likely Arf-mediated vesicle trafficking to the midbody) is not resolved. Cached text is abstract-only. supported_by: - reference_id: PMID:23108400 supporting_text: Overexpression as well as downregulation correlates with the generation of multinucleate cells. - reference_id: PMID:23108400 supporting_text: we have established SDCCAG3 as a novel endosomal protein, which is involved in the regulation of cytokinesis - term: id: GO:0036064 label: ciliary basal body evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN004793274 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN004793274, grounded on human ENTR1 basal-body localization. action: ACCEPT reason: Human ENTR1 is the experimental donor; the target in WITH/FROM is expected and not circular. supported_by: - reference_id: PMID:27767179 supporting_text: Using the commercially available anti-SDCCAG3 antibody we observed localization of SDCCAG3 to the cilia basal body as revealed by double staining with pericentrin (PCNT) - term: id: GO:0036064 label: ciliary basal body evidence_type: IDA original_reference_id: PMID:27767179 qualifier: located_in review: summary: Endogenous ENTR1 localizes to the basal body of primary cilia in human RPE1 and HEK cells and mouse IMCD3 cells; residues 1-100 are necessary and sufficient. action: ACCEPT reason: >- Endogenous-protein immunofluorescence with a validated antibody, confirmed with EGFP fusions and deletion mapping. Later work in mouse kidney cells detected ENTR1 also along the cilium itself (PMID:38849673). supported_by: - reference_id: PMID:27767179 supporting_text: Using the commercially available anti-SDCCAG3 antibody we observed localization of SDCCAG3 to the cilia basal body as revealed by double staining with pericentrin (PCNT) - reference_id: PMID:27767179 supporting_text: Interestingly, this construct lost completely its ability to localize to cilia - term: id: GO:0045724 label: positive regulation of cilium assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN004793274 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN004793274, grounded on the human ENTR1 IMP. action: ACCEPT reason: Human ENTR1 is the experimental donor; the IMP is a knockdown with rescue (see below). supported_by: - reference_id: PMID:27767179 supporting_text: We observed that reduced expression levels of SDCCAG3 strongly correlated with a reduced percentage of ciliated cells - term: id: GO:0045724 label: positive regulation of cilium assembly evidence_type: IMP original_reference_id: PMID:27767179 qualifier: involved_in review: summary: Three independent siRNAs reduce the percentage of ciliated RPE1 cells and cilium length; in IMCD3 cells the defect is rescued by siRNA-resistant human ENTR1 but not by a construct lacking residues 1-100. action: ACCEPT reason: >- Knockdown with multiple siRNAs and rescue by the human protein, with domain specificity. ENTR1 is not a structural cilium component; it acts at the basal body (plausibly by vesicle delivery/docking via IFT88/IFT20), so the regulatory term is appropriate. supported_by: - reference_id: PMID:27767179 supporting_text: We observed that reduced expression levels of SDCCAG3 strongly correlated with a reduced percentage of ciliated cells - reference_id: PMID:27767179 supporting_text: Expression of EGFP-SDCCAG3 in SDCCAG3 siRNA treated cells led to a complete rescue of the phenotype restoring the percentage of ciliated cells to almost control levels - term: id: GO:0055037 label: recycling endosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - PANTHER:PTN002039065 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN002039065, grounded on human ENTR1 recycling-endosome localization. action: ACCEPT reason: Human ENTR1 is the experimental donor; target in WITH/FROM is expected. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0055037 label: recycling endosome evidence_type: IDA original_reference_id: PMID:23108400 qualifier: located_in review: summary: ENTR1 localizes primarily to the early/recycling endosomal compartment. action: ACCEPT reason: Direct localization data (abstract-only cache; deferring to the curator who read the full text). supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:0055037 label: recycling endosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0232 review: summary: UniProt subcellular-location mapping to recycling endosome. action: ACCEPT reason: Consistent with the IDA and IBA rows for this term. supported_by: - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - term: id: GO:1903566 label: positive regulation of protein localization to cilium evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN004793274 - UniProtKB:Q96C92 review: summary: PAINT propagation from PTN004793274, grounded on the human ENTR1 IMP for polycystin-2 ciliary localization. action: ACCEPT reason: Human ENTR1 is the experimental donor; the underlying knockdown/rescue experiment is sound. supported_by: - reference_id: PMID:27767179 supporting_text: We observed a significantly reduced localization of Polycystin-2 to cilia in SDCCAG3 siRNA treated cells compared to cells treated with control siRNA - term: id: GO:1903566 label: positive regulation of protein localization to cilium evidence_type: IMP original_reference_id: PMID:27767179 qualifier: involved_in review: summary: ENTR1 knockdown in IMCD3 cells reduces ciliary polycystin-2 (rescued by human ENTR1) without affecting ciliary Rab8. action: ACCEPT reason: >- Knockdown with rescue by the human protein, and cargo selectivity (Rab8 unaffected). Independently supported in mouse kidney epithelial cells, where ENTR1 forms a complex with IFT20 and DLG1 and DLG1 loss reduces ciliary ENTR1, IFT20 and polycystin-2 (PMID:38849673). supported_by: - reference_id: PMID:27767179 supporting_text: We observed a significantly reduced localization of Polycystin-2 to cilia in SDCCAG3 siRNA treated cells compared to cells treated with control siRNA - reference_id: PMID:27767179 supporting_text: Thus besides having an effect on the formation of cilia, SDCCAG3 also affects localization of selective cargo to cilia. - reference_id: PMID:38849673 supporting_text: In summary, the IP and Alpha Fold modeling results suggest that SDCCAG3 and IFT20 form a heterodimeric complex that associates, at least indirectly, with DLG1. - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: IMP original_reference_id: PMID:31308371 review: summary: >- In human HeLa and HCT-116 cells, ENTR1 depletion or knockout delays sorting of internalized Fas into intraluminal vesicles and its delivery to lysosomes, slows Fas degradation and increases Fas recycling and surface levels; this requires ENTR1 binding to PTPN13 and to dysbindin (via the ENTR1 C-terminal 16 residues). action: NEW reason: >- A full-text human study (siRNA with three independent oligos, CRISPR knockout, rescue, binding-site mutants) post-dating the existing GOA set. ENTR1 sits on the endosomes where the sorting occurs and acts there through physical complexes with PTPN13 and the dysbindin-HRS axis, so it contributes to the sorting machinery itself rather than being a cargo or an upstream requirement. The process term is the broad endosome-to-lysosome transport term because the cargo studied in depth is a single receptor; the more specific multivesicular-body pathway child (GO:0032510) is plausible from the intraluminal-vesicle sorting data but was not chosen to avoid over-precision. supported_by: - reference_id: PMID:31308371 supporting_text: ENTR1 regulates, via binding to the coiled coil domain protein Dysbindin, the delivery of Fas from endosomes to lysosomes thereby controlling termination of Fas signal transduction. - reference_id: PMID:31308371 supporting_text: However, in ENTR1 depleted cells, transport to lysosomes was significantly impaired - reference_id: PMID:31308371 supporting_text: Here we present evidence for a role of ENTR1 and the multi-PDZ domain protein PTPN13 in post-endocytic sorting of Fas to lysosomes. references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:23108400 title: The serologically defined colon cancer antigen-3 interacts with the protein tyrosine phosphatase PTPN13 and is involved in the regulation of cytokinesis. findings: - statement: ENTR1 is an early/recycling endosomal protein that accumulates at the midbody in cytokinesis, binds PTPN13 and GIT1, and whose over- or under-expression produces multinucleate cells. supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Founding human cell-biology paper; PMID matches title and UniProt RX line. Cached text is abstract-only. - id: PMID:25278552 title: Identification of molecular heterogeneity in SNX27-retromer-mediated endosome-to-plasma-membrane recycling. findings: - statement: ENTR1 is a VPS35 interactor on retromer-decorated endosomes; its depletion reduces GLUT1 surface and total levels and mildly affects CD97 and TRAILR1. supporting_text: Suppression of SDCCAG3 led to a decrease in GLUT1 surface expression and a reduction in whole-cell levels reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text read; SDCCAG3 is one of three validated new VPS35 interactors. - id: PMID:27767179 title: The serologically defined colon cancer antigen-3 (SDCCAG3) is involved in the regulation of ciliogenesis. findings: - statement: ENTR1 localizes to centrosomes and ciliary basal bodies via residues 1-100, binds IFT88, and is required (knockdown with rescue) for cilium number, length and polycystin-2 ciliary localization. supporting_text: Here we show that the endosomal protein SDCCAG3 is important for cilia formation and cargo localization to cilia. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text read; experiments in human RPE1/HeLa/HEK cells and mouse IMCD3 cells rescued with human ENTR1. - id: PMID:27812135 title: Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Screen identifying ENTR1 among NOD2 interactors; no ENTR1 function assigned; genetic association with Crohn disease not replicated. - id: PMID:31308371 title: Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95. findings: - statement: In human cells ENTR1, with PTPN13 and dysbindin, promotes sorting of internalized Fas into intraluminal vesicles and lysosomes, limiting Fas surface levels and Fas-induced apoptosis; ENTR1 is cleaved by caspases during Fas signalling. supporting_text: We demonstrate that ENTR1 is cleaved during Fas-induced apoptosis in a caspase-dependent manner reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text (PMC6629679); not yet reflected in GOA. Basis of the NEW endosome-to-lysosome transport row. - id: PMID:38849673 title: DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2. findings: - statement: In mouse kidney epithelial cells ENTR1 associates with IFT20 and DLG1, and DLG1 is required for ciliary levels of ENTR1, IFT20 and polycystin-2. supporting_text: We conclude that DLG1 is required for localizing SDCCAG3 and IFT20, but not SEC8, to the primary cilium of kidney epithelial cells in vitro and in vivo. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mostly mouse cells and tissue; corroborates the ciliary-trafficking role of ENTR1 established in human cells. A duplicate PubMed record (PMID:37987012) exists for the same title and was not cached. - id: PMID:27373827 title: Interaction of serologically defined colon cancer antigen-3 with Arf6 and its predominant expression in the mouse testis. findings: - statement: ENTR1 binds active Arf6 through its C-terminal 101 residues and this binding is needed for midbody recruitment of exogenous ENTR1 in HeLa cells. supporting_text: SDCCAG3 interacts specifically with Arf6 among the Arf family members through its 101 C-terminal amino acids. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract-only cache; mouse SDCCAG3 two-hybrid screen with HeLa midbody assay. - id: PMID:16332174 title: Serologically defined colon cancer antigen 3 is necessary for the presentation of TNF receptor 1 on cell surface. findings: - statement: A dominant-negative coiled-coil fragment of mouse Entr1 reduces surface TNFR1 and confers resistance to TNF-induced apoptosis in NIH3T3 and HeLa cells. supporting_text: The presentation of TNFR1 at the surface of these cells was reduced, which affected the sensitivity of the cells to the TNF treatment. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract-only cache. The only characterisation paper for mouse Entr1 (A2AIW0); dominant-negative fragment only, no loss-of-function, so not used to add a human annotation. - id: PMID:41494271 title: ENTR1 stabilizes MAVS by inhibiting NIX-mediated mitophagy to restrict BPIV3 and VSV replication. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Abstract-only; cell system and species not stated in the abstract (bovine virus model). Proposes an antiviral role via MAVS stabilization; not used for annotation pending independent confirmation. core_functions: - description: >- Endosome-associated sorting regulator: on early/recycling endosomes ENTR1 associates with retromer (VPS35), PTPN13 and dysbindin and controls the fate of internalized membrane receptors, promoting lysosomal sorting of Fas and supporting surface levels of SNX27-retromer cargo such as GLUT1. No enzymatic or specific binding activity term is established, so no molecular function is asserted. directly_involved_in: - id: GO:0008333 label: endosome to lysosome transport - id: GO:0032456 label: endocytic recycling locations: - id: GO:0005769 label: early endosome - id: GO:0055037 label: recycling endosome supported_by: - reference_id: PMID:31308371 supporting_text: Here we present evidence for a role of ENTR1 and the multi-PDZ domain protein PTPN13 in post-endocytic sorting of Fas to lysosomes. - reference_id: PMID:25278552 supporting_text: Suppression of SDCCAG3 led to a decrease in GLUT1 surface expression and a reduction in whole-cell levels - reference_id: PMID:23108400 supporting_text: We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. - description: >- Ciliogenesis and ciliary cargo targeting: through its N-terminal 100 residues ENTR1 localizes to the centrosome/ciliary basal body and binds IFT88 (and IFT20), and is required for normal cilium formation and length and for ciliary delivery of polycystin-2. directly_involved_in: - id: GO:0045724 label: positive regulation of cilium assembly - id: GO:1903566 label: positive regulation of protein localization to cilium locations: - id: GO:0036064 label: ciliary basal body - id: GO:0005813 label: centrosome supported_by: - reference_id: PMID:27767179 supporting_text: Here we show that the endosomal protein SDCCAG3 is important for cilia formation and cargo localization to cilia. - description: >- Cytokinesis: ENTR1 accumulates at the midbody in a complex with PTPN13 and GIT1 (and binds Arf6), and balanced ENTR1 levels are needed for successful abscission. directly_involved_in: - id: GO:0032465 label: regulation of cytokinesis locations: - id: GO:0030496 label: midbody supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. suggested_questions: - question: >- Does ENTR1 have a definable molecular activity (for example a molecular adaptor activity bridging PTPN13, dysbindin or IFT20/IFT88 to endosomal membranes), or is it best left without an MF term until a direct binding-dependent mechanism is reconstituted? - question: >- PANTHER splits one-to-one mammalian ENTR1 orthologs between PTHR31259:SF6 (human) and SF3 (mouse, horse). Is this a genuine functional split or an artefact of alternative-exon content, and should PAINT nodes PTN002039065/PTN004793274 be checked to confirm that SF3 members inherit them? - question: >- Should the Fas endolysosomal-sorting data (PMID:31308371) be annotated to the multivesicular-body pathway (GO:0032510) rather than the broader GO:0008333? suggested_experiments: - hypothesis: ENTR1 couples endosomal receptor sorting to ciliary vesicle delivery through mutually exclusive partner complexes (PTPN13/dysbindin versus IFT88/IFT20). description: >- Map binding interfaces for PTPN13, dysbindin, IFT88 and IFT20 on ENTR1, generate separation-of-function point mutants, and test each in ENTR1-knockout RPE1 cells for Fas degradation, GLUT1 surface levels, ciliogenesis and polycystin-2 ciliary targeting. experiment_type: separation-of-function rescue - hypothesis: Mouse Entr1 (subfamily SF3) retains the endosomal and ciliary functions shown for human ENTR1 (SF6). description: Knock out Entr1 in mouse IMCD3 or mCCD cells and assay ciliogenesis, polycystin-2 targeting and Fas/TNFR1 surface levels, with rescue by mouse versus human ENTR1. experiment_type: cross-species complementation