id: A0A8C4MKL2 gene_symbol: ENTR1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9793 label: Equus asinus description: >- ENTR1 (endosome-associated-trafficking regulator 1, also known as SDCCAG3) is a cytoplasmic coiled-coil protein of early and recycling endosomes, conserved as a single-copy gene across vertebrates (PANTHER family PTHR31259). Characterized in human cells, it is recruited to retromer-decorated endosomes through the WASH complex and has been implicated in SNX27-retromer-dependent recycling of cargo such as GLUT1 to the cell surface; it also relocates to the midbody during cytokinesis, where it acts with the phosphatase PTPN13 and the ArfGAP GIT1, and localizes to the centrosome and ciliary basal body, where it binds IFT88 and supports cilium assembly and ciliary delivery of polycystin-2. The donkey entry A0A8C4MKL2 (356 aa) conserves the C-terminal ENTR1 coiled-coil region (81% identity to human ENTR1) but lacks the segment corresponding to human residues 9-85 and does not begin with methionine, so it most likely represents an N-terminally incomplete gene model of the donkey ENTR1 gene; the missing segment overlaps the N-terminal region that mediates basal-body targeting, IFT88 binding and GIT1 binding in human ENTR1. existing_annotations: - term: id: GO:0005769 label: early endosome evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN009117290 review: summary: Early endosome localization is experimentally established for human ENTR1 and is the principal steady-state location of the protein. action: ACCEPT reason: Human ENTR1 is primarily localized at the early/recycling endosomal compartment (PMID:23108400) and the same term is an IBA on human ENTR1 (PAINT node PTN002039065), so PAINT curators judged it ancestral to the clade. Donkey A0A8C4MKL2 is in PTHR31259:SF3; human ENTR1 sits in the hominid-only split SF6, but both are the single ENTR1 ortholog (a human ENTR1 fragment, A0A0A0MRP9, scores into SF3), so the subfamily difference is an HMM partition within one orthologous lineage, not a paralog boundary. The conserved C-terminal coiled-coil region is retained in this gene model. supported_by: - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt supporting_text: Early endosome {ECO:0000269|PubMed:23108400}. - reference_id: PMID:23108400 supporting_text: SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment - reference_id: PMID:27767179 supporting_text: is a recently described novel endosomal protein mainly localized at early and recycling endosomes - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS-rereview.md supporting_text: '| A0A0A0MRP9 | Homo sapiens (Human) | 223 | unreviewed | PTHR31259;PTHR31259:SF3; |' - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN009117290 review: summary: Centrosome localization is reported for human ENTR1 and propagated by PAINT; it accompanies the ciliary role rather than the endosomal one. action: KEEP_AS_NON_CORE reason: Human ENTR1 colocalizes with IFT88 and pericentrin at the centrosome (PMID:27767179) and the term is an IBA on human ENTR1 (PTN002039065). It is a secondary localization; in addition, the donkey entry lacks the N-terminal region that in human directs basal-body (mother centriole) targeting, so the localization holds for the gene rather than being expected of this truncated sequence model. supported_by: - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: Colocalizes with IFT88 and pericentrin at the centrosome - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md supporting_text: Paired coverage is 81.61% of the human sequence and 99.72% of the donkey sequence. - term: id: GO:0030496 label: midbody evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN009117290 review: summary: Midbody localization during cytokinesis is reported for human ENTR1. action: KEEP_AS_NON_CORE reason: Human ENTR1 accumulates at the midbody during cytokinesis and colocalizes with PTPN13 there (PMID:23108400); PAINT propagated the term from human (PTN002039065). It is a cell-cycle-stage localization accompanying a non-core role. 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: file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: During cytokinesis colocalized with PTPN13 at the midbody - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN009117290 review: summary: Human ENTR1 is implicated in regulating cytokinesis together with PTPN13 and GIT1. action: KEEP_AS_NON_CORE reason: In human cells both overexpression and depletion of ENTR1 increase multinucleation, and ENTR1 forms a complex with PTPN13 and binds GIT1 (PMID:23108400, IDA in human GOA); PAINT propagated the term (PTN002039065). The evidence is perturbation-based and the mechanism is undefined, so this is kept as a secondary process. The GIT1-binding N-terminus is absent from this donkey sequence model. supported_by: - reference_id: PMID:23108400 supporting_text: Overexpression as well as downregulation correlates with the generation of multinucleate cells - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Involved in the regulation of cytokinesis; the function may involve PTPN13 and GIT1 - term: id: GO:0036064 label: ciliary basal body evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN009117290 review: summary: Human ENTR1 localizes to the basal body of primary cilia through its N-terminal 100 residues, which are largely missing from this donkey entry. action: KEEP_AS_NON_CORE reason: The localization is experimentally established in human (PMID:27767179) and was propagated by PAINT (PTN004793274), a fair gene-level transfer to donkey ENTR1. However, the targeting determinant (human aa 1-100) is mostly absent from A0A8C4MKL2, so this particular sequence model would not be expected to reach the basal body on its own. supported_by: - reference_id: PMID:27767179 supporting_text: Amino acids 1-100 of SDCCAG3 are necessary and sufficient for basal body localization - reference_id: file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md supporting_text: Paired coverage is 81.61% of the human sequence and 99.72% of the donkey sequence. - term: id: GO:0045724 label: positive regulation of cilium assembly evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN009117290 review: summary: ENTR1 knockdown in human cells reduces cilia number and length; the effect depends on the N-terminal region absent from this donkey model. action: KEEP_AS_NON_CORE reason: Human IMP evidence (PMID:27767179) supports a role in ciliogenesis, propagated by PAINT (PTN004793274); the Delta1-100 construct failed to rescue, so the role maps to the N-terminus that this entry lacks. Retained as a non-core, gene-level process. supported_by: - reference_id: PMID:27767179 supporting_text: decreased expression levels of SDCCAG3 correlate with decreased ciliary length and a reduced percentage of ciliated cells - term: id: GO:0055037 label: recycling endosome evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN009117290 review: summary: Recycling endosome localization is experimentally established for human ENTR1. action: ACCEPT reason: Human ENTR1 is primarily localized at the early/recycling endosomal compartment (PMID:23108400; PMID:27767179) and the term is an IBA on human ENTR1 (PTN002039065). Same orthology reasoning as for early endosome. supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment - reference_id: PMID:27767179 supporting_text: is a recently described novel endosomal protein mainly localized at early and recycling endosomes - term: id: GO:1903566 label: positive regulation of protein localization to cilium evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN009117290 review: summary: Human ENTR1 is required for ciliary localization of polycystin-2. action: KEEP_AS_NON_CORE reason: Supported by human IMP data (PMID:27767179) and propagated by PAINT (PTN004793274). Non-core, and gene-level given the missing N-terminal region in this sequence model. supported_by: - reference_id: PMID:27767179 supporting_text: we demonstrate that SDCCAG3 is important for ciliary localization of the membrane protein Polycystin-2 references: - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations 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: Human ENTR1 (SDCCAG3) is an early/recycling endosomal protein that accumulates at the midbody during cytokinesis, complexes with PTPN13 and binds GIT1; its over- or under-expression increases multinucleation. supporting_text: SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract-only cache (Hagemann et al. 2013, Oncogene). Source of the human IDA endosome, midbody and regulation-of-cytokinesis annotations that PAINT propagated. - id: PMID:24980502 title: Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. findings: - statement: Human ENTR1 (SDCCAG3) associates with retromer indirectly, through the WASH complex, and this association is needed for its targeting to retromer-labelled endosomes. supporting_text: Together, these data establish that the association of ANKRD50, SDCCAG3, and RME-8 to retromer is mediated through binding to the WASH complex, and for SDCCAG3 this is necessary for targeting to retromer-labeled endosomes. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached full text (McGough et al. 2014, Curr Biol). Establishes ENTR1 as a WASH-dependent retromer-associated protein rather than a retromer subunit. - id: PMID:25278552 title: Identification of molecular heterogeneity in SNX27-retromer-mediated endosome-to-plasma-membrane recycling. findings: - statement: The VPS35 interactome includes SDCCAG3 (ENTR1); its depletion reduces GLUT1 surface levels, with only minor effects on other SNX27-retromer cargo. 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_review: relevance: HIGH correctness: VERIFIED review_notes: Cached full text; human ENTR1 (SDCCAG3) endosomal recycling study. Source of the human IMP endocytic recycling and colocalizes_with retromer complex annotations. In the 2026-10 re-review it no longer supports a proposed donkey endocytic-recycling annotation (withdrawn, see notes) and is retained as background for the recycling role. - id: PMID:27767179 title: The serologically defined colon cancer antigen-3 (SDCCAG3) is involved in the regulation of ciliogenesis. findings: - statement: The N-terminal 100 residues of human ENTR1 are necessary and sufficient for basal body localization and mediate IFT88 binding. supporting_text: Amino acids 1-100 of SDCCAG3 are necessary and sufficient for basal body localization reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached full text; defines the N-terminal ciliary-targeting region that is mostly absent from the donkey sequence model. - id: file:EQUAS/ENTR1/ENTR1-bioinformatics/human_Q96C92-uniprot.txt title: UniProtKB Swiss-Prot record Q96C92 (human ENTR1), fetched 2026-10-14 findings: [] - id: file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS.md title: 'ENTR1: donkey-human sequence comparison' findings: [] - id: file:EQUAS/ENTR1/ENTR1-bioinformatics/RESULTS-rereview.md title: 'ENTR1: PANTHER PTHR31259 subfamily placement (re-review)' findings: [] core_functions: - description: Endosome-associated coiled-coil protein that resides on early and recycling endosomes, where (in human cells) it is recruited to retromer-decorated membranes via the WASH complex and has been implicated in endosome-to-plasma-membrane recycling of SNX27-retromer cargo such as GLUT1. locations: - id: GO:0055037 label: recycling endosome - id: GO:0005769 label: early endosome supported_by: - reference_id: PMID:23108400 supporting_text: SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment - reference_id: PMID:24980502 supporting_text: Together, these data establish that the association of ANKRD50, SDCCAG3, and RME-8 to retromer is mediated through binding to the WASH complex, and for SDCCAG3 this is necessary for targeting to retromer-labeled endosomes. suggested_questions: - question: Does the donkey ENTR1 locus encode a full-length protein with the N-terminal basal-body-targeting region, and is A0A8C4MKL2 an incomplete gene model or a genuine N-terminally truncated isoform? - question: Human ENTR1 carries an IMP annotation to GO:0032456 endocytic recycling (PMID:25278552, 2014), yet PAINT curators propagated its endosome, cytokinesis and cilium terms (2019, 2024) but not endocytic recycling. Was that omission deliberate (the SDCCAG3 knockdown phenotype is cargo-selective and modest), and should the recycling role be represented at the family level? - question: Is the hominid-restricted PANTHER subfamily split (human ENTR1 in PTHR31259:SF6, other mammals in SF3) biologically meaningful, or an HMM partition within a single orthologous lineage?