id: A0A9L0JQ61 gene_symbol: PIKFYVE product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9793 label: Equus asinus description: 'PIKFYVE encodes the phosphoinositide 5-kinase that converts phosphatidylinositol 3-phosphate to phosphatidylinositol 3,5-bisphosphate (and phosphatidylinositol to phosphatidylinositol 5-phosphate) on endosomal membranes. The full-length enzyme (about 2100 residues) is recruited to endosomes by its PtdIns3P-binding FYVE finger, works in a complex with the scaffold VAC14 and the phosphatase FIG4, and controls endolysosomal maturation, phagosome-lysosome fusion, melanosome biogenesis and neutrophil chemotaxis and ROS production. This entry, A0A9L0JQ61, is not the full-length kinase: its 460-residue sequence corresponds to the short human PIKFYVE splice isoform 3 (96% identity), which keeps the N-terminal region and the DEP domain but lacks most of the FYVE finger, the chaperonin-like domain and the entire PIPK catalytic domain. It is the product of a non-canonical transcript of the same donkey gene, whose canonical 2108-residue product (A0A8C4L106) it matches at 99.6% identity over its whole length. The function of this short isoform has not been characterized; it may not be a stable protein, and if it is, any role it has would come from its N-terminal and DEP regions rather than from lipid-kinase activity.' existing_annotations: - term: id: GO:0000285 label: 1-phosphatidylinositol-3-phosphate 5-kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables supporting_entities: - InterPro:IPR037378 - InterPro:IPR043548 - PANTHER:PTN001347166 review: summary: 1-phosphatidylinositol-3-phosphate 5-kinase activity, combined from InterPro (PIKfyve family and PIKfyve DEP entries) and the PANTHER node PTN001347166. The activity belongs to the C-terminal PIPK domain of full-length PIKFYVE; this 460-residue isoform contains no part of that domain. action: REMOVE reason: The family and DEP-domain signatures are shared with the full-length kinase, but the catalytic domain (human 1758-2084) is absent from this product, which corresponds to human isoform 3 (truncated at residue 548). An enzyme activity cannot be assigned to a protein that lacks its catalytic domain. The gene's full-length products (separate entries; Ensembl canonical A0A8C4L106) do carry this activity, and the PANTHER subfamily placement (PTHR46715:SF1, shared with human and mouse PIKFYVE) is correct at the gene level. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS-rereview.md supporting_text: The catalytic domain is encoded only by the canonical and other full-length transcripts, so the gene's lipid-kinase function belongs to those products. - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["FT:VAR_SEQ"] supporting_text: Missing (in isoform 2, isoform 3 and isoform 4) - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: It also lacks the chaperonin-like domain (human 616-868) and the entire PIPK catalytic domain (human 1758-2084). - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: The donkey sequence aligns to human isoform Q9Y2I7-3 (462 residues) with 96.08% identity among 459 paired residues - term: id: GO:0012506 label: vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter vesicle membrane from PTN001347166. Full-length PIKFYVE is targeted to late endocytic membranes through its FYVE finger binding PtdIns3P. action: UNDECIDED reason: Six of the eight zinc-binding cysteines of the FYVE finger are absent, so the targeting mechanism of the full-length protein is unavailable; whether the short isoform associates with vesicle membranes (for example through its DEP domain) is not known. Neither transfer nor refutation is supported. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:DOMAIN"] supporting_text: Interaction of FYVE-type domain with phosphatidylinositol 3- - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: Cys-164, Cys-167, Cys-180, Cys-183, Cys-188 and Cys-191 have no donkey counterpart - term: id: GO:0030593 label: neutrophil chemotaxis evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter neutrophil chemotaxis from PTN001347166, derived from the requirement for PIKFYVE kinase activity in neutrophils. action: REMOVE reason: The neutrophil phenotypes of PIKFYVE are attributed to its PI(3,5)P2-producing activity (and are probed with the kinase inhibitors apilimod and YM201636); this product lacks the catalytic domain, so there is no basis to assign it this process. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: In neutrophils, critical to perform chemotaxis, generate - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:ACTIVITY REGULATION"] supporting_text: 'ACTIVITY REGULATION: Inhibited by apilimod and YM201636.' - term: id: GO:0031410 label: cytoplasmic vesicle evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter cytoplasmic vesicle from PTN001347166. action: UNDECIDED reason: As for vesicle membrane; the localization of the full-length kinase depends on the FYVE finger, which this isoform largely lacks, and no localization data exist for the short isoform. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: Cys-164, Cys-167, Cys-180, Cys-183, Cys-188 and Cys-191 have no donkey counterpart - term: id: GO:0032438 label: melanosome organization evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter melanosome organization from PTN001347166. action: REMOVE reason: Melanosome biogenesis depends on PIKFYVE lipid-kinase activity controlling endosome-to-melanosome delivery; the kinase-less isoform cannot be assumed to do this work. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Regulates melanosome biogenesis by controlling - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: It also lacks the chaperonin-like domain (human 616-868) and the entire PIPK catalytic domain (human 1758-2084). - term: id: GO:0035556 label: intracellular signal transduction evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR000591 review: summary: InterPro2GO intracellular signal transduction from the DEP domain (IPR000591), which the isoform retains. action: MARK_AS_OVER_ANNOTATED reason: The DEP-domain mapping is a generic association (DEP domains occur in many signalling proteins) and implies no specific activity. There is no evidence that the short PIKFYVE isoform transduces a signal; the role of the full-length kinase in hormone-induced signalling depends on its catalytic output. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: The DEP domain (human 365-440; donkey 277-352) is retained. - term: id: GO:0052810 label: 1-phosphatidylinositol-5-kinase activity evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: enables supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter 1-phosphatidylinositol-5-kinase activity from PTN001347166, a second lipid-kinase activity of the full-length enzyme's PIPK domain. action: REMOVE reason: Same domain-architecture objection as the PtdIns3P 5-kinase row; the TreeGrafter placement in the PIKFYVE family is right at the gene level but this isoform lacks the catalytic domain. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS-rereview.md supporting_text: The catalytic domain is encoded only by the canonical and other full-length transcripts, so the gene's lipid-kinase function belongs to those products. - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: It also lacks the chaperonin-like domain (human 616-868) and the entire PIPK catalytic domain (human 1758-2084). - term: id: GO:0090385 label: phagosome-lysosome fusion evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter phagosome-lysosome fusion from PTN001347166. action: REMOVE reason: Phagosome maturation and fusion with lysosomes require PI(3,5)P2 synthesis by full-length PIKFYVE; this product lacks the catalytic domain and the endosomal FYVE targeting module. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: In neutrophils, critical to perform chemotaxis, generate - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md supporting_text: It also lacks the chaperonin-like domain (human 616-868) and the entire PIPK catalytic domain (human 1758-2084). - term: id: GO:1903426 label: regulation of reactive oxygen species biosynthetic process evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN001347166 review: summary: TreeGrafter regulation of reactive oxygen species biosynthetic process from PTN001347166, from the neutrophil ROS phenotype of PIKFYVE inhibition or loss. action: REMOVE reason: As for neutrophil chemotaxis; the ROS phenotype reflects loss of PI(3,5)P2 production, which this isoform cannot catalyze. supported_by: - reference_id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: In neutrophils, critical to perform chemotaxis, generate references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS.md title: 'PIKFYVE: donkey A0A9L0JQ61 versus human PIKFYVE isoforms' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reproducible global alignments (script and JSON outputs in the same folder) against canonical human Q9Y2I7 and human isoform Q9Y2I7-3; shows the donkey entry is the short isoform lacking the catalytic and chaperonin-like domains and most of the FYVE finger. - id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/RESULTS-rereview.md title: 'PIKFYVE re-review: donkey A0A9L0JQ61 versus the donkey canonical product' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reproducible alignment (PEP 723 script and raw output in the same folder) of the short entry against the Ensembl-canonical donkey product A0A8C4L106 of the same gene ENSEASG00005003072; confirms the entry is a non-canonical splice product lacking the FYVE core and the C-terminal catalytic region. - id: file:EQUAS/PIKFYVE/PIKFYVE-bioinformatics/human-Q9Y2I7-uniprot.txt title: UniProtKB/Swiss-Prot record Q9Y2I7 (human PIKFYVE), downloaded 2026-10-14 findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reviewed human record; describes the full-length kinase with experimental evidence and lists isoforms 2-4 (truncated after residue 548) from cDNA sequencing only. suggested_questions: - question: Is the short PIKFYVE isoform (human isoform 3, donkey A0A9L0JQ61) translated as a stable protein, and if so does it act as a regulator, for example a dominant-negative competitor of full-length PIKFYVE for VAC14/FIG4 or membrane sites? suggested_experiments: - description: Detect the short PIKFYVE isoform protein in equine or human tissues with an isoform-specific antibody or targeted proteomics of its unique NSLQHPQEN junction peptide, and test whether its expression alters PI(3,5)P2 levels or endolysosome size. knowledge_gaps: - gap_statement: The molecular function, if any, of the short kinase-less PIKFYVE isoform (DEP domain retained, FYVE finger largely and PIPK domain wholly absent) is unknown. gap_kind: - BIOLOGY