id: A0A9L0T3C1 gene_symbol: A0A9L0T3C1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9796 label: Equus caballus description: >- A0A9L0T3C1 is a 507-residue product of the horse MTMR9 gene (Ensembl ENSECAG00000014120, transcript ENSECAT00000122597) that skips one 126-nt coding exon and therefore lacks 42 residues (human Q96QG7 positions 98-139) at the junction between the GRAM domain and the phosphatase-like myotubularin domain; elsewhere it is 97.8% identical to human MTMR9 and it retains the C-terminal coiled coil that mediates partner binding. MTMR9 is a catalytically inactive member of the myotubularin family (PANTHER PTHR10807:SF56): its phosphatase-like domain lacks the catalytic cysteine of the CX5R motif. In human and mouse it heterodimerizes through the coiled coil with the active phosphoinositide 3-phosphatases MTMR6, MTMR7 and MTMR8, increasing their catalytic activity, shifting their substrate preference (MTMR6/MTMR9 toward PtdIns(3,5)P2, MTMR8/MTMR9 toward PtdIns(3)P) and raising partner protein levels. It is a soluble cytoplasmic protein with perinuclear and partial endoplasmic reticulum pools and is recruited to membrane ruffles during macropinocytosis. Whether the exon-skipped horse product is expressed as a protein and retains full partner-activating function has not been tested. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0095 review: summary: Partial endoplasmic reticulum localization is experimentally observed for human MTMR9, the SF56 ortholog; it is a minor pool of a mainly cytoplasmic protein. action: KEEP_AS_NON_CORE reason: Human MTMR9 partially localizes to the ER (PMID:19038970). The horse product is a 1:1 ortholog in the same PANTHER subfamily (PTHR10807:SF56), 97.8% identical over its length, so the localization transfers; the 42-residue exon-3 skip does not remove any known targeting element (the GRAM domain, residues 4-99, is almost entirely retained). The ER pool is a secondary location, not where the partner-activating function is defined, hence non-core. Consistent with the human review. supported_by: - reference_id: file:human/MTMR9/MTMR9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: CC Partially localizes to the endoplasmic reticulum (PubMed:19038970). - reference_id: file:HORSE/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md supporting_text: '| A0A9L0T3C1 | 507 | 97.8% | 98-139 | 0 | ETEDGMQESP |' - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in supporting_entities: - ARBA:ARBA00029243 review: summary: MTMR9 is a soluble cytoplasmic protein; cytosol is a correct location for the ortholog and is retained for this horse product. action: ACCEPT reason: Human MTMR9 is cytoplasmic by direct observation (PMID:16787938, PMID:19038970) and lacks transmembrane segments; Reactome places the MTMR6/MTMR9 and MTMR8/MTMR9 complexes in the cytosol. The horse product retains the full phosphatase-like domain and coiled coil, with no predicted membrane or secretory signals, so a cytosolic location transfers by orthology. The ARBA rule itself is not cited as support. supported_by: - reference_id: file:human/MTMR9/MTMR9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16787938,' - reference_id: PMID:19038970 supporting_text: We demonstrate that human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells. - term: id: GO:0030234 label: enzyme regulator activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables supporting_entities: - ARBA:ARBA00026580 review: summary: Correct but general. MTMR9 orthologs specifically activate partner myotubularin lipid phosphatases; the specific term is phosphatase activator activity. action: MODIFY reason: Phosphatase activator activity is experimentally established for human MTMR9 on MTMR6 and MTMR8 (EXP, PMID:19038970, PMID:22647598) and, independently, for mouse MTMR9 on MTMR7 (PMID:12890864, where the MTMR9 coiled coil alone suffices for binding). Human and mouse lie on one side of the boreoeutherian split and horse on the other, so the shared activity places this function at least at their common ancestor, from which the horse MTMR9 gene descends (all three are in PTHR10807:SF56). Note that PAINT node PTN002246859 propagates only protein phosphatase binding and negative regulation of autophagy from human MTMR9 and does not propagate the activator term; the transfer here therefore rests on the two independent mammalian experimental orthologs, not on a PAINT IBD. The horse product retains the coiled coil (466-500) used for partner binding, but lacks 42 residues at the GRAM/phosphatase-like domain junction; the term is asserted for the gene's function, with the caveat that activity of this exon-skipped form is untested. GO:0019211 is_a enzyme activator activity, a descendant of enzyme regulator activity, and matches the human review's MODIFY of the same ARBA row. proposed_replacement_terms: - id: GO:0019211 label: phosphatase activator activity supported_by: - reference_id: PMID:22647598 supporting_text: Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity - reference_id: PMID:19038970 supporting_text: MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold. - reference_id: PMID:12890864 supporting_text: The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. - reference_id: file:HORSE/MTMR9/MTMR9-uniprot.txt record_section: ["FT:COILED"] supporting_text: FT COILED 466..500 - term: id: GO:0032587 label: ruffle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0301 review: summary: MTMR9 is recruited to membrane ruffles with MTMR6 during macropinocytosis; a transient, stimulus-dependent location. action: KEEP_AS_NON_CORE reason: MTMR6 and its binding partner MTMR9 act in membrane ruffles late in macropinocytosis in mammalian cells (PMID:24591580; UniProt records ruffle localization for mouse Mtmr9 by similarity). This is a stimulus-dependent pool rather than the principal site of the protein, so it is retained as non-core, consistent with the human review. supported_by: - reference_id: PMID:24591580 supporting_text: MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. - reference_id: PMID:24591580 supporting_text: These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0198 review: summary: Perinuclear colocalization with MTMR6 is observed for human MTMR9; a sub-pool of its cytoplasmic distribution. action: KEEP_AS_NON_CORE reason: Human MTMR9 colocalizes with MTMR6 in the perinuclear region (PMID:19038970, PMID:16787938). This is a more specific description of part of the cytoplasmic pool and transfers to the horse SF56 ortholog, but it is not where a distinct function has been defined, so it is non-core. supported_by: - reference_id: file:human/MTMR9/MTMR9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: CC Colocalizes with MTMR6 to the perinuclear region (PubMed:19038970). references: - 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: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: file:human/MTMR9/MTMR9-uniprot.txt title: human/MTMR9/MTMR9-uniprot.txt findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Swiss-Prot entry for the human SF56 ortholog Q96QG7; only its curated statements tied to publications are quoted. - id: file:HORSE/MTMR9/MTMR9-bioinformatics/RESULTS.md title: HORSE/MTMR9/MTMR9-bioinformatics/RESULTS.md findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Earlier paired human-horse comparison. Its identity figures and the 98-139 gap are reproduced by RESULTS-rereview.md, which supersedes it as cited support in this review because it also identifies the gap as an Ensembl exon skip and compares all three horse models. Kept for provenance; no longer cited in supported_by. - id: file:HORSE/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md title: HORSE/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reproducible comparison (compare_models_rereview.py) of the three horse MTMR9 UniProt models with human, mouse and bovine SF56 orthologs plus Ensembl exon structures. - id: file:HORSE/MTMR9/MTMR9-uniprot.txt title: HORSE/MTMR9/MTMR9-uniprot.txt findings: [] - id: PMID:22647598 title: Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. full_text_unavailable: true findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Human MTMR9 activates MTMR6 and MTMR8 and sets their substrate preference; abstract read. - id: PMID:19038970 title: MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. full_text_unavailable: true findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Human MTMR6/MTMR9 heteromer, activation and mutual stabilization; abstract read. - id: PMID:12890864 title: Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. full_text_unavailable: true findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Mouse MTMR9 binds MTMR7 via its coiled coil and increases MTMR7 activity; independent mammalian ortholog evidence for the activator function. - id: PMID:16787938 title: 'Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosome related functions.' full_text_unavailable: true findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Identifies MTMR8-MTMR9 heteromer and myotubularin localizations in human cells. - id: PMID:24591580 title: Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis. full_text_unavailable: true findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: MTMR6 and its partner MTMR9 required late in macropinocytosis at membrane ruffles; abstract read. core_functions: - description: Catalytically inactive myotubularin that heterodimerizes through its C-terminal coiled coil with active myotubularin phosphoinositide 3-phosphatases (MTMR6, MTMR7, MTMR8) and increases their activity and alters their substrate preference, acting in the cytosol. Function inferred from human and mouse SF56 orthologs; the exon-skipped horse product retains the coiled coil but lacks 42 residues at the GRAM/phosphatase-like domain junction. molecular_function: id: GO:0019211 label: phosphatase activator activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:22647598 supporting_text: Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity - reference_id: PMID:12890864 supporting_text: The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. - reference_id: file:HORSE/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md supporting_text: '| A0A9L0T3C1 | 507 | 97.8% | 98-139 | 0 | ETEDGMQESP |' suggested_questions: - question: Is the exon-3-skipped horse MTMR9 transcript (ENSECAT00000122597, product A0A9L0T3C1) expressed as a stable protein, and does removing human-equivalent residues 98-139 affect folding of the phosphatase-like domain or MTMR6/MTMR8 activation? - question: The horse MTMR9 Ensembl canonical model (F7CCR9) replaces the conserved C-terminal coiled-coil sequence with an unrelated tail, whereas A0A5F5PR89 matches the human protein over its full length. Which horse model should serve as the gene representative in PANTHER and UniProt? suggested_experiments: - description: RT-PCR across exons 2-4 of horse MTMR9 in several tissues to quantify the exon-3-skipped isoform, followed by co-expression with MTMR6 or MTMR8 and phosphoinositide phosphatase assays comparing the 507- and 549-residue products.