id: Q9Z2D0 gene_symbol: Mtmr9 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:10090 label: Mus musculus description: Mtmr9 (myotubularin-related protein 9) is a catalytically inactive member of the myotubularin family of phosphoinositide 3-phosphatases. It has an N-terminal PH-GRAM domain, a myotubularin phosphatase-like domain in which the catalytic cysteine and arginine of the CX5R loop are replaced (HGTEGTDST), and a C-terminal coiled coil. It acts as a noncatalytic regulatory subunit of active myotubularins. In mouse neuroblastoma cells it co-purifies with Mtmr7; its coiled coil is sufficient for this interaction, and binding raises the inositol 1,3-bisphosphate 3-phosphatase activity of Mtmr7. Mouse Mtmr9 also homodimerizes and heterodimerizes with Mtmr6. It is a cytoplasmic protein that is recruited to membrane ruffles during EGF-induced macropinocytosis, and this recruitment depends on its N-terminal GRAM region. Its human ortholog, which is in the same PANTHER subfamily and has an identical inactive loop, increases the catalytic rate, substrate preference and stability of MTMR6 and MTMR8. Through these partners it restrains autophagy, protects against DNA damage-induced apoptosis and is needed for macropinocytosis in cultured cells. These partner-specific roles are expected to be conserved in mouse but have not been tested in the mouse protein. existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12890864 qualifier: enables supporting_entities: - PR:Q9Z2C9 review: summary: Mouse Mtmr9 was identified by mass spectrometry as the protein co-immunoprecipitating with Mtmr7 from N1E-115 neuroblastoma cells; its coiled coil is sufficient for the interaction. action: MODIFY reason: 'Generic protein binding is uninformative. The partner (PR:Q9Z2C9, mouse Mtmr7) is an active myotubularin lipid phosphatase, so the informative molecular function is phosphatase binding (GO:0019902). The functional consequence of the binding, activation of Mtmr7, is captured separately by phosphatase activator activity. The issue is term scope: ''protein phosphatase binding'' and its children (PP1, PP2A, calcineurin binding and so on) denote phosphatases that act on phosphoproteins, whereas the Mtmr9 partners Mtmr6, Mtmr7 and Mtmr8 are phosphoinositide 3-phosphatases. The parent term phosphatase binding (GO:0019902) states the supported claim without implying a protein substrate. The same replacement is used on every partner-binding row here and in the human MTMR9 review, and the question is raised in suggested_questions.' supported_by: - reference_id: PMID:12890864 supporting_text: An MTMR7-binding protein was found in an anti-MTMR7 immunoprecipitate from N1E-115 - &id011 reference_id: PMID:12890864 supporting_text: The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. - &id004 reference_id: Reactome:R-MMU-6809495 supporting_text: Mouse Mtmr7 binds enzymatically inactive mouse Mtmr9 proposed_replacement_terms: - &id012 id: GO:0019902 label: phosphatase binding - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:24591580 qualifier: located_in review: summary: Mtmr9 is a soluble cytoplasmic protein. action: ACCEPT reason: Cytoplasmic localization of mouse Mtmr9 is experimentally recorded in this species (UniProt ECO:0000269 from PMID:24591580). The protein has no transmembrane segment or signal peptide, it is recruited peripherally to ruffle membranes through its GRAM domain, and PAINT places cytoplasm at the family root node PTN000743854. All cytoplasm rows (EXP, IBA, IEA, ISO) state the same correct claim. supported_by: - &id001 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580}' - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - AGI_LocusCode:AT3G10550 - AGI_LocusCode:AT5G04540 - FB:FBgn0025742 - FB:FBgn0025802 - MGI:MGI:1099452 - MGI:MGI:1858271 - MGI:MGI:1891693 - MGI:MGI:1921831 - MGI:MGI:1924366 - MGI:MGI:2145637 - MGI:MGI:2442842 - MGI:MGI:2443034 - PANTHER:PTN000743854 - RGD:1305378 - RGD:1311865 - UniProtKB:A4FU01 - UniProtKB:O95248 - UniProtKB:Q13496 - UniProtKB:Q13613 - UniProtKB:Q13614 - UniProtKB:Q13615 - UniProtKB:Q585F9 - UniProtKB:Q86WG5 - UniProtKB:Q96EF0 - UniProtKB:Q96QG7 - UniProtKB:Q9C0I1 - UniProtKB:Q9NXD2 - UniProtKB:Q9NYA4 - UniProtKB:Q9Y216 - UniProtKB:Q9Y217 - WB:WBGene00003475 - WB:WBGene00003476 - WB:WBGene00003478 - WB:WBGene00003479 review: summary: Mtmr9 is a soluble cytoplasmic protein. action: ACCEPT reason: Cytoplasmic localization of mouse Mtmr9 is experimentally recorded in this species (UniProt ECO:0000269 from PMID:24591580). The protein has no transmembrane segment or signal peptide, it is recruited peripherally to ruffle membranes through its GRAM domain, and PAINT places cytoplasm at the family root node PTN000743854. All cytoplasm rows (EXP, IBA, IEA, ISO) state the same correct claim. supported_by: - *id001 propagation_review: root_cause: NO_FAILURE_CORE failure_modes: [] source_entities: - source_id: PANTHER:PTN000743854 comment: Family-root myotubularin node; cytoplasm is supported by experimental data from many members, including mouse Mtmr9 itself (MGI:2442842 is a seed). source_status: SUPPORTS_TRANSFER - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 - UniProtKB-SubCell:SL-0086 review: summary: Mtmr9 is a soluble cytoplasmic protein. action: ACCEPT reason: Cytoplasmic localization of mouse Mtmr9 is experimentally recorded in this species (UniProt ECO:0000269 from PMID:24591580). The protein has no transmembrane segment or signal peptide, it is recruited peripherally to ruffle membranes through its GRAM domain, and PAINT places cytoplasm at the family root node PTN000743854. All cytoplasm rows (EXP, IBA, IEA, ISO) state the same correct claim. supported_by: - *id001 - term: id: GO:0005737 label: cytoplasm evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 is a soluble cytoplasmic protein. action: ACCEPT reason: Cytoplasmic localization of mouse Mtmr9 is experimentally recorded in this species (UniProt ECO:0000269 from PMID:24591580). The protein has no transmembrane segment or signal peptide, it is recruited peripherally to ruffle membranes through its GRAM domain, and PAINT places cytoplasm at the family root node PTN000743854. All cytoplasm rows (EXP, IBA, IEA, ISO) state the same correct claim. supported_by: - *id001 - 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, transferred from human MTMR9. action: KEEP_AS_NON_CORE reason: UniProt records partial ER localization for mouse Mtmr9 only by similarity to human MTMR9 (Q96QG7, same PANTHER subfamily PTHR10807:SF56); it has not been tested for the mouse protein. Partial association with one membrane system is a minor feature of a mainly cytoplasmic regulatory subunit, not a defining site of function, so the term is kept but marked non-core. All three rows (IEA, ISO, ISS) carry the same claim and the same action. supported_by: - &id002 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: Partially localizes to the endoplasmic reticulum (By similarity). - &id003 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["DR:PANTHER"] supporting_text: PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Partial endoplasmic reticulum localization, transferred from human MTMR9. action: KEEP_AS_NON_CORE reason: UniProt records partial ER localization for mouse Mtmr9 only by similarity to human MTMR9 (Q96QG7, same PANTHER subfamily PTHR10807:SF56); it has not been tested for the mouse protein. Partial association with one membrane system is a minor feature of a mainly cytoplasmic regulatory subunit, not a defining site of function, so the term is kept but marked non-core. All three rows (IEA, ISO, ISS) carry the same claim and the same action. supported_by: - *id002 - *id003 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Partial endoplasmic reticulum localization, transferred from human MTMR9. action: KEEP_AS_NON_CORE reason: UniProt records partial ER localization for mouse Mtmr9 only by similarity to human MTMR9 (Q96QG7, same PANTHER subfamily PTHR10807:SF56); it has not been tested for the mouse protein. Partial association with one membrane system is a minor feature of a mainly cytoplasmic regulatory subunit, not a defining site of function, so the term is kept but marked non-core. All three rows (IEA, ISO, ISS) carry the same claim and the same action. supported_by: - *id002 - *id003 - 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 and its Mtmr7 complex are cytosolic. action: ACCEPT reason: Cytosol is consistent with the experimental cytoplasmic localization of mouse Mtmr9, the absence of membrane-spanning or secretory signals, and Reactome's placement of the mouse Mtmr7:Mtmr9 complex acting on the soluble substrate Ins(1,3)P2. The ARBA IEA row and the two Reactome TAS rows make the same claim. supported_by: - *id001 - *id004 - &id005 reference_id: Reactome:R-MMU-6809627 supporting_text: Formation of the complex between mouse Mtmr9 and mouse Mtmr7 results in 2- to 5-fold increase in Mtmr7 inositol-1,3-bisphosphate 3-phosphatase catalytic activity - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-MMU-6809495 qualifier: located_in review: summary: Mtmr9 and its Mtmr7 complex are cytosolic. action: ACCEPT reason: Cytosol is consistent with the experimental cytoplasmic localization of mouse Mtmr9, the absence of membrane-spanning or secretory signals, and Reactome's placement of the mouse Mtmr7:Mtmr9 complex acting on the soluble substrate Ins(1,3)P2. The ARBA IEA row and the two Reactome TAS rows make the same claim. supported_by: - *id001 - *id004 - *id005 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-MMU-6809627 qualifier: located_in review: summary: Mtmr9 and its Mtmr7 complex are cytosolic. action: ACCEPT reason: Cytosol is consistent with the experimental cytoplasmic localization of mouse Mtmr9, the absence of membrane-spanning or secretory signals, and Reactome's placement of the mouse Mtmr7:Mtmr9 complex acting on the soluble substrate Ins(1,3)P2. The ARBA IEA row and the two Reactome TAS rows make the same claim. supported_by: - *id001 - *id004 - *id005 - term: id: GO:0010507 label: negative regulation of autophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN002246859 - UniProtKB:Q96QG7 review: summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. action: KEEP_AS_NON_CORE reason: In human cells the MTMR8/MTMR9 complex lowers PI3P and inhibits autophagy (PMID:22647598). MTMR9 does part of this work by activating MTMR8, so the process claim is legitimate, and PAINT placed it at the eumetazoan MTMR9-lineage node PTN002246859, which includes mouse Mtmr9 (PTHR10807:SF56). The seeding of that node by human MTMR9 alone is expected, not weak support. However, the effect has not been tested in mouse, and it is a downstream cellular consequence of regulating one partner's lipid phosphatase activity rather than the core function, so all three rows (IBA, IEA, ISO) are kept as non-core. supported_by: - &id006 reference_id: PMID:22647598 supporting_text: the MTMR8/R9 complex inhibits autophagy - &id007 reference_id: PMID:22647598 supporting_text: the MTMR8/R9 complex reduces cellular PtdIns(3)P levels propagation_review: root_cause: NO_FAILURE_NON_CORE failure_modes: [] source_entities: - source_id: PANTHER:PTN002246859 comment: Eumetazoan MTMR9-lineage node seeded by human MTMR9 (PMID:22647598); mouse Mtmr9 is in the same subfamily and inherits it soundly. source_status: SUPPORTS_TRANSFER - term: id: GO:0010507 label: negative regulation of autophagy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 review: summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. action: KEEP_AS_NON_CORE reason: In human cells the MTMR8/MTMR9 complex lowers PI3P and inhibits autophagy (PMID:22647598). MTMR9 does part of this work by activating MTMR8, so the process claim is legitimate, and PAINT placed it at the eumetazoan MTMR9-lineage node PTN002246859, which includes mouse Mtmr9 (PTHR10807:SF56). The seeding of that node by human MTMR9 alone is expected, not weak support. However, the effect has not been tested in mouse, and it is a downstream cellular consequence of regulating one partner's lipid phosphatase activity rather than the core function, so all three rows (IBA, IEA, ISO) are kept as non-core. supported_by: - *id006 - *id007 - term: id: GO:0010507 label: negative regulation of autophagy evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. action: KEEP_AS_NON_CORE reason: In human cells the MTMR8/MTMR9 complex lowers PI3P and inhibits autophagy (PMID:22647598). MTMR9 does part of this work by activating MTMR8, so the process claim is legitimate, and PAINT placed it at the eumetazoan MTMR9-lineage node PTN002246859, which includes mouse Mtmr9 (PTHR10807:SF56). The seeding of that node by human MTMR9 alone is expected, not weak support. However, the effect has not been tested in mouse, and it is a downstream cellular consequence of regulating one partner's lipid phosphatase activity rather than the core function, so all three rows (IBA, IEA, ISO) are kept as non-core. supported_by: - *id006 - *id007 - term: id: GO:0010922 label: positive regulation of phosphatase activity evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 raises the catalytic activity of its partner phosphatases. action: ACCEPT reason: 'Although this row is an ISO transfer from human MTMR9, the activity is also shown for the mouse protein: mouse Mtmr9 increased the Ins(1,3)P2 phosphatase activity of mouse Mtmr7 (PMID:12890864; Reactome R-MMU-6809627 gives 2- to 5-fold). Human MTMR9 activates MTMR6 and MTMR8 (PMID:19038970, PMID:22647598). This is the process counterpart of the core activity phosphatase activator activity.' supported_by: - &id008 reference_id: PMID:12890864 supporting_text: The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. - *id005 - &id009 reference_id: PMID:19038970 supporting_text: MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold - &id010 reference_id: PMID:22647598 supporting_text: Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity - term: id: GO:0019211 label: phosphatase activator activity evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: enables supporting_entities: - UniProtKB:Q96QG7 review: summary: 'Core molecular function: noncatalytic activator of myotubularin phosphatases.' action: ACCEPT reason: Mtmr9 lacks the catalytic cysteine and arginine of the myotubularin CX5R loop (HGTEGTDST in place of HCSDGWDRT; UniProt CAUTION and the catalytic-motif analysis), so it has no phosphatase activity of its own. Its activity is to raise the catalytic rate of an active partner. In mouse this was shown directly for Mtmr7 (PMID:12890864); in human for MTMR6 and MTMR8, where MTMR9 also sets substrate preference (PMID:19038970, PMID:22647598). Mouse and human MTMR9 are in the same PANTHER subfamily (PTHR10807:SF56) with identical catalytic loops, so the human data transfer as orthologous function. supported_by: - *id008 - *id005 - *id009 - *id010 - &id022 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:CAUTION"] supporting_text: lacks the conserved active site cysteine residue at position - &id020 reference_id: file:human/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md supporting_text: MTMR9 lacks both the catalytic cysteine and the catalytic arginine - *id003 - term: id: GO:0019903 label: protein phosphatase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - PANTHER:PTN002246859 - UniProtKB:Q96QG7 review: summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. action: MODIFY reason: 'The binding itself is sound and, for Mtmr7, experimentally shown in mouse (PMID:12890864). The issue is term scope: ''protein phosphatase binding'' and its children (PP1, PP2A, calcineurin binding and so on) denote phosphatases that act on phosphoproteins, whereas the Mtmr9 partners Mtmr6, Mtmr7 and Mtmr8 are phosphoinositide 3-phosphatases. The parent term phosphatase binding (GO:0019902) states the supported claim without implying a protein substrate. The same replacement is used on every partner-binding row here and in the human MTMR9 review, and the question is raised in suggested_questions. PAINT placed the term at the eumetazoan MTMR9-lineage node PTN002246859, seeded by human MTMR9; mouse Mtmr9 is correctly inside that clade, so only the term choice is at issue.' supported_by: - *id011 - &id013 reference_id: PMID:19038970 supporting_text: human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells - &id014 reference_id: PMID:22647598 supporting_text: MTMR8, all of which dimerize with the catalytically inactive MTMR9 - &id015 reference_id: PMID:16787938 supporting_text: 'identified novel heteromeric interactions: MTMR8 with MTMR9' proposed_replacement_terms: - *id012 propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - GRANULARITY_MISMATCH source_entities: - source_id: PANTHER:PTN002246859 comment: Eumetazoan MTMR9-lineage node; the node placement and the binding it asserts are sound. Only the term's scope (protein vs lipid phosphatase) is at issue. source_status: SUPPORTS_TRANSFER - term: id: GO:0019903 label: protein phosphatase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 review: summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. action: MODIFY reason: 'The binding itself is sound and, for Mtmr7, experimentally shown in mouse (PMID:12890864). The issue is term scope: ''protein phosphatase binding'' and its children (PP1, PP2A, calcineurin binding and so on) denote phosphatases that act on phosphoproteins, whereas the Mtmr9 partners Mtmr6, Mtmr7 and Mtmr8 are phosphoinositide 3-phosphatases. The parent term phosphatase binding (GO:0019902) states the supported claim without implying a protein substrate. The same replacement is used on every partner-binding row here and in the human MTMR9 review, and the question is raised in suggested_questions. PAINT placed the term at the eumetazoan MTMR9-lineage node PTN002246859, seeded by human MTMR9; mouse Mtmr9 is correctly inside that clade, so only the term choice is at issue.' supported_by: - *id011 - *id013 - *id014 - *id015 proposed_replacement_terms: - *id012 propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - GRANULARITY_MISMATCH source_entities: - source_id: UniProtKB:Q96QG7 source_label: MTMR9 comment: Human ortholog in the same PANTHER subfamily; its binding to MTMR6/MTMR8 is experimentally sound. Only the term's scope is at issue. source_status: SUPPORTS_TRANSFER - term: id: GO:0019903 label: protein phosphatase binding evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: enables supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. action: MODIFY reason: 'The binding itself is sound and, for Mtmr7, experimentally shown in mouse (PMID:12890864). The issue is term scope: ''protein phosphatase binding'' and its children (PP1, PP2A, calcineurin binding and so on) denote phosphatases that act on phosphoproteins, whereas the Mtmr9 partners Mtmr6, Mtmr7 and Mtmr8 are phosphoinositide 3-phosphatases. The parent term phosphatase binding (GO:0019902) states the supported claim without implying a protein substrate. The same replacement is used on every partner-binding row here and in the human MTMR9 review, and the question is raised in suggested_questions. PAINT placed the term at the eumetazoan MTMR9-lineage node PTN002246859, seeded by human MTMR9; mouse Mtmr9 is correctly inside that clade, so only the term choice is at issue.' supported_by: - *id011 - *id013 - *id014 - *id015 proposed_replacement_terms: - *id012 propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - GRANULARITY_MISMATCH source_entities: - source_id: UniProtKB:Q96QG7 source_label: MTMR9 comment: Human ortholog in the same PANTHER subfamily; its binding to MTMR6/MTMR8 is experimentally sound. Only the term's scope is at issue. source_status: SUPPORTS_TRANSFER - term: id: GO:0030234 label: enzyme regulator activity evidence_type: IDA original_reference_id: PMID:12890864 qualifier: enables review: summary: Mtmr9 regulates the activity of the phosphatase Mtmr7 (and, by orthology, MTMR6 and MTMR8). action: MODIFY reason: True, but less specific than the evidence supports. In the cited mouse study the enzyme regulated is the phosphatase Mtmr7 and the regulation is activation, so phosphatase activator activity (GO:0019211, a descendant of enzyme regulator activity and already carried by the gene) is the supported term. The ARBA IEA row receives the same replacement. supported_by: - *id008 - *id005 - &id016 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Acts as an adapter for myotubularin-related phosphatases proposed_replacement_terms: - &id017 id: GO:0019211 label: phosphatase activator activity - 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: Mtmr9 regulates the activity of the phosphatase Mtmr7 (and, by orthology, MTMR6 and MTMR8). action: MODIFY reason: True, but less specific than the evidence supports. In the cited mouse study the enzyme regulated is the phosphatase Mtmr7 and the regulation is activation, so phosphatase activator activity (GO:0019211, a descendant of enzyme regulator activity and already carried by the gene) is the supported term. The ARBA IEA row receives the same replacement. supported_by: - *id008 - *id005 - *id016 proposed_replacement_terms: - *id017 - 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 during EGF-induced macropinocytosis. action: KEEP_AS_NON_CORE reason: 'This is one of the two experimentally established localizations of mouse Mtmr9: UniProt records ruffle membrane from PMID:24591580 (ECO:0000269), and deletion of the N-terminal region containing the GRAM domain (residues 2-108) abolishes recruitment to the cell membrane after EGF stimulation. The term is correct and as precise as the evidence allows. It is kept as non-core because the recruitment is stimulus-dependent and transient; the defining activity of Mtmr9, activating its partner phosphatases, is not confined to ruffles.' supported_by: - &id023 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: ruffles during EGF-induced macropinocytosis (PubMed:24591580) - reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:DOMAIN"] supporting_text: The GRAM domain is required for cell membrane localization. - reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["FT:MUTAGEN"] supporting_text: 'Missing: Loss of cell membrane recruitment following' - reference_id: PMID:24591580 supporting_text: its binding partner MTMR9, are required for macropinocytosis - term: id: GO:0032991 label: protein-containing complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 review: summary: Mtmr9 forms heterodimeric complexes with active myotubularins. action: ACCEPT reason: Complex formation is the basis of Mtmr9 function. In mouse it forms a complex with Mtmr7 (PMID:12890864, IP-mass spectrometry), and UniProt records homodimers and Mtmr6 heterodimers from the same paper. The human ortholog dimerizes with MTMR6, MTMR7 and MTMR8. GO has no specific complex term for these heterodimers, so the general term is as precise as the ontology allows. supported_by: - &id018 reference_id: PMID:12890864 supporting_text: Our results show that MTMR7 forms a complex with MTMR9 - &id019 reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: (via coiled coil domain) with lipid phosphatase MTMR7 (via C-terminus) - *id014 - term: id: GO:0032991 label: protein-containing complex evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: part_of supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 forms heterodimeric complexes with active myotubularins. action: ACCEPT reason: Complex formation is the basis of Mtmr9 function. In mouse it forms a complex with Mtmr7 (PMID:12890864, IP-mass spectrometry), and UniProt records homodimers and Mtmr6 heterodimers from the same paper. The human ortholog dimerizes with MTMR6, MTMR7 and MTMR8. GO has no specific complex term for these heterodimers, so the general term is as precise as the ontology allows. supported_by: - *id018 - *id019 - *id014 - term: id: GO:0046856 label: phosphatidylinositol dephosphorylation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1891693 - PANTHER:PTN008506586 - UniProtKB:Q96EF0 - UniProtKB:Q9Y217 review: summary: Mtmr9 takes part in phosphatidylinositol 3-dephosphorylation as the activating subunit of active myotubularins. action: ACCEPT reason: 'Mtmr9 cannot hydrolyse phosphate itself, but it is the activating and stabilizing subunit of heterodimers that 3-dephosphorylate PI3P and PI(3,5)P2, so it contributes structure and activation to the step (the cofactor case in the participation test). The PAINT curator made this explicit: at the MTMR9-lineage node PTN000086907 they recorded NOT for the catalytic activities GO:0004438 and GO:0106018 but did not negate GO:0046856, inherited from the eukaryotic node PTN008506586. Keeping the process while negating catalysis is a deliberate decision and is biologically sound.' supported_by: - *id010 - *id009 - *id008 - *id020 propagation_review: root_cause: NO_FAILURE_CORE failure_modes: [] source_entities: - source_id: PANTHER:PTN008506586 comment: Eukaryotic myotubularin node seeded by active MTMR6, MTMR8 and mouse Mtmr7 (MGI:1891693). The catalytic MF terms were negated at descendant node PTN000086907 (MTMR9 lineage) but this process was deliberately left in place. source_status: SUPPORTS_TRANSFER - 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 localization with MTMR6, transferred from human MTMR9. action: KEEP_AS_NON_CORE reason: UniProt records perinuclear localization for mouse Mtmr9 only by similarity to human MTMR9, where it colocalizes with MTMR6. The location is plausible for the ortholog in the same PANTHER subfamily, but it is a descriptive sub-location of the cytoplasmic pool and not established in mouse, so it is kept as non-core. supported_by: - reference_id: file:mouse/Mtmr9/Mtmr9-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: Colocalizes with MTMR6 to the perinuclear region (By similarity). - *id003 - term: id: GO:0050821 label: protein stabilization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 review: summary: Mtmr9 stabilizes its partner phosphatase, and is itself stabilized, by heterodimer formation. action: ACCEPT reason: 'Shown for the human proteins: MTMR6-MTMR9 heteromer formation raises the protein levels of both subunits, probably by inhibiting degradation (PMID:19038970). Mtmr9 contributes the stabilizing binding itself, so this is participation, not a downstream effect. The function is transferred from the ortholog in the same PANTHER subfamily (PTHR10807:SF56); it has not been tested for the mouse protein. The IEA and ISO rows carry the same claim.' supported_by: - &id021 reference_id: PMID:19038970 supporting_text: the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9 - *id013 - term: id: GO:0050821 label: protein stabilization evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 stabilizes its partner phosphatase, and is itself stabilized, by heterodimer formation. action: ACCEPT reason: 'Shown for the human proteins: MTMR6-MTMR9 heteromer formation raises the protein levels of both subunits, probably by inhibiting degradation (PMID:19038970). Mtmr9 contributes the stabilizing binding itself, so this is participation, not a downstream effect. The function is transferred from the ortholog in the same PANTHER subfamily (PTHR10807:SF56); it has not been tested for the mouse protein. The IEA and ISO rows carry the same claim.' supported_by: - *id021 - *id013 - term: id: GO:0060304 label: regulation of phosphatidylinositol dephosphorylation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 - ensembl:ENSP00000221086 review: summary: Mtmr9 regulates phosphatidylinositol 3-dephosphorylation by its partner phosphatases. action: ACCEPT reason: Core process. Human MTMR9 raises MTMR6 activity toward PI(3,5)P2 and MTMR8 activity toward PI3P and changes cellular PtdIns(5)P and PtdIns(3)P levels accordingly (PMID:22647598). Mouse Mtmr9 activates Mtmr7, which dephosphorylates PI3P and Ins(1,3)P2 (PMID:12890864). The lipid-specific part is transferred from the human ortholog in the same PANTHER subfamily. The IEA and ISO rows make the same claim. supported_by: - *id010 - *id007 - *id008 - term: id: GO:0060304 label: regulation of phosphatidylinositol dephosphorylation evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q96QG7 review: summary: Mtmr9 regulates phosphatidylinositol 3-dephosphorylation by its partner phosphatases. action: ACCEPT reason: Core process. Human MTMR9 raises MTMR6 activity toward PI(3,5)P2 and MTMR8 activity toward PI3P and changes cellular PtdIns(5)P and PtdIns(3)P levels accordingly (PMID:22647598). Mouse Mtmr9 activates Mtmr7, which dephosphorylates PI3P and Ins(1,3)P2 (PMID:12890864). The lipid-specific part is transferred from the human ortholog in the same PANTHER subfamily. The IEA and ISO rows make the same claim. supported_by: - *id010 - *id007 - *id008 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: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000119 title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:12890864 title: Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary mouse study (abstract-only in cache; PMC187840). Identifies mouse Mtmr9 as the Mtmr7-binding protein by IP-MS from N1E-115 cells, maps binding to the Mtmr9 coiled coil, and shows Mtmr9 raises Mtmr7 Ins(1,3)P2 phosphatase activity. Source of the IPI and IDA rows; homodimer and Mtmr6 heterodimer statements are from the full text via UniProt. - id: PMID:24591580 title: Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract-only in cache (PMC3964036 not retrievable). MTMR6 and MTMR9 are required for macropinocytosis; the mouse Mtmr9 ruffle localization and GRAM-region deletion are recorded from this paper in UniProt (ECO:0000269). The requirement is knockdown (necessity) evidence, so no macropinocytosis process term is added. - id: Reactome:R-MMU-6809495 title: Mtmr7 binds Mtmr9 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse Reactome reaction based on PMID:12890864. - id: Reactome:R-MMU-6809627 title: I(1,3)P2 is dephosphorylated into I1P by Mtmr7:Mtmr9 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse Reactome reaction; gives 2- to 5-fold activation of Mtmr7 by Mtmr9. - id: PMID:19038970 title: MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Human MTMR6-MTMR9 study; supports ortholog-transferred activator, stabilization and apoptosis claims. Not a mouse experiment. - id: PMID:22647598 title: Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Human MTMR6/7/8-MTMR9 study; substrate specificity and autophagy. Not a mouse experiment. - id: PMID:16787938 title: 'Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosome related functions.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Human two-hybrid and co-IP survey that identified MTMR8-MTMR9; supports partner binding by orthology. - id: file:mouse/Mtmr9/Mtmr9-uniprot.txt title: mouse/Mtmr9/Mtmr9-uniprot.txt findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Mouse Swiss-Prot entry; ECO:0000269 statements distinguish mouse experimental data (PMID:12890864, PMID:24591580) from by-similarity transfers from Q96QG7. - id: file:human/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md title: MTMR9 catalytic-motif check (re-review) findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Catalytic-loop comparison including mouse Q9Z2D0; confirmed by reading the mouse sequence (H332-G333...S339). core_functions: - description: Noncatalytic activating subunit of myotubularin lipid phosphatases. It heterodimerizes with active partners (Mtmr7 shown in mouse; MTMR6 and MTMR8 by orthology) and raises their 3-phosphatase activity, setting substrate preference and so regulating 3-phosphoinositide turnover. molecular_function: *id017 directly_involved_in: - id: GO:0060304 label: regulation of phosphatidylinositol dephosphorylation - id: GO:0046856 label: phosphatidylinositol dephosphorylation locations: - id: GO:0005829 label: cytosol supported_by: - *id008 - *id005 - *id010 - *id022 - *id020 - *id023 - description: Binds its active myotubularin partners through its coiled coil and C-terminal region, and the heterodimer stabilizes both subunits (stabilization shown for human MTMR6-MTMR9). molecular_function: *id012 directly_involved_in: - id: GO:0050821 label: protein stabilization locations: - id: GO:0005737 label: cytoplasm supported_by: - *id011 - *id019 - *id021 suggested_questions: - question: Should binding of an inactive myotubularin to an active myotubularin lipid phosphatase be annotated to GO:0019903 protein phosphatase binding (as PAINT does at PTN002246859) or to the parent GO:0019902 phosphatase binding? The children of GO:0019903 all name protein-substrate phosphatases. - question: In mouse tissues where Mtmr6, Mtmr7 and Mtmr8 are co-expressed (for example brain, where Mtmr7 is enriched), how is the Mtmr9 pool partitioned among them, and does the partner determine whether Mtmr9 acts on PI3P, PI(3,5)P2 or soluble Ins(1,3)P2? suggested_experiments: - hypothesis: Mtmr9 is required in vivo for normal Mtmr6/Mtmr7/Mtmr8 protein levels and 3-phosphoinositide turnover. description: Generate Mtmr9 knockout mice or primary cells; measure partner protein half-lives, PI3P, PI(3,5)P2 and PI5P levels, and rescue with wild-type versus coiled-coil-deleted Mtmr9. experiment_type: genetic perturbation - hypothesis: The GRAM domain of Mtmr9 recruits the Mtmr6-Mtmr9 complex to ruffles to complete macropinocytosis. description: In Mtmr9-null mouse cells, re-express wild-type or GRAM-deleted Mtmr9 and score Mtmr6 ruffle recruitment, ruffle PI3P and dextran uptake after EGF stimulation. experiment_type: cell biology