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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:12890864 Characterization of myotubularin-related protein 7 and its b... | MODIFY | 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. 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. Proposed replacements: phosphatase binding Supporting Evidence: PMID:12890864 An MTMR7-binding protein was found in an anti-MTMR7 immunoprecipitate from N1E-115 PMID:12890864 The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. Reactome:R-MMU-6809495 Mouse Mtmr7 binds enzymatically inactive mouse Mtmr9 |
| GO:0005737 cytoplasm | EXP PMID:24591580 Sequential breakdown of 3-phosphorylated phosphoinositides i... | ACCEPT | Summary: Mtmr9 is a soluble cytoplasmic protein. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Mtmr9 is a soluble cytoplasmic protein. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000743854 SUPPORTS TRANSFER Family-root myotubularin node; cytoplasm is supported by experimental data from many members, including mouse Mtmr9 itself (MGI:2442842 is a seed). Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Mtmr9 is a soluble cytoplasmic protein. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: Mtmr9 is a soluble cytoplasmic protein. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Partial endoplasmic reticulum localization, transferred from human MTMR9. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt Partially localizes to the endoplasmic reticulum (By similarity). file:mouse/Mtmr9/Mtmr9-uniprot.txt PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Partial endoplasmic reticulum localization, transferred from human MTMR9. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt Partially localizes to the endoplasmic reticulum (By similarity). file:mouse/Mtmr9/Mtmr9-uniprot.txt PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Partial endoplasmic reticulum localization, transferred from human MTMR9. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt Partially localizes to the endoplasmic reticulum (By similarity). file:mouse/Mtmr9/Mtmr9-uniprot.txt PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Mtmr9 and its Mtmr7 complex are cytosolic. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} Reactome:R-MMU-6809495 Mouse Mtmr7 binds enzymatically inactive mouse Mtmr9 Reactome:R-MMU-6809627 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 |
| GO:0005829 cytosol | TAS Reactome:R-MMU-6809495 | ACCEPT | Summary: Mtmr9 and its Mtmr7 complex are cytosolic. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} Reactome:R-MMU-6809495 Mouse Mtmr7 binds enzymatically inactive mouse Mtmr9 Reactome:R-MMU-6809627 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 |
| GO:0005829 cytosol | TAS Reactome:R-MMU-6809627 | ACCEPT | Summary: Mtmr9 and its Mtmr7 complex are cytosolic. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24591580} Reactome:R-MMU-6809495 Mouse Mtmr7 binds enzymatically inactive mouse Mtmr9 Reactome:R-MMU-6809627 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 |
| GO:0010507 negative regulation of autophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002246859 SUPPORTS TRANSFER Eumetazoan MTMR9-lineage node seeded by human MTMR9 (PMID:22647598); mouse Mtmr9 is in the same subfamily and inherits it soundly. Supporting Evidence: PMID:22647598 the MTMR8/R9 complex inhibits autophagy PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels |
| GO:0010507 negative regulation of autophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. 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. Supporting Evidence: PMID:22647598 the MTMR8/R9 complex inhibits autophagy PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels |
| GO:0010507 negative regulation of autophagy | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Negative regulation of autophagy through the MTMR8-MTMR9 complex, a function shown for the human proteins. 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. Supporting Evidence: PMID:22647598 the MTMR8/R9 complex inhibits autophagy PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels |
| GO:0010922 positive regulation of phosphatase activity | ISO GO_REF:0000119 | ACCEPT | Summary: Mtmr9 raises the catalytic activity of its partner phosphatases. 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. Supporting Evidence: PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. Reactome:R-MMU-6809627 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 PMID:19038970 MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity |
| GO:0019211 phosphatase activator activity | ISO GO_REF:0000119 | ACCEPT | Summary: Core molecular function: noncatalytic activator of myotubularin phosphatases. 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. Supporting Evidence: PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. Reactome:R-MMU-6809627 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 PMID:19038970 MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity file:mouse/Mtmr9/Mtmr9-uniprot.txt lacks the conserved active site cysteine residue at position file:human/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md MTMR9 lacks both the catalytic cysteine and the catalytic arginine file:mouse/Mtmr9/Mtmr9-uniprot.txt PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 |
| GO:0019903 protein phosphatase binding | IBA GO_REF:0000033 | MODIFY | Summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002246859 SUPPORTS TRANSFER 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. Proposed replacements: phosphatase binding Supporting Evidence: PMID:12890864 The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells PMID:22647598 MTMR8, all of which dimerize with the catalytically inactive MTMR9 PMID:16787938 identified novel heteromeric interactions: MTMR8 with MTMR9 |
| GO:0019903 protein phosphatase binding | IEA GO_REF:0000107 | MODIFY | Summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q96QG7 · MTMR9 SUPPORTS TRANSFER Human ortholog in the same PANTHER subfamily; its binding to MTMR6/MTMR8 is experimentally sound. Only the term's scope is at issue. Proposed replacements: phosphatase binding Supporting Evidence: PMID:12890864 The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells PMID:22647598 MTMR8, all of which dimerize with the catalytically inactive MTMR9 PMID:16787938 identified novel heteromeric interactions: MTMR8 with MTMR9 |
| GO:0019903 protein phosphatase binding | ISO GO_REF:0000119 | MODIFY | Summary: Mtmr9 binds the myotubularin lipid phosphatases Mtmr6, Mtmr7 and Mtmr8. 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q96QG7 · MTMR9 SUPPORTS TRANSFER Human ortholog in the same PANTHER subfamily; its binding to MTMR6/MTMR8 is experimentally sound. Only the term's scope is at issue. Proposed replacements: phosphatase binding Supporting Evidence: PMID:12890864 The coiled-coil domain of MTMR9 was sufficient for binding to MTMR7. PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells PMID:22647598 MTMR8, all of which dimerize with the catalytically inactive MTMR9 PMID:16787938 identified novel heteromeric interactions: MTMR8 with MTMR9 |
| GO:0030234 enzyme regulator activity | IDA PMID:12890864 Characterization of myotubularin-related protein 7 and its b... | MODIFY | Summary: Mtmr9 regulates the activity of the phosphatase Mtmr7 (and, by orthology, MTMR6 and MTMR8). 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. Proposed replacements: phosphatase activator activity Supporting Evidence: PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. Reactome:R-MMU-6809627 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 file:mouse/Mtmr9/Mtmr9-uniprot.txt Acts as an adapter for myotubularin-related phosphatases |
| GO:0030234 enzyme regulator activity | IEA GO_REF:0000117 | MODIFY | Summary: Mtmr9 regulates the activity of the phosphatase Mtmr7 (and, by orthology, MTMR6 and MTMR8). 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. Proposed replacements: phosphatase activator activity Supporting Evidence: PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. Reactome:R-MMU-6809627 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 file:mouse/Mtmr9/Mtmr9-uniprot.txt Acts as an adapter for myotubularin-related phosphatases |
| GO:0032587 ruffle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mtmr9 is recruited to membrane ruffles during EGF-induced macropinocytosis. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt ruffles during EGF-induced macropinocytosis (PubMed:24591580) file:mouse/Mtmr9/Mtmr9-uniprot.txt The GRAM domain is required for cell membrane localization. file:mouse/Mtmr9/Mtmr9-uniprot.txt Missing: Loss of cell membrane recruitment following PMID:24591580 its binding partner MTMR9, are required for macropinocytosis |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | ACCEPT | Summary: Mtmr9 forms heterodimeric complexes with active myotubularins. 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. Supporting Evidence: PMID:12890864 Our results show that MTMR7 forms a complex with MTMR9 file:mouse/Mtmr9/Mtmr9-uniprot.txt (via coiled coil domain) with lipid phosphatase MTMR7 (via C-terminus) PMID:22647598 MTMR8, all of which dimerize with the catalytically inactive MTMR9 |
| GO:0032991 protein-containing complex | ISO GO_REF:0000119 | ACCEPT | Summary: Mtmr9 forms heterodimeric complexes with active myotubularins. 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. Supporting Evidence: PMID:12890864 Our results show that MTMR7 forms a complex with MTMR9 file:mouse/Mtmr9/Mtmr9-uniprot.txt (via coiled coil domain) with lipid phosphatase MTMR7 (via C-terminus) PMID:22647598 MTMR8, all of which dimerize with the catalytically inactive MTMR9 |
| GO:0046856 phosphatidylinositol dephosphorylation | IBA GO_REF:0000033 | ACCEPT | Summary: Mtmr9 takes part in phosphatidylinositol 3-dephosphorylation as the activating subunit of active myotubularins. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008506586 SUPPORTS TRANSFER 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. Supporting Evidence: PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity PMID:19038970 MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. file:human/MTMR9/MTMR9-bioinformatics/RESULTS-rereview.md MTMR9 lacks both the catalytic cysteine and the catalytic arginine |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Perinuclear localization with MTMR6, transferred from human MTMR9. 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. Supporting Evidence: file:mouse/Mtmr9/Mtmr9-uniprot.txt Colocalizes with MTMR6 to the perinuclear region (By similarity). file:mouse/Mtmr9/Mtmr9-uniprot.txt PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9 |
| GO:0050821 protein stabilization | IEA GO_REF:0000107 | ACCEPT | Summary: Mtmr9 stabilizes its partner phosphatase, and is itself stabilized, by heterodimer formation. 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. Supporting Evidence: PMID:19038970 the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9 PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells |
| GO:0050821 protein stabilization | ISO GO_REF:0000119 | ACCEPT | Summary: Mtmr9 stabilizes its partner phosphatase, and is itself stabilized, by heterodimer formation. 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. Supporting Evidence: PMID:19038970 the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9 PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells |
| GO:0060304 regulation of phosphatidylinositol dephosphorylation | IEA GO_REF:0000107 | ACCEPT | Summary: Mtmr9 regulates phosphatidylinositol 3-dephosphorylation by its partner phosphatases. 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. Supporting Evidence: PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. |
| GO:0060304 regulation of phosphatidylinositol dephosphorylation | ISO GO_REF:0000119 | ACCEPT | Summary: Mtmr9 regulates phosphatidylinositol 3-dephosphorylation by its partner phosphatases. 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. Supporting Evidence: PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels PMID:12890864 The binding of MTMR9 increased the Ins(1,3)P2 phosphatase activity of MTMR7. |
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Download this section (compressed HTML)Q: 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.
Q: 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?
Experiment: 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.
Hypothesis: Mtmr9 is required in vivo for normal Mtmr6/Mtmr7/Mtmr8 protein levels and 3-phosphoinositide turnover.
Type: genetic perturbation
Experiment: 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.
Hypothesis: The GRAM domain of Mtmr9 recruits the Mtmr6-Mtmr9 complex to ruffles to complete macropinocytosis.
Type: cell biology
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