BioPAX pathway converted from "PI(3,5)P2 is dephosphorylated to PI5P by MTMR9-bound MTMR6 or MTMR8 at the plasma membrane" in the Reactome database.LEFT-TO-RIGHT3.1.3PI(3,5)P2 is dephosphorylated to PI5P by MTMR9-bound MTMR6 or MTMR8 at the plasma membraneFormation of a complex with MTMR9 results in a 30-fold increase of phosphatidylinositol-(3,5)-bisphosphate 3-phosphatase catalytic activity of MTMR6 and a modest increase in the catalytic activity of MTMR8 (Zou et al. 2009, Zou et al. 2012). Authored: Orlic-Milacic, Marija, 2015-11-13Reviewed: Rush, Mark G, 2017-01-10Edited: Orlic-Milacic, Marija, 2017-01-25PI(3,5)P21-phosphatidyl-1D-myo-inositol 3,5-bisphosphateReactome DB_ID: 1806224plasma membraneGENE ONTOLOGYGO:00058861-phosphatidyl-1D-myo-inositol 3,5-bisphosphate [ChEBI:16851]1-phosphatidyl-1D-myo-inositol 3,5-bisphosphatePtsIns(3,5)P21,2-Diacyl-sn-glycero-3-phospho-(1'-myo-inositol-3',5'-bisphosphate)PtsIns-3,5-P2ChEBICHEBI:16851Reactome Database ID Release 701806224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1806224ReactomeR-ALL-18062243Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1806224.3Reactomehttp://www.reactome.orgH2OwaterReactome DB_ID: 29356cytosolGENE ONTOLOGYGO:0005829water [ChEBI:15377]waterChEBICHEBI:15377Reactome Database ID Release 7029356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356ReactomeR-ALL-293564Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.4PI5P1-phosphatidyl-1D-myo-inositol 5-phosphateReactome DB_ID: 18062401-phosphatidyl-1D-myo-inositol 5-phosphate [ChEBI:16500]1-phosphatidyl-1D-myo-inositol 5-phosphatePI5PChEBICHEBI:16500Reactome Database ID Release 701806240Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1806240ReactomeR-ALL-18062403Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1806240.3PiOrthophosphatephosphate(3-)PhosphateInorganic PhosphateReactome DB_ID: 29372phosphate(3-) [ChEBI:18367]phosphate(3-)ChEBICHEBI:18367Reactome Database ID Release 7029372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372ReactomeR-ALL-293723Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.3ACTIVATIONConverted from EntitySet in ReactomeMTMR6:MTMR9,MTMR8:MTMR9Reactome DB_ID: 6809318MTMR6:MTMR9Reactome DB_ID: 6809246MTMR9Myotubularin-related protein 9Reactome DB_ID: 6809239UniProt:Q96QG7 MTMR9MTMR9C8orf9MTMR8FUNCTION Acts as an adapter for myotubularin-related phosphatases (PubMed:19038970, PubMed:22647598). Increases lipid phosphatase MTMR6 catalytic activity, specifically towards phosphatidylinositol 3,5-bisphosphate, and MTMR6 binding affinity for phosphorylated phosphatidylinositols (PubMed:19038970, PubMed:22647598). Positively regulates lipid phosphatase MTMR7 catalytic activity (By similarity). Increases MTMR8 catalytic activity towards phosphatidylinositol 3-phosphate (PubMed:22647598). The formation of the MTMR6-MTMR9 complex, stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970). Stabilizes MTMR8 protein levels (PubMed:22647598). Plays a role in the late stages of macropinocytosis possibly by regulating MTMR6-mediated dephosphorylation of phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Negatively regulates autophagy, in part via its association with MTMR8 (PubMed:22647598). Negatively regulates DNA damage-induced apoptosis, in part via its association with MTMR6 (PubMed:19038970, PubMed:22647598). Does not bind mono-, di- and tri-phosphorylated phosphatidylinositols, phosphatidic acid and phosphatidylserine (PubMed:19038970).SUBUNIT Homodimer (PubMed:19038970). Heterodimer (via C-terminus) with lipid phosphatase MTMR6 (via C-terminus) (PubMed:16787938, PubMed:12890864, PubMed:19038970, PubMed:23188820). Heterodimer (via coiled coil domain) with lipid phosphatase MTMR7 (via C-terminus) (By similarity). Heterodimer with lipid phosphatase MTMR8 (PubMed:22647598, PubMed:16787938).TISSUE SPECIFICITY Expressed in many tissues.DOMAIN The GRAM domain is required for cell membrane localization.DOMAIN The coiled coil domain mediates interaction with MTMR9.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.CAUTION Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 333 in the dsPTPase catalytic loop, suggesting that it has no phosphatase activity.Homo sapiensNCBI Taxonomy9606UniProtQ96QG71EQUAL549EQUALReactome Database ID Release 706809239Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809239ReactomeR-HSA-68092391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809239.11MTMR6Reactome DB_ID: 1604666UniProt:Q9Y217 MTMR6MTMR6FUNCTION Phosphatase that acts on lipids with a phosphoinositol headgroup (PubMed:19038970, PubMed:22647598). Dephosphorylates phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate (PubMed:19038970, PubMed:22647598) (Probable). Binds with high affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) but also to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P), phosphatidic acid and phosphatidylserine (PubMed:19038970). Negatively regulates ER-Golgi protein transport (By similarity). Probably in association with MTMR9, plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Acts as a negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells possibly by decreasing intracellular levels of phosphatidylinositol 3-phosphate (PubMed:15831468). Negatively regulates proliferation of reactivated CD4(+) T-cells (PubMed:16847315). In complex with MTMR9, negatively regulates DNA damage-induced apoptosis (PubMed:19038970, PubMed:22647598). The formation of the MTMR6-MTMR9 complex stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970).ACTIVITY REGULATION Allosterically activated by phosphatidylserine and/or phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:19038970). Interaction with MTMR9 increases catalytic activity towards phosphatidylinositol 3,5-bisphosphate (PubMed:19038970).SUBUNIT Homodimer (PubMed:19038970). Heterodimer (via C-terminus) with MTMR9 (via C-terminus) (PubMed:12890864, PubMed:16787938, PubMed:19038970, PubMed:23188820). Interacts with ALKBH4 (PubMed:23145062). Interacts with KCNN4 (PubMed:15831468). Interacts (via GRAM domain) with RAB1B (in GDP-bound form); the interaction regulates MTMR6 recruitment to the endoplasmic reticulum-Golgi intermediate compartment (PubMed:23188820).TISSUE SPECIFICITY Expressed in CD4+ T-cells.DOMAIN The GRAM domain is required for cell membrane localization.DOMAIN The C-terminus domain (aa 502-621) mediates interaction with MTMR9.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.UniProtQ9Y2171EQUAL621EQUALReactome Database ID Release 701604666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604666ReactomeR-HSA-16046661Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1604666.11Reactome Database ID Release 706809246Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809246ReactomeR-HSA-68092461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809246.1MTMR8:MTMR9Reactome DB_ID: 6809252MTMR8Reactome DB_ID: 1604671UniProt:Q96EF0 MTMR8MTMR8FUNCTION Phosphatase that acts on lipids with a phosphoinositol headgroup (PubMed:22647598, PubMed:26143924). Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PubMed:22647598, PubMed:26143924). In complex with MTMR9, negatively regulates autophagy (PubMed:22647598).ACTIVITY REGULATION Interaction with MTMR9 increases phosphatase activity.SUBUNIT Homodimer (PubMed:26143924). Heterodimer with MTMR9 (PubMed:16787938, PubMed:22647598).SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.UniProtQ96EF01EQUAL704EQUALReactome Database ID Release 701604671Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604671ReactomeR-HSA-16046711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1604671.111Reactome Database ID Release 706809252Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809252ReactomeR-HSA-68092521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809252.1Reactome Database ID Release 706809318Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809318ReactomeR-HSA-68093181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809318.1GENE ONTOLOGYGO:0052629gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 706809317Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809317Reactome Database ID Release 706809320Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809320ReactomeR-HSA-68093201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809320.122647598Pubmed2012Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8Zou, JZhang, ChunfenMarjanovic, JasnaKisseleva, Marina VMajerus, PWWilson, Monita PProc. Natl. Acad. Sci. U.S.A. 109:9539-4419038970Pubmed2009MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosisZou, JChang, Shao-ChunMarjanovic, JasnaMajerus, PWJ. Biol. Chem. 284:2064-71