BioPAX pathway converted from "PI(3,5)P2 is dephosphorylated to PI5P by SYNJ/MTMs at the plasma membrane" in the Reactome database.LEFT-TO-RIGHT3.1.3PI(3,5)P2 is dephosphorylated to PI5P by SYNJ/MTMs at the plasma membraneAt the plasma membrane, synaptojanin-1 aka Synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1) (Guo et al. 1999), -2 (SYNJ2) and some myotubularins (MTMs) dephosphorylate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 5-phosphate (PI5P). The MTMs involved are: myotubularin (MTM1) (Cao et al. 2007, Tronchere et al. 2004, Schaletzky et al. 2003, Laporte et al. 2002) and myotubularin-related proteins 1 (MTMR1) (Tronchere et al. 2004), 3 (MTMR3) (Walker et al. 2001, Lorenzo et al. 2005), 6 (MTMR6) (Schaletzky et al. 2003, Choudhury et al. 2006), and 14 (MTMR14) (Tosch et al. 2006).Authored: Williams, MG, 2011-10-18Reviewed: Wakelam, Michael, 2012-05-14Reviewed: Rush, Mark G, 2017-01-10Edited: Williams, MG, 2011-08-12Edited: 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 751806224Database 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 7529356Database 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-293565Reactome 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-29356.5COMPOUNDC00001additional informationMIMI:0361PiOrthophosphatehydrogenphosphatePhosphateInorganic PhosphateReactome DB_ID: 29372hydrogenphosphate [ChEBI:43474]hydrogenphosphatehydrogen phosphatephosphate[PO3(OH)](2-)INORGANIC PHOSPHATE GROUPHYDROGENPHOSPHATE IONHPO4(2-)[P(OH)O3](2-)ChEBICHEBI:43474Reactome Database ID Release 7529372Database 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-293724Reactome 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-29372.4COMPOUNDC00009PI5P1-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 751806240Database 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-1806240.3ACTIVATIONConverted from EntitySet in ReactomeSYNJ/MTM(1)MTM1,MTMR1,MTMR3,MTMR6,MTMR14,SYNJ1,SYNJ2Reactome DB_ID: 1806223CG2MTM1Reactome DB_ID: 1604646UniProt:Q13496 MTM1MTM1CG2FUNCTION Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (PubMed:11001925, PubMed:10900271, PubMed:12646134, PubMed:14722070). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine-containing peptides (PubMed:9537414). Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome (PubMed:14722070). Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture (PubMed:21135508). Plays a role in mitochondrial morphology and positioning (PubMed:21135508). Required for skeletal muscle maintenance but not for myogenesis (PubMed:21135508). In skeletal muscles, stabilizes MTMR12 protein levels (PubMed:23818870).ACTIVITY REGULATION Allosterically activated by phosphatidylinositol 5-phosphate (PI5P).SUBUNIT Heterodimer with MTMR12 (PubMed:12847286, PubMed:23818870). Interacts with KMT2A/MLL1 (via SET domain) (PubMed:9537414). Interacts with DES in skeletal muscle but not in cardiac muscle (PubMed:21135508). Interacts with SPEG (PubMed:25087613).DOMAIN The GRAM domain mediates binding to PI(3,5)P2 and, with lower affinity, to other phosphoinositides.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.Homo sapiensNCBI Taxonomy9606UniProtQ134961EQUAL603EQUALReactome Database ID Release 751604646Database 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=1604646ReactomeR-HSA-16046461Reactome 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-1604646.1MTMR1Reactome DB_ID: 1604647UniProt:Q13613 MTMR1MTMR1FUNCTION Lipid phosphatase that has high specificity for phosphatidylinositol 3-phosphate and has no activity with phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (PubMed:11733541, PubMed:27018598). Activity with phosphatidylinositol (3,5)-bisphosphate is controversial; it has been shown by PubMed:27018598, while PubMed:11733541 find no activity with this substrate.SUBUNIT Homodimer.DOMAIN The C-terminal region is required for dimerization.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.UniProtQ136131EQUAL665EQUALReactome Database ID Release 751604647Database 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=1604647ReactomeR-HSA-16046471Reactome 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-1604647.1MTMR3KIAA0371ZFYVE10Reactome DB_ID: 1604635UniProt:Q13615 MTMR3MTMR3KIAA0371ZFYVE10FUNCTION Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. May also dephosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues (PubMed:10733931).SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.UniProtQ136151EQUAL1198EQUALReactome Database ID Release 751604635Database 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=1604635ReactomeR-HSA-16046351Reactome 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-1604635.1MTMR6Reactome 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 751604666Database 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-1604666.1MTMR14C3orf29Reactome DB_ID: 1604632UniProt:Q8NCE2 MTMR14MTMR14C3orf29FUNCTION Lipid phosphatase which efficiently dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2; inactive toward PtdIns4P, PtdIns(3,4)P2, PtdIns(4,5)P2 and PtdIns(3,4,5)P3.TISSUE SPECIFICITY Expressed in various tissues, including heart, skeletal muscle, placenta, liver, lung, kidney and pancreas.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.UniProtQ8NCE21EQUAL650EQUALReactome Database ID Release 751604632Database 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=1604632ReactomeR-HSA-16046321Reactome 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-1604632.1SYNJ1KIAA0910Reactome DB_ID: 1604634UniProt:O43426 SYNJ1SYNJ1KIAA0910FUNCTION Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (PubMed:27435091). Has a role in clathrin-mediated endocytosis (By similarity). Hydrolyzes PIP2 bound to actin regulatory proteins resulting in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2 (By similarity).SUBUNIT Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Binds AMPH, SH3GL1, SH3GL2 and SH3GL3 (PubMed:10542231). Interacts with MYO1E (via SH3 domain) (PubMed:17257598). Interacts with BIN1 and DNM1 (By similarity).TISSUE SPECIFICITY Concentrated at clathrin-coated endocytic intermediates in nerve terminals. Isoform 1 is more enriched than isoform 2 in developing brain as well as non-neuronal cells. Isoform 2 is very abundant in nerve terminals.DOMAIN Binds to EPS15 (a clathrin coat-associated protein) via a C-terminal domain containing three Asn-Pro-Phe (NPF) repeats.DOMAIN The C-terminal proline-rich region mediates binding to a variety of SH3 domain-containing proteins including AMPH, SH3GL1, SH3GL2, SH3GL3 and GRB2.SIMILARITY Belongs to the synaptojanin family.SIMILARITY In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.UniProtO434261EQUAL1573EQUALReactome Database ID Release 751604634Database 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=1604634ReactomeR-HSA-16046341Reactome 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-1604634.1SYNJ2KIAA0348Reactome DB_ID: 1806193UniProt:O15056 SYNJ2SYNJ2KIAA0348FUNCTION Inositol 5-phosphatase which may be involved in distinct membrane trafficking and signal transduction pathways. May mediate the inhibitory effect of Rac1 on endocytosis.SUBUNIT Binds to GRB2. Isoform 2A binds to SYNJ2BP/OMP25. Isoform 2B2 C-terminal proline-rich region binds to a variety of SH3 domain-containing proteins including SH3GL1, SH3GL2, SH3GL3 and GRB2.SIMILARITY Belongs to the synaptojanin family.SIMILARITY In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.UniProtO150561EQUAL1496EQUALReactome Database ID Release 751806193Database 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=1806193ReactomeR-HSA-18061931Reactome 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-1806193.1Reactome Database ID Release 751806223Database 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=1806223ReactomeR-HSA-18062232Reactome 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-1806223.2GENE ONTOLOGYGO:0052629gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 751806177Database 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=1806177Reactome Database ID Release 751676203Database 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=1676203ReactomeR-HSA-16762033Reactome 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-1676203.314660569Pubmed2004Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cellsTronchère, HLaporte, JPendaries, CChaussade, CLiaubet, LPirola, LMandel, JLPayrastre, BJ Biol Chem 279:7304-1215840652Pubmed2005Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3Lorenzo, OUrbé, SClague, MJJ Cell Sci 118:2005-1212646134Pubmed2003Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatasesSchaletzky, JDove, SKShort, BLorenzo, OClague, MJBarr, Francis ACurr Biol 13:504-911676921Pubmed2001Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificityWalker, DMUrbé, SDove, SKTenza, DRaposo, GClague, MJCurr Biol 11:1600-517651088Pubmed2007Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomesCao, CLaporte, JBacker, JMWandinger-Ness, AStein, MPTraffic 8:1052-6717008356Pubmed2006A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathyTosch, VRohde, HMTronchère, HZanoteli, EMonroy, NKretz, CDondaine, NPayrastre, BMandel, JLLaporte, JHum Mol Genet 15:3098-10610224048Pubmed1999SAC1-like domains of yeast SAC1, INP52, and INP53 and of human synaptojanin encode polyphosphoinositide phosphatasesGuo, SStolz, LELemrow, SMYork, JDJ Biol Chem 274:12990-512118066Pubmed2002The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane rufflesLaporte, JBlondeau, FGansmuller, ALutz, YVonesch, JLMandel, JLJ Cell Sci 115:3105-1716914545Pubmed2006Specificity of the myotubularin family of phosphatidylinositol-3-phosphatase is determined by the PH/GRAM domainChoudhury, PSrivastava, SLi, ZKo, KAlbaqumi, MNarayan, KCoetzee, WALemmon, MASkolnik, EYJ Biol Chem 281:31762-9