ID SHIP1_RAT Reviewed; 1190 AA. AC P97573; DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 02-SEP-2026, entry version 147. DE RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1; DE EC=3.1.3.86 {ECO:0000269|PubMed:8910587}; DE AltName: Full=Inositol polyphosphate-5-phosphatase D; DE EC=3.1.3.56 {ECO:0000250|UniProtKB:Q92835}; DE AltName: Full=Phosphatidylinositol-4,5-bisphosphate 5-phosphatase; DE EC=3.1.3.36 {ECO:0000250|UniProtKB:Q92835}; DE AltName: Full=SH2 domain-containing inositol 5'-phosphatase 1; DE Short=SH2 domain-containing inositol phosphatase 1; DE Short=SHIP-1; GN Name=Inpp5d; Synonyms=Ship, Ship1; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, PHOSPHORYLATION, AND RP INTERACTION WITH MS4A2; SHC1; GRB2 AND FCER1G. RX PubMed=8910587; DOI=10.1074/jbc.271.46.29271; RA Osborne M.A., Zenner G., Lubinus M., Zhang X., Songyang Z., Cantley L.C., RA Majerus P., Burn P., Kochan J.P.; RT "The inositol 5'-phosphatase SHIP binds to immunoreceptor signaling motifs RT and responds to high affinity IgE receptor aggregation."; RL J. Biol. Chem. 271:29271-29278(1996). RN [2] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245; THR-963 AND SER-971, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22673903; DOI=10.1038/ncomms1871; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). CC -!- FUNCTION: Phosphatidylinositol (PtdIns) phosphatase that specifically CC hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate CC (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively CC regulating the PI3K (phosphoinositide 3-kinase) pathways CC (PubMed:8910587). Also, is able to hydrolyze the 5-phosphate of CC phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3), 1D-myo-inositol CC 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate (By CC similarity). Acts as a negative regulator of B-cell antigen receptor CC signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), CC playing a central role in terminating signal transduction from CC activating immune/hematopoietic cell receptor systems. Acts as a CC negative regulator of myeloid cell proliferation/survival and CC chemotaxis, mast cell degranulation, immune cells homeostasis, integrin CC alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. CC Regulates proliferation of osteoclast precursors, macrophage CC programming, phagocytosis and activation and is required for endotoxin CC tolerance. Involved in the control of cell-cell junctions, CD32a CC signaling in neutrophils and modulation of EGF-induced phospholipase C CC activity. Key regulator of neutrophil migration, by governing the CC formation of the leading edge and polarization required for chemotaxis. CC Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the CC activin/TGF-beta-induced apoptosis through its Smad-dependent CC expression (By similarity). {ECO:0000250|UniProtKB:Q92835, CC ECO:0000269|PubMed:8910587}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- CC trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:25528, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658, CC ChEBI:CHEBI:57836; EC=3.1.3.86; CC Evidence={ECO:0000269|PubMed:8910587}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O = 1D-myo- CC inositol 1,3,4-trisphosphate + phosphate; Xref=Rhea:RHEA:11392, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57895, CC ChEBI:CHEBI:58414; EC=3.1.3.56; CC Evidence={ECO:0000250|UniProtKB:Q92835}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5- CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol 4-phosphate) + phosphate; Xref=Rhea:RHEA:22764, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178, CC ChEBI:CHEBI:58456; EC=3.1.3.36; CC Evidence={ECO:0000250|UniProtKB:Q92835}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1D-myo-inositol 1,4,5-trisphosphate + H2O = 1D-myo-inositol CC 1,4-bisphosphate + phosphate; Xref=Rhea:RHEA:19797, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58282, CC ChEBI:CHEBI:203600; EC=3.1.3.56; CC Evidence={ECO:0000250|UniProtKB:Q92835}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19798; CC Evidence={ECO:0000250|UniProtKB:Q92835}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000255|PROSITE- CC ProRule:PRU01427}; CC -!- ACTIVITY REGULATION: Activated upon translocation to the sites of CC synthesis of PtdIns(3,4,5)P3 in the membrane. {ECO:0000250}. CC -!- SUBUNIT: Interacts with tyrosine phosphorylated forms of SHC1 CC (PubMed:8910587). Interacts with tyrosine phosphorylated form of DOK1 CC (By similarity). Interacts with tyrosine phosphorylated form of DOK3 CC (By similarity). Interacts with tyrosine phosphorylated form of CC SLAMF1/CD150 (By similarity). Interacts with PTPN11/SHP-2 in response CC to IL-3 (By similarity). Interacts with receptor EPOR (By similarity). CC Interacts with receptors MS4A2/FCER1B and FCER1G (PubMed:8910587). CC Interacts with receptors FCGR2B and FCGR3 (By similarity). Interacts CC with receptor FCGR2A, leading to regulate gene expression during the CC phagocytic process (By similarity). Interacts with GRB2 CC (PubMed:8910587). Interacts with PLCG1 (By similarity). Interacts with CC tyrosine kinases SRC and TEC (By similarity). Interacts with c-Met/MET CC (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (By CC similarity). Can weakly interact (via NPXY motif 2) with DAB2 (via PID CC domain); the interaction is impaired by tyrosine phosphorylation of the CC NPXY motif (By similarity). Interacts (via SH2 domain) with tyrosine CC phosphorylated KLRC1 (via ITIM). Interacts with MPL/TPOR (By CC similarity). {ECO:0000250|UniProtKB:Q92835, CC ECO:0000250|UniProtKB:Q9ES52, ECO:0000269|PubMed:8910587}. CC -!- INTERACTION: CC P97573; Q96RU3: FNBP1; Xeno; NbExp=2; IntAct=EBI-8008869, EBI-1111248; CC P97573; Q15642-1: TRIP10; Xeno; NbExp=2; IntAct=EBI-8008869, EBI-16191375; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9ES52}. Cell CC membrane {ECO:0000250|UniProtKB:Q9ES52}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q9ES52}. Membrane raft CC {ECO:0000250|UniProtKB:Q9ES52}. Cytoplasm, cytoskeleton CC {ECO:0000250|UniProtKB:Q9ES52}. Note=Translocates to the plasma CC membrane when activated, translocation is probably due to different CC mechanisms depending on the stimulus and cell type. Translocates from CC the cytoplasm to membrane ruffles in a FCGR3/CD16-dependent manner. CC Colocalizes with FC-gamma-RIIB receptor (FCGR2B) or FCGR3/CD16 at CC membrane ruffles. Tyrosine phosphorylation may also participate in CC membrane localization. {ECO:0000250|UniProtKB:Q9ES52}. CC -!- DOMAIN: The SH2 domain interacts with tyrosine phosphorylated forms of CC proteins such as SHC1 or PTPN11/SHP-2. It competes with that of GRB2 CC for binding to phosphorylated SHC1 to inhibit the Ras pathway. It is CC also required for tyrosine phosphorylation (By similarity). CC {ECO:0000250|UniProtKB:Q9ES52}. CC -!- DOMAIN: The NPXY sequence motif found in many tyrosine-phosphorylated CC proteins is required for the specific binding of the PID domain. CC {ECO:0000250|UniProtKB:Q9ES52}. CC -!- PTM: Tyrosine phosphorylated by the members of the SRC family after CC exposure to a diverse array of extracellular stimuli such as cytokines, CC growth factors, antibodies, chemokines, integrin ligands and hypertonic CC and oxidative stress. Phosphorylated upon IgG receptor FCGR2B-binding. CC {ECO:0000269|PubMed:8910587}. CC -!- SIMILARITY: Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase CC family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U55192; AAB40610.1; -; mRNA. DR RefSeq; NP_062184.2; NM_019311.2. DR AlphaFoldDB; P97573; -. DR SMR; P97573; -. DR BioGRID; 248482; 6. DR DIP; DIP-42709N; -. DR FunCoup; P97573; 771. DR IntAct; P97573; 15. DR MINT; P97573; -. DR STRING; 10116.ENSRNOP00000040111; -. DR GlyGen; P97573; 2 sites. DR iPTMnet; P97573; -. DR PhosphoSitePlus; P97573; -. DR PaxDb; 10116-ENSRNOP00000040111; -. DR GeneID; 54259; -. DR KEGG; rno:54259; -. DR UCSC; RGD:2914; rat. DR AGR; RGD:2914; -. DR CTD; 3635; -. DR RGD; 2914; Inpp5d. DR eggNOG; KOG0565; Eukaryota. DR InParanoid; P97573; -. DR PhylomeDB; P97573; -. DR Reactome; R-RNO-1660499; Synthesis of PIPs at the plasma membrane. DR Reactome; R-RNO-1855204; Synthesis of IP3 and IP4 in the cytosol. DR Reactome; R-RNO-202424; Downstream TCR signaling. DR Reactome; R-RNO-210990; PECAM1 interactions. DR Reactome; R-RNO-912526; Interleukin receptor SHC signaling. DR PRO; PR:P97573; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0005884; C:actin filament; IDA:RGD. DR GO; GO:0030863; C:cortical cytoskeleton; IDA:RGD. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:RGD. DR GO; GO:0016020; C:membrane; ISO:RGD. DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0052659; F:inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity; ISS:UniProtKB. DR GO; GO:0052658; F:inositol-1,4,5-trisphosphate 5-phosphatase activity; IEA:RHEA. DR GO; GO:0030487; F:inositol-4,5-bisphosphate 5-phosphatase activity; IDA:RGD. DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; ISO:RGD. DR GO; GO:0034594; F:phosphatidylinositol trisphosphate phosphatase activity; ISO:RGD. DR GO; GO:0034485; F:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; EXP:UniProtKB. DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; ISS:UniProtKB. DR GO; GO:0051425; F:PTB domain binding; ISO:RGD. DR GO; GO:0017124; F:SH3 domain binding; ISO:RGD. DR GO; GO:0008340; P:determination of adult lifespan; ISO:RGD. DR GO; GO:0016064; P:immunoglobulin mediated immune response; ISO:RGD. DR GO; GO:0035556; P:intracellular signal transduction; ISO:RGD. DR GO; GO:0050869; P:negative regulation of B cell activation; ISO:RGD. DR GO; GO:0030889; P:negative regulation of B cell proliferation; ISO:RGD. DR GO; GO:0045779; P:negative regulation of bone resorption; ISO:RGD. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD. DR GO; GO:0030853; P:negative regulation of granulocyte differentiation; ISO:RGD. DR GO; GO:0050777; P:negative regulation of immune response; ISO:RGD. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISO:RGD. DR GO; GO:0045656; P:negative regulation of monocyte differentiation; ISO:RGD. DR GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; ISO:RGD. DR GO; GO:0045659; P:negative regulation of neutrophil differentiation; ISO:RGD. DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; ISO:RGD. DR GO; GO:0009968; P:negative regulation of signal transduction; ISO:RGD. DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:RGD. DR GO; GO:0045579; P:positive regulation of B cell differentiation; ISO:RGD. DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; ISO:RGD. DR GO; GO:0045621; P:positive regulation of lymphocyte differentiation; ISO:RGD. DR GO; GO:0050776; P:regulation of immune response; IBA:GO_Central. DR CDD; cd09100; INPP5c_SHIP1-INPP5D; 1. DR CDD; cd10343; SH2_SHIP; 1. DR FunFam; 3.30.505.10:FF:000035; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1; 1. DR FunFam; 3.60.10.10:FF:000005; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1; 1. DR Gene3D; 3.60.10.10; Endonuclease/exonuclease/phosphatase; 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR InterPro; IPR057509; C2_SHIP1-2_2nd. DR InterPro; IPR057510; C2_SHIP1-2_first. DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf. DR InterPro; IPR000300; IPPc. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR PANTHER; PTHR46051:SF3; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE 5-PHOSPHATASE 1; 1. DR PANTHER; PTHR46051; SH2 DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF24147; C2_SHIP1-2_2nd; 1. DR Pfam; PF24150; C2_SHIP1-2_first; 1. DR Pfam; PF22669; Exo_endo_phos2; 1. DR Pfam; PF00017; SH2; 1. DR PRINTS; PR00401; SH2DOMAIN. DR SMART; SM00128; IPPc; 1. DR SMART; SM00252; SH2; 1. DR SUPFAM; SSF56219; DNase I-like; 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR PROSITE; PS52082; 5_PPASE; 1. DR PROSITE; PS50001; SH2; 1. PE 1: Evidence at protein level; KW Apoptosis; Cell membrane; Cytoplasm; Cytoskeleton; Hydrolase; Immunity; KW Lipid metabolism; Magnesium; Membrane; Metal-binding; Phosphoprotein; KW Reference proteome; Repeat; SH2 domain; SH3-binding. FT CHAIN 1..1190 FT /note="Phosphatidylinositol 3,4,5-trisphosphate 5- FT phosphatase 1" FT /id="PRO_0000302868" FT DOMAIN 8..104 FT /note="SH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT DOMAIN 401..717 FT /note="5-PPase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01427" FT REGION 111..130 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 946..1190 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1014..1028 FT /note="Interaction with DAB2" FT /evidence="ECO:0000250" FT MOTIF 126..131 FT /note="SH3-binding 1" FT MOTIF 914..917 FT /note="NPXY motif 1" FT MOTIF 969..974 FT /note="SH3-binding 2" FT MOTIF 1017..1020 FT /note="NPXY motif 2" FT MOTIF 1038..1049 FT /note="SH3-binding 3" FT COMPBIAS 111..120 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 961..971 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 989..998 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1031..1045 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1140..1149 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1161..1183 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 589 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01427" FT BINDING 455 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01427" FT MOD_RES 245 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 917 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q92835" FT MOD_RES 934 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9ES52" FT MOD_RES 944 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9ES52" FT MOD_RES 963 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 966 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9ES52" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 1020 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9ES52" SQ SEQUENCE 1190 AA; 133593 MW; 85DD4F2190F98700 CRC64; MPAMVPGWNH GNITRSKAEE LLSRAGKDGS FLVRASESIP RAYALCVLFR NCVYTYRILP NEDDKFTVQA SEGVPMRFFT KLDQLIEFYK KENMGLVTHL QFPVPLEEED AIDEPEEDTE SVMSPPELPP RNIPVSGGPC EAKDLPLPTE NPRAPEVTRL SLSETLFQRL QSMDTSGLPE EHLKAIQDYL STQLMLDSDF LKTGSSNLPH LKKLTSLLCK ELHGEVIRTL PSLESLQRLF DQQLSPGLRP RPQVPGEANP ITMVAKLSQL TSLLSSIEDK VKALLHEGSE STNRRSLIPP VTFEVKSESL GIPQKMHLKV DVESGKLIIK KSRDGSEDKF YSHKKILQLI KSQKFLNKLV ILVETEKEKI LRKEYVFSDS KKREGFCQLL QQMKNKHSEQ SEPDMITIFI GTWNMGNAPP PKKITSWFLS KGQGKTRDDS ADYIPHDIYV IGTQEDPLGE KEWLEILRHS LQEVTSMTFK TVAIHTLWNI RIVVLAKPEH ENRISHICTD NVKTGIANTL GNKGAVGVSF MFNGTSLGFV NSHLTSGSEK KLRRNQNYMN ILRFLALGDK KLSPFNITHR FTHLFWLGDL NYRVELPTWE AEAIIQKIKQ QQYSDLLAHD QLLLERKEQE VFLHFEEEEI TFAPTYRFER LTRDKYAYTK QKATGMKYNL PSWCDRVLWK SYPLVHVVCQ SYGSTSDIMT SDHSPVFATF EAGVTSQFVS KNGPGAVDSQ GQIEFLACYA TLKTKSQTKF YLELHSSCLE SFVKSQEGEN EEGDEGELVV RFGETLPKLK PIISDPEYLL DQHILISIKS SDSDESYGEG CIALRLETTE SQLPIYTPLT HHGEMTGHFR GEIKLQTSEG KMREKLYDFV KTERDESSGM KCLKNLTSHD PMRQWEPAGR VPACGISSLN EIINPNYIGM GPFGQPLHGK STLSPDQQLT AWSYDQLPKD SSLGPGRGEG PPTPPSQPPL SPKKFSSSTA NRGSCPRVQE TRPGDLGKVE ALPQEDLPLT KPEMFENPLY GSVSPFPKLV PRKEQESPKM MRKEPPPCPD PGVSSPSIML PKAQEVENVK GTSKQAPVPV FGPTPRIRSF TCSSSAEGRM PSGDKSQGKP KAPASSQAPV PVKRPVKPSR SEMSQQTTPI PAPRPPLPVK SPAVLQLQHS KGRDYRDNTE LPHHGKHRQE ESLLGRTAMQ //