RBCC Red Blood Cell Collection

INPP5D (SHIP, SHIP1) [Confidence: low (only semi-automatic identification from reviews)]
Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1; 3.1.3.86 (Inositol polyphosphate-5-phosphatase of 145 kDa; SIP-145; SH2 domain-containing inositol 5'-phosphatase 1; SH2 domain-containing inositol phosphatase 1; SHIP-1; p150Ship; hp51CN)

UniProt Q92835
ID SHIP1_HUMAN Reviewed; 1189 AA.
AC Q92835; O00145; Q13544; Q13545; Q6P5A4; Q92656; Q9UE80;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-SEP-2007, sequence version 2.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1;
DE EC=3.1.3.86;
DE AltName: Full=Inositol polyphosphate-5-phosphatase of 145 kDa;
DE Short=SIP-145;
DE AltName: Full=SH2 domain-containing inositol 5'-phosphatase 1;
DE Short=SH2 domain-containing inositol phosphatase 1;
DE Short=SHIP-1;
DE AltName: Full=p150Ship;
DE Short=hp51CN;
GN Name=INPP5D; Synonyms=SHIP, SHIP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ENZYME ACTIVITY, TISSUE
RP SPECIFICITY, AND VARIANT TYR-1169.
RX PubMed=8769125; DOI=10.1006/bbrc.1996.1161;
RA Drayer A.L., Pesesse X., De Smedt F., Woscholski R., Parker P.,
RA Erneux C.;
RT "Cloning and expression of a human placenta inositol 1,3,4,5-
RT tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-
RT phosphatase.";
RL Biochem. Biophys. Res. Commun. 225:243-249(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, AND
RP INTERACTION WITH SHC1.
RX PubMed=8874179;
RA Ware M.D., Rosten P., Damen J.E., Liu L., Humphries R.K., Krystal G.;
RT "Cloning and characterization of human SHIP, the 145-kD inositol 5-
RT phosphatase that associates with SHC after cytokine stimulation.";
RL Blood 88:2833-2840(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 1-1139 (ISOFORM 1), ENZYME ACTIVITY, AND INTERACTION WITH GRB2.
RC TISSUE=Lung;
RX PubMed=8723348; DOI=10.1016/S0960-9822(02)00511-0;
RA Kavanaugh W.M., Pot D.A., Chin S.M., Deuter-Reinhard M.,
RA Jefferson A.B., Norris F.A., Masiarz F.R., Cousens L.S., Majerus P.W.,
RA Williams L.T.;
RT "Multiple forms of an inositol polyphosphate 5-phosphatase form
RT signaling complexes with Shc and Grb2.";
RL Curr. Biol. 6:438-445(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=9058707;
RA Geier S.J., Algate P.A., Carlberg K., Flowers D., Friedman C.,
RA Trask B., Rohrschneider L.R.;
RT "The human SHIP gene is differentially expressed in cell lineages of
RT the bone marrow and blood.";
RL Blood 89:1876-1885(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY,
RP PHOSPHORYLATION, AND INTERACTION WITH GRB2.
RX PubMed=9108392;
RA Odai H., Sasaki K., Iwamatsu A., Nakamoto T., Ueno H., Yamagata T.,
RA Mitani K., Yazaki Y., Hirai H.;
RT "Purification and molecular cloning of SH2- and SH3-containing
RT inositol polyphosphate-5-phosphatase, which is involved in the
RT signaling pathway of granulocyte-macrophage colony-stimulating factor,
RT erythropoietin, and Bcr-Abl.";
RL Blood 89:2745-2756(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP TYR-1169.
RC TISSUE=B-cell, and Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP INTERACTION WITH SLAMF1.
RX PubMed=10229804;
RA Mikhalap S.V., Shlapatska L.M., Berdova A.G., Law C.L., Clark E.A.,
RA Sidorenko S.P.;
RT "CDw150 associates with src-homology 2-containing inositol phosphatase
RT and modulates CD95-mediated apoptosis.";
RL J. Immunol. 162:5719-5727(1999).
RN [8]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND INTERACTION WITH DOK1.
RX PubMed=10822173; DOI=10.1016/S0898-6568(00)00073-5;
RA Dunant N.M., Wisniewski D., Strife A., Clarkson B., Resh M.D.;
RT "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates
RT with the dok1 phosphoprotein in bcr-Abl transformed cells.";
RL Cell. Signal. 12:317-326(2000).
RN [9]
RP FUNCTION.
RX PubMed=12421919;
RA Freeburn R.W., Wright K.L., Burgess S.J., Astoul E., Cantrell D.A.,
RA Ward S.G.;
RT "Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-
RT trisphosphate metabolism in T lymphocytes and can regulate novel
RT phosphoinositide 3-kinase effectors.";
RL J. Immunol. 169:5441-5450(2002).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-915, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP FUNCTION.
RX PubMed=16682172; DOI=10.1016/j.cellsig.2006.03.012;
RA Vaillancourt M., Levasseur S., Tremblay M.-L., Marois L.,
RA Rollet-Labelle E., Naccache P.H.;
RT "The Src homology 2-containing inositol 5-phosphatase 1 (SHIP1) is
RT involved in CD32a signaling in human neutrophils.";
RL Cell. Signal. 18:2022-2032(2006).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP STRUCTURE BY NMR OF 1-112.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the human SHIP SH2 domain.";
RL Submitted (APR-2008) to the PDB data bank.
RN [14]
RP VARIANT GLU-685.
RX PubMed=12529653; DOI=10.1038/sj.leu.2402725;
RA Luo J.-M., Yoshida H., Komura S., Ohishi N., Pan L., Shigeno K.,
RA Hanamura I., Miura K., Iida S., Ueda R., Naoe T., Akao Y., Ohno R.,
RA Ohnishi K.;
RT "Possible dominant-negative mutation of the SHIP gene in acute myeloid
RT leukemia.";
RL Leukemia 17:1-8(2003).
CC -!- FUNCTION: Phosphatidylinositol (PtdIns) phosphatase that
CC specifically hydrolyzes the 5-phosphate of phosphatidylinositol-
CC 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2,
CC thereby negatively regulating the PI3K (phosphoinositide 3-kinase)
CC pathways. Acts as a negative regulator of B-cell antigen receptor
CC signaling. Mediates signaling from the FC-gamma-RIIB receptor
CC (FCGR2B), playing a central role in terminating signal
CC transduction from activating immune/hematopoietic cell receptor
CC systems. Acts as a negative regulator of myeloid cell
CC proliferation/survival and chemotaxis, mast cell degranulation,
CC immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in
CC platelets and JNK signaling in B-cells. Regulates proliferation of
CC osteoclast precursors, macrophage programming, phagocytosis and
CC activation and is required for endotoxin tolerance. Involved in
CC the control of cell-cell junctions, CD32a signaling in neutrophils
CC and modulation of EGF-induced phospholipase C activity. Key
CC regulator of neutrophil migration, by governing the formation of
CC the leading edge and polarization required for chemotaxis.
CC Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates
CC the activin/TGF-beta-induced apoptosis through its Smad-dependent
CC expression. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus
CC affect the levels of the higher inositol polyphosphates like
CC InsP6.
CC -!- CATALYTIC ACTIVITY: 1-phosphatidyl-1D-myo-inositol 3,4,5-
CC triphosphate + H(2)O = 1-phosphatidyl-1D-myo-inositol 3,4-
CC diphosphate + phosphate.
CC -!- ENZYME REGULATION: Activated upon translocation to the sites of
CC synthesis of PtdIns(3,4,5)P3 in the membrane (By similarity).
CC -!- SUBUNIT: Interacts with tyrosine phosphorylated forms of SHC1,
CC DOK1, DOK3, PTPN11/SHP-2, SLAMF1/CD150. Interacts with PTPN11 in
CC response to IL-3. Interacts with receptors EPOR, MS4A2/FCER1B and
CC FCER1G, FCGR2A, FCGR2B and FCGR3. Interacts with GRB2 and PLCG1.
CC Interacts with tyrosine kinases SRC and TEC. Interacts with
CC FCGR2A, leading to regulate gene expression during the phagocytic
CC process. Interacts with c-Met/MET (By similarity). Interacts with
CC MILR1 (tyrosine-phosphorylated). Can weakly interact (via NPXY
CC motif 2) with DAB2 (via PID domain); the interaction is impaired
CC by tyrosine phosphorylation of the NPXY motif (By similarity).
CC -!- INTERACTION:
CC P31994:FCGR2B; NbExp=2; IntAct=EBI-1380477, EBI-724784;
CC Q96B97:SH3KBP1; NbExp=6; IntAct=EBI-1380477, EBI-346595;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane
CC protein. Note=Translocates to the plasma membrane when activated,
CC translocation is probably due to different mechanisms depending on
CC the stimulus and cell type. Partly translocated via its SH2 domain
CC which mediates interaction with tyrosine phosphorylated receptors
CC such as the FC-gamma-RIIB receptor (FCGR2B) or CD16/FCGR3.
CC Tyrosine phosphorylation may also participate in membrane
CC localization (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q92835-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92835-2; Sequence=VSP_027978;
CC Name=3; Synonyms=SIP-110;
CC IsoId=Q92835-3; Sequence=VSP_027977, VSP_027979;
CC -!- TISSUE SPECIFICITY: Specifically expressed in immune and
CC hematopoietic cells. Expressed in bone marrow and blood cells.
CC Levels vary considerably within this compartment. Present in at
CC least 74% of immature CD34+ cells, whereas within the more mature
CC population of CD33+ cells, it is present in only 10% of cells.
CC Present in the majority of T-cells, while it is present in a
CC minority of B-cells (at protein level).
CC -!- DOMAIN: The SH2 domain interacts with tyrosine phosphorylated
CC forms of proteins such as SHC1 or PTPN11/SHP-2. It competes with
CC that of GRB2 for binding to phosphorylated SHC1 to inhibit the Ras
CC pathway. It is also required for tyrosine phosphorylation (By
CC similarity).
CC -!- DOMAIN: The NPXY sequence motif found in many tyrosine-
CC phosphorylated proteins is required for the specific binding of
CC the PID domain (By similarity).
CC -!- PTM: Tyrosine phosphorylated by the members of the SRC family
CC after exposure to a diverse array of extracellular stimuli such as
CC cytokines, growth factors, antibodies, chemokines, integrin
CC ligands and hypertonic and oxidative stress. Phosphorylated upon
CC IgG receptor FCGR2B-binding.
CC -!- SIMILARITY: Belongs to the inositol 1,4,5-trisphosphate 5-
CC phosphatase family.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC50454.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; X98429; CAA67071.1; -; mRNA.
DR EMBL; U57650; AAB53573.1; -; mRNA.
DR EMBL; U50040; AAC50453.1; -; mRNA.
DR EMBL; U50041; AAC50454.1; ALT_INIT; mRNA.
DR EMBL; U84400; AAB49680.1; -; mRNA.
DR EMBL; U53470; AAD00081.1; -; mRNA.
DR EMBL; BC062985; AAH62985.1; -; mRNA.
DR EMBL; BC099920; AAH99920.1; -; mRNA.
DR EMBL; BC113580; AAI13581.1; -; mRNA.
DR EMBL; BC113582; AAI13583.1; -; mRNA.
DR PIR; JC4889; JC4889.
DR RefSeq; NP_001017915.1; NM_001017915.1.
DR RefSeq; NP_005532.2; NM_005541.3.
DR UniGene; Hs.262886; -.
DR UniGene; Hs.601911; -.
DR PDB; 2YSX; NMR; -; A=1-112.
DR PDBsum; 2YSX; -.
DR ProteinModelPortal; Q92835; -.
DR SMR; Q92835; 1-112, 402-714.
DR IntAct; Q92835; 15.
DR MINT; MINT-123561; -.
DR STRING; 9606.ENSP00000352575; -.
DR ChEMBL; CHEMBL1781870; -.
DR PhosphoSite; Q92835; -.
DR DMDM; 158564077; -.
DR PaxDb; Q92835; -.
DR PRIDE; Q92835; -.
DR Ensembl; ENST00000359570; ENSP00000352575; ENSG00000168918.
DR GeneID; 3635; -.
DR KEGG; hsa:3635; -.
DR UCSC; uc010zmo.2; human.
DR CTD; 3635; -.
DR GeneCards; GC02P233924; -.
DR H-InvDB; HIX0057065; -.
DR HGNC; HGNC:6079; INPP5D.
DR HPA; CAB016300; -.
DR MIM; 601582; gene.
DR neXtProt; NX_Q92835; -.
DR PharmGKB; PA29887; -.
DR eggNOG; COG5411; -.
DR HOVERGEN; HBG106726; -.
DR KO; K03084; -.
DR OrthoDB; EOG75F4CD; -.
DR BioCyc; MetaCyc:HS09849-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q92835; -.
DR ChiTaRS; INPP5D; human.
DR EvolutionaryTrace; Q92835; -.
DR GeneWiki; INPP5D; -.
DR GenomeRNAi; 3635; -.
DR NextBio; 14225; -.
DR PRO; PR:Q92835; -.
DR ArrayExpress; Q92835; -.
DR Bgee; Q92835; -.
DR CleanEx; HS_INPP5D; -.
DR Genevestigator; Q92835; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; TAS:ProtInc.
DR GO; GO:0034594; F:phosphatidylinositol trisphosphate phosphatase activity; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl.
DR GO; GO:0016064; P:immunoglobulin mediated immune response; IEA:Ensembl.
DR GO; GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:Ensembl.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0030889; P:negative regulation of B cell proliferation; IEA:Ensembl.
DR GO; GO:0045779; P:negative regulation of bone resorption; IEA:Ensembl.
DR GO; GO:0050777; P:negative regulation of immune response; IEA:Ensembl.
DR GO; GO:0045409; P:negative regulation of interleukin-6 biosynthetic process; IEA:Ensembl.
DR GO; GO:0045656; P:negative regulation of monocyte differentiation; IEA:Ensembl.
DR GO; GO:0045659; P:negative regulation of neutrophil differentiation; IEA:Ensembl.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0009968; P:negative regulation of signal transduction; IEA:Ensembl.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0045579; P:positive regulation of B cell differentiation; IEA:Ensembl.
DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR Gene3D; 3.30.505.10; -; 1.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR000300; IPPc.
DR InterPro; IPR000980; SH2.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00128; IPPc; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Complete proteome;
KW Cytoplasm; Hydrolase; Immunity; Membrane; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; SH2 domain; SH3-binding.
FT CHAIN 1 1189 Phosphatidylinositol 3,4,5-trisphosphate
FT 5-phosphatase 1.
FT /FTId=PRO_0000302866.
FT DOMAIN 5 101 SH2.
FT REGION 1016 1030 Interaction with DAB2 (By similarity).
FT MOTIF 124 129 SH3-binding 1.
FT MOTIF 912 915 NPXY motif 1.
FT MOTIF 969 974 SH3-binding 2.
FT MOTIF 1019 1022 NPXY motif 2.
FT MOTIF 1040 1051 SH3-binding 3.
FT COMPBIAS 920 1148 Pro-rich.
FT MOD_RES 915 915 Phosphotyrosine.
FT MOD_RES 934 934 Phosphoserine (By similarity).
FT MOD_RES 944 944 Phosphotyrosine (By similarity).
FT MOD_RES 1022 1022 Phosphotyrosine (By similarity).
FT VAR_SEQ 1 212 Missing (in isoform 3).
FT /FTId=VSP_027977.
FT VAR_SEQ 117 117 Missing (in isoform 2).
FT /FTId=VSP_027978.
FT VAR_SEQ 213 222 TTLLCKELYG -> MFTLSPAPR (in isoform 3).
FT /FTId=VSP_027979.
FT VARIANT 685 685 V -> E (in one patient with acute myeloid
FT leukemya; somatic mutation).
FT /FTId=VAR_034979.
FT VARIANT 1169 1169 H -> Y (in dbSNP:rs9247).
FT /FTId=VAR_059358.
FT CONFLICT 25 26 DG -> GT (in Ref. 4; AAB49680).
FT CONFLICT 1029 1029 P -> H (in Ref. 4; AAB49680).
FT STRAND 4 9
FT HELIX 12 22
FT STRAND 27 32
FT STRAND 39 45
FT STRAND 50 57
FT STRAND 63 65
FT STRAND 70 72
FT STRAND 76 78
FT HELIX 79 85
FT STRAND 88 95
SQ SEQUENCE 1189 AA; 133292 MW; 7958E91A64A4B68B CRC64;
MVPCWNHGNI TRSKAEELLS RTGKDGSFLV RASESISRAY ALCVLYRNCV YTYRILPNED
DKFTVQASEG VSMRFFTKLD QLIEFYKKEN MGLVTHLQYP VPLEEEDTGD DPEEDTVESV
VSPPELPPRN IPLTASSCEA KEVPFSNENP RATETSRPSL SETLFQRLQS MDTSGLPEEH
LKAIQDYLST QLAQDSEFVK TGSSSLPHLK KLTTLLCKEL YGEVIRTLPS LESLQRLFDQ
QLSPGLRPRP QVPGEANPIN MVSKLSQLTS LLSSIEDKVK ALLHEGPESP HRPSLIPPVT
FEVKAESLGI PQKMQLKVDV ESGKLIIKKS KDGSEDKFYS HKKILQLIKS QKFLNKLVIL
VETEKEKILR KEYVFADSKK REGFCQLLQQ MKNKHSEQPE PDMITIFIGT WNMGNAPPPK
KITSWFLSKG QGKTRDDSAD YIPHDIYVIG TQEDPLSEKE WLEILKHSLQ EITSVTFKTV
AIHTLWNIRI VVLAKPEHEN RISHICTDNV KTGIANTLGN KGAVGVSFMF NGTSLGFVNS
HLTSGSEKKL RRNQNYMNIL RFLALGDKKL SPFNITHRFT HLFWFGDLNY RVDLPTWEAE
TIIQKIKQQQ YADLLSHDQL LTERREQKVF LHFEEEEITF APTYRFERLT RDKYAYTKQK
ATGMKYNLPS WCDRVLWKSY PLVHVVCQSY GSTSDIMTSD HSPVFATFEA GVTSQFVSKN
GPGTVDSQGQ IEFLRCYATL KTKSQTKFYL EFHSSCLESF VKSQEGENEE GSEGELVVKF
GETLPKLKPI ISDPEYLLDQ HILISIKSSD SDESYGEGCI ALRLEATETQ LPIYTPLTHH
GELTGHFQGE IKLQTSQGKT REKLYDFVKT ERDESSGPKT LKSLTSHDPM KQWEVTSRAP
PCSGSSITEI INPNYMGVGP FGPPMPLHVK QTLSPDQQPT AWSYDQPPKD SPLGPCRGES
PPTPPGQPPI SPKKFLPSTA NRGLPPRTQE SRPSDLGKNA GDTLPQEDLP LTKPEMFENP
LYGSLSSFPK PAPRKDQESP KMPRKEPPPC PEPGILSPSI VLTKAQEADR GEGPGKQVPA
PRLRSFTCSS SAEGRAAGGD KSQGKPKTPV SSQAPVPAKR PIKPSRSEIN QQTPPTPTPR
PPLPVKSPAV LHLQHSKGRD YRDNTELPHH GKHRPEEGPP GPLGRTAMQ
//

MIM 601582
*RECORD*
*FIELD* NO
601582
*FIELD* TI
*601582 INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 145-KD; INPP5D
;;SH2-CONTAINING INOSITOL PHOSPHATASE; SHIP;;
read moreSHIP1
*FIELD* TX

CLONING

The phosphatidylinositols serve as precursors for a number of different
messenger molecules. Agonist stimulation of cells results in
phosphatidylinositol turnover and the generation of inositol
1,4,5-triphosphate (Ins(1,4,5)P3), which mobilizes intracellular
calcium. The inositol-polyphosphate 5-phosphatase (INPP5) enzymes
hydrolyze Ins(1,4,5)P3 in a signal-terminating reaction. Known INPP5s
include the 40-kD INPP5A (600106), the 75-kD INPP5B (147264), and the
enzyme associated with Lowe oculocerebrorenal syndrome (300535). Damen
et al. (1996) cloned and sequenced a cDNA encoding a 145-kD protein from
a mouse hematopoietic cell line; the protein became tyrosine
phosphorylated and associated with SHC (600560) after cytokine
stimulation. Based on its domains and enzymatic activity, Damen et al.
(1996) named this protein SHIP for 'SH2-containing inositol
phosphatase.'

Ware et al. (1996) described the cloning of the human homolog of murine
Ship from a human megakaryocytic cell line cDNA library using 2
nonoverlapping mouse Ship cDNA fragments as probes. Northern blot
analysis suggested that human SHIP is expressed as a 5.3-kb mRNA in bone
marrow and a wide variety of other tissues. Sequence analysis of the
cDNA predicted a protein of 1,188 amino acids exhibiting 87.2% overall
sequence identity with mouse Ship. Contained within the defined open
reading frame was an N-terminal, group I src homology (SH2) domain; 3
NXXY motifs that, if phosphorylated, could be bound by
phosphotyrosine-binding (PTB) domains; a C-terminal proline-rich region;
and 2 centrally located inositol polyphosphate 5-phosphatase motifs.

Using the sequences of known inositol and phosphatidylinositol
polyphosphate 5-phosphatases, Drayer et al. (1996) designed degenerate
oligonucleotides and subsequently cloned a novel 5-phosphatase, which
they called 51CN. They cloned a full-length cDNA from a human placenta
library and found that it encodes a 1,188-amino acid protein with a
predicted molecular mass of 133 kD. The sequence predicted an N-terminal
region containing an SH2 domain, a central 5-phosphatase domain, and a
C-terminal proline-rich region with consensus sites for SH3-domain
interactions. Northern blot analysis revealed a 5-kb message expressed
strongly in placenta and heart and weakly in brain and lung tissues. The
authors also noted the presence of an 8-kb transcript in heart and
skeletal muscle. Following expression in COS-7 cells, Drayer et al.
(1996) showed that this enzyme has a specificity for substrates
phosphorylated at the 3-position. Kavanaugh et al. (1996) found 3 splice
variants of the 51CN gene which, based on their molecular masses, they
termed SIP-110, SIP-130, and SIP-145. The SIP-110 protein was isolated
based on its binding to the SH3 domain of GRB2 (108355). The SIP-130 and
SIP-145 proteins were isolated based on their binding to the PTB domain
of SHC. The authors stated that INPP5s may be associated with GRB2- and
SHC-mediated signal transduction.

By using a modified yeast 2-hybrid system to find proteins that bind the
SHC phosphotyrosine-binding domain, Lioubin et al. (1996) independently
cloned INPP5D and designated it p150(Ship).

GENE FUNCTION

Liu et al. (1998) studied the expression of the Ship gene during mouse
development. They found that the gene is expressed in late
primitive-streak stage embryos (7.5 days postcoitum), when hematopoiesis
is thought to begin, and the expression is restricted to the
hematopoietic lineage. In adult mice, Ship expression continues in most
cells of hematopoietic origin, including granulocytes, monocytes, and
lymphocytes, and is also found in the spermatids of the testis.
Furthermore, the level of Ship expression is developmentally regulated
during T-cell maturation. These results suggested a possible role for
Ship in the differentiation and maintenance of the hematopoietic
lineages and in spermatogenesis.

Valderrama-Carvajal et al. (2002) studied the signaling pathway
activated by inhibin (147290) and TGF-beta (TGFB1; 190180) during
apoptosis in mouse and human hematopoietic cell lines. They determined
that the downstream effectors include SMAD (see 601595) and SHIP.
Activation of the SMAD pathway induced SHIP expression, resulting in
intracellular changes in phospholipid pools and inhibited
phosphorylation of protein kinase B (AKT1; 164730).

Using microarray analysis, O'Connell et al. (2009) identified Ship1
among transcripts repressed by stable expression of human MIR155
(609337) in a mouse macrophage cell line. Transgenic mice expressing
human or mouse MIR155 or a small interfering RNA directed to Ship1
showed similar myeloproliferative disorder phenotypes in spleen and bone
marrow. Bone marrow was pale and contained an elevated population of
granulocyte/monocyte progenitors, and spleen showed splenomegaly with
abnormal architecture and expanded interfollicular regions containing
developing myeloid populations, erythroid precursors, and
megakaryocytes. O'Connell et al. (2009) concluded that repression of
SHIP1 is a critical aspect of MIR155 function in the hematopoietic
system.

Sly et al. (2009) noted that gram-negative bacterial infections do not
protect against subsequent viral infections, even though
lipopolysaccharide (LPS), like double-stranded RNA (dsRNA), activates
the TRIF (TICAM1; 607601) pathway and stimulates production of type I
IFN (e.g., IFNA; 147660). They found that Ship protein levels were
dramatically increased in murine macrophages via the Myd88
(602170)-dependent pathway by upregulating Tgfb. Increased Ship, via
inhibition of PI3K, mediated CpG- and LPS-induced tolerance and
restrained Ifnb (147640) production induced by subsequent exposure to
LPS or dsRNA. Ship -/- mice overproduced Ifnb in response to LPS,
responded well against virus, and exhibited severe hypothermia rather
than fever after low- or high-dose LPS challenge. Sly et al. (2009)
concluded that upregulation of SHIP in response to gram-negative
bacterial infections explains the inability of such infections to
protect against subsequent viral infections.

Khalil et al. (2012) showed that most proliferating germinal center B
cells do not demonstrate active B cell receptor signaling. Rather,
spontaneous and induced signaling was limited by increased phosphatase
activity. Accordingly, both SH2 domain-containing phosphatase-1 (SHP1;
176883) and SHIP1 were hyperphosphorylated in germinal center cells and
remained colocalized with B cell receptors after ligation. Furthermore,
SHP1 was required for germinal cell maintenance. Intriguingly, germinal
center B cells in the cell cycle G2 period regained responsiveness to B
cell receptor stimulation.

MAPPING

Liu et al. (1997) mapped the mouse INPP5D homolog to 1C5 by fluorescence
in situ hybridization (FISH). By FISH, using the full-length human SHIP
cDNA as a probe, Ware et al. (1996) mapped SHIP to the border of 2q36
and 2q37.

ANIMAL MODEL

Helgason et al. (1998) generated mice homozygous for a targeted
disruption of the SHIP gene. Although viable and fertile, the SHIP-null
mice failed to thrive, and survival was only 40% by 14 weeks of age. The
mice exhibited a myeloproliferative-like syndrome with consolidation of
the lungs caused by infiltration of macrophages. Helgason et al. (1998)
concluded that SHIP plays a crucial role in modulating cytokine
signaling within the hematopoietic system.

To clarify the role that SHIP plays in mast cell degranulation, Huber et
al. (1998) disrupted the SHIP gene in mice by homologous recombination
in embryonic stem cells. Homozygous SHIP -/- mast cells were found to be
far more prone to degranulation, after the crosslinking of IgE preloaded
cells, than SHIP +/- or +/+ cells. IgE alone also stimulated massive
degranulation in SHIP -/- but not +/+ mast cells. This degranulation
with IgE alone, which may be due to low levels of IgE aggregates,
correlated with a higher and more sustained intracellular calcium level
than that observed with SHIP +/+ cells and was dependent on the entry of
extracellular calcium. The results showed the critical role that SHIP
plays in setting the threshold for degranulation and demonstrated that
SHIP directly modulates a 'positive-acting' receptor.

Wang et al. (2002) generated mice with a targeted mutation in SHIP,
resulting in Ship -/- mice. Flow cytometric analysis demonstrated that
natural killer (NK) cells develop normally in juvenile Ship-deficient
mice, but that adult mice express 10-fold higher levels of NK1.1
receptor and an overall increase in NK cell levels due to prolonged
survival. The prolonged survival is accompanied by significantly altered
levels of Ly49 (see 604274) and CD94 (602894) receptors, indicating that
Ship-deficient mice express a repertoire of inhibitory receptors that
are both self-specific and promiscuous for other ligands. Western blot
analysis showed significant increases in Akt (164730) and Akt
phosphorylation, as well as increased Bcl2 (151430), in the NK cells of
Ship-deficient mice, indicating the activation of the PIK3 (see 171834)
pathway. Wang et al. (2002) noted that the recruitment of Ship by Ly49
in mice is analogous to SHIP recruitment by KIR (604936) in humans and
that this may limit the in vivo survival of NK cells and limit NK
effector function. Transplantation experiments determined that fully
MHC-mismatched bone marrow is rejected by wildtype, but not Ship -/-,
mice. The mutant mice, however, were able to reject B2M (109700) -/-
marrow, suggesting that the NK compartment of Ship-deficient mice is not
broadly disabled. In addition, most of the mutant mice did not develop
graft-versus-host disease (GVHD; see 614395), whereas most wildtype mice
did not survive the mismatched transplant. Wang et al. (2002) proposed
that inhibiting SHIP activity prior to bone marrow transplant can
restrict the NK inhibitory repertoire, such that selecting a donor with
an appropriate MHC ligand or ligands might enable engraftment in the
absence of GVHD.

Because Ship -/- mice contain increased numbers of osteoclast
precursors, i.e., macrophages, Takeshita et al. (2002) examined bones
from these animals and found that osteoclast number was increased
2-fold. The increased number was the result of prolonged life span of
these cells and hypersensitivity of precursors to macrophage
colony-stimulating factor (MCSF; 120420) and receptor activator of
nuclear factor-kappa-B ligand (RANKL; 602642). Similar to the
osteoclasts of Paget disease of bone (602080), Ship -/- osteoclasts were
enlarged, containing upwards of 100 nuclei, and exhibited enhanced
resorptive activity. Moreover, as in Paget disease, serum levels of
interleukin-6 (IL6; 147620) were markedly increased in Ship -/- mice.
Consistent with accelerated resorptive activity, a 22% loss of
bone-mineral density and a 49% decrease in fracture energy were
observed. Thus, SHIP negatively regulates osteoclast formation and
function, and the absence of this enzyme results in severe osteoporosis.

Severin et al. (2007) found that Ship1 deficiency in mice affected
platelet aggregation in response to several agonists, with minor effects
of fibrinogen (see 134820) binding and beta-3 integrin (ITGB3; 173470)
tyrosine phosphorylation. Accordingly, Ship1-null mice showed defects in
arterial thrombus formation in response to localized laser-induced
injury, and these mice had prolonged tail bleeding time. Upon
stimulation, Ship1-deficient platelets showed large membrane extensions,
abnormalities in the open canalicular system, and a dramatic decrease in
close cell-cell contacts. Ship1 appeared to be required for platelet
contractility, thrombus organization, and fibrin clot retraction.

Antignano et al. (2010) observed increased numbers of splenic dendritic
cells (DCs) in Ship -/- mice and increased expansion of DCs from Ship
-/- DC precursors ex vivo in response to Gmcsf (CSF2; 138960). However,
Ship -/- DCs had an immature phenotype, characterized by lower
expression of MHC class II, Cd40 (109535), Cd80 (112203), and Cd86
(601020), and they produced less Il12 (see 161560) and Il10 (124092),
but more Tnf (191160) and Il6, compared with wildtype DCs. Ship -/- DCs
were also less able to stimulate antigen-specific T-cell proliferation
and Th1 cytokine production. The immature phenotype of Ship -/- DCs
could be reversed by phosphatidylinositol 3-kinase (PI3K; see 601232)
inhibitors, suggesting that SHIP promotes DC maturation by reducing PI3K
second messenger levels. Antignano et al. (2010) concluded that SHIP is
a negative regulator of GMCSF-derived DC generation, but a positive
regulator of GMCSF-derived maturation and function.

Using Ship -/- mice and mice with a conditional deletion of Ship in
hemopoietic stem cells (HSCs), Hazen et al. (2009) showed that the
reconstitution capacity of the HSCs was not compromised if resident in a
Ship-competent bone marrow milieu. The same cells in Ship -/- mice were
functionally compromised for repopulation. Hazen et al. (2009) concluded
that SHIP is required in bone marrow for functionally competent HSCs.

By flow cytometric analysis, Collazo et al. (2009) showed that Ship -/-
mice had increased Cd4-positive/Cd25-positive/Foxp3 (300292)-positive
regulatory T (Treg) cells, as well as
Cd4-positive/Cd25-negative/Foxp3-positive naive T cells. Ship -/-
Cd4-positive/Cd25-negative T cells, like conventional Treg cells, were
unresponsive to MHC-mismatched stimulator cells and suppressed
allogeneic T-cell responses in vitro. In addition, Ship -/-
Cd4-positive/Cd25-negative T cells mediated reduced lethal GVHD on
adoptive transfer to MHC-mismatched hosts. Hosts with induced Ship
deficiency had delayed rejection of mismatched heart grafts. Collazo et
al. (2009) concluded that SHIP is required for robust GVHD and
host-versus-graft responses, suggesting that SHIP could be targeted in
clinical transplantation.

*FIELD* RF
1. Antignano, F.; Ibaraki, M.; Kim, C.; Ruschmann, J.; Zhang, A.;
Helgason, C. D.; Krystal, G.: SHIP is required for dendritic cell
maturation. J. Immun. 184: 2805-2813, 2010.

2. Collazo, M. M.; Wood, D.; Paraiso, K. H. T.; Lund, E.; Engelman,
R. W.; Le, C.-T.; Stauch, D.; Kotsch, K.; Kerr, W. G.: SHIP limits
immunoregulatory capacity in the T-cell compartment. Blood 113:
2934-2944, 2009.

3. Damen, J. E.; Liu, L.; Rosten, P.; Humphries, R. K.; Jefferson,
A. B.; Majerus, P. W.; Krystal, G.: The 145-kDa protein induced to
associate with Shc by multiple cytokines is an inositol tetraphosphate
and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc.
Nat. Acad. Sci. 93: 1689-1693, 1996.

4. Drayer, A. L.; Pesesse, X.; De Smedt, F.; Woscholski, R.; Parker,
P.; Erneux, C.: Cloning and expression of a human placenta inositol
1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-triphosphate
5-phosphatase. Biochem. Biophys. Res. Commun. 225: 243-249, 1996.

5. Hazen, A. L.; Smith, M. J.; Desponts, C.; Winter, O.; Moser, K.;
Kerr, W. G.: SHIP is required for a functional hematopoietic stem
cell niche. Blood 113: 2924-2933, 2009.

6. Helgason, C. D.; Damen, J. E.; Rosten, P.; Grewal, R.; Sorensen,
P.; Chappel, S. M.; Borowski, A.; Jirik, F.; Krystal, G.; Humphries,
R. K.: Targeted disruption of SHIP leads to hemopoietic perturbations,
lung pathology, and a shortened life span. Genes Dev. 12: 1610-1620,
1998.

7. Huber, M.; Helgason, C. D.; Damen, J. E.; Liu, L.; Humphries, R.
K.; Krystal, G.: The src homology 2-containing inositol phosphatase
(SHIP) is the gatekeeper of mast cell degranulation. Proc. Nat. Acad.
Sci. 95: 11330-11335, 1998.

8. Kavanaugh, W. M.; Pot, D. A.; Chin, S. M.; Deuter-Reinhard, M.;
Jefferson, A. B.; Norris, F. A.; Masiarz, F. R.; Cousens, L. S.; Majerus,
P. W.; Williams, L. T.: Multiple forms of an inositol polyphosphate
5-phosphatase form signaling complexes with Shc and Grb2. Curr.
Biol. 6: 438-445, 1996.

9. Khalil, A. M.; Cambier, J. C.; Shlomchik, M. J.: B cell receptor
signal transduction in the GC is short-circuited by high phosphatase
activity. Science 336: 1178-1181, 2012.

10. Lioubin, M. N.; Algate, P. A.; Tsai, S.; Carlberg, K.; Aebersold,
R.; Rohrschneider, L. R.: p150(Ship), a signal transduction molecule
with inositol polyphosphate-5-phosphatase activity. Genes Dev. 10:
1084-1095, 1996.

11. Liu, Q.; Amgen EST Program; Dumont, D. J.: Molecular cloning
and chromosomal localization in human and mouse of the SH2-containing
inositol phosphatase, INPP5D (SHIP). Genomics 39: 109-112, 1997.

12. Liu, Q.; Shalaby, F.; Jones, J.; Bouchard, D.; Dumont, D. J.:
The SH2-containing inositol polyphosphate 5-phosphatase, Ship, is
expressed during hematopoiesis and spermatogenesis. Blood 91: 2753-2759,
1998.

13. O'Connell, R. M.; Chaudhuri, A. A.; Rao, D. S.; Baltimore, D.
: Inositol phosphatase SHIP1 is a primary target of miR-155. Proc.
Nat. Acad. Sci. 106: 7113-7118, 2009.

14. Severin, S.; Gratacap, M.-P.; Lenain, N.; Alvarez, L.; Hollande,
E.; Penninger, J. M.; Gachet, C.; Plantavid, M.; Payrastre, B.: Deficiency
of Src homology 2 domain-containing inositol 5-phosphatase 1 affects
platelet responses and thrombus growth. J. Clin. Invest. 117: 944-952,
2007.

15. Sly, L. M.; Hamilton, M. J.; Kuroda, E.; Ho, V. W.; Antignano,
F. L.; Omeis, S. L.; van Netten-Thomas, C. J.; Wong, D.; Brugger,
H. K.; Williams, O.; Feldman, M. E.; Houseman, B. T.; Fiedler, D.;
Shokat, K. M.; Krystal, G.: SHIP prevents lipopolysaccharide from
triggering an antiviral response in mice. Blood 113: 2945-2954,
2009.

16. Takeshita, S.; Namba, N.; Zhao, J. J.; Jiang, Y.; Genant, H. K.;
Silva, M. J.; Brodt, M. D.; Helgason, C. D.; Kalesnikoff, J.; Rauh,
M. J.; Humphries, R. K.; Krystal, G.; Teitelbaum, S. L.; Ross, F.
P.: SHIP-deficient mice are severely osteoporotic due to increased
numbers of hyper-resorptive osteoclasts. Nature Med. 8: 943-949,
2002.

17. Valderrama-Carvajal, H.; Cocolakis, E.; Lacerte, A.; Lee, E.-H.;
Krystal, G.; Ali, S.; Lebrun, J.-J.: Activin/TGF-beta induce apoptosis
through Smad-dependent expression of the lipid phosphatase SHIP. Nature
Cell Biol. 4: 963-969, 2002.

18. Wang, J.-W.; Howson, J. M.; Ghansah, T.; Desponts, C.; Ninos,
J. M.; May, S. L.; Nguyen, K. H. T.; Toyama-Sorimachi, N.; Kerr, W.
G.: Influence of SHIP on the NK repertoire and allogeneic bone marrow
transplantation. Science 295: 2094-2097, 2002.

19. Ware, M. D.; Rosten, P.; Damen, J. E.; Liu, L.; Humphries, R.
K.; Krystal, G.: Cloning and characterization of human SHIP, the
145-kD inositol 5-phosphatase that associates with SHC after cytokine
stimulation. Blood 88: 2833-2840, 1996.

*FIELD* CN
Paul J. Converse - updated: 11/6/2013
Ada Hamosh - updated: 7/19/2012
Paul J. Converse - updated: 10/26/2010
Patricia A. Hartz - updated: 8/26/2010
Patricia A. Hartz - updated: 10/18/2007
Patricia A. Hartz - updated: 3/5/2003
Victor A. McKusick - updated: 8/20/2002
Victor A. McKusick - updated: 10/5/1998
Rebekah S. Rasooly - updated: 7/23/1998
Victor A. McKusick - updated: 7/1/1998

*FIELD* CD
Victor A. McKusick: 12/17/1996

*FIELD* ED
mgross: 11/13/2013
mcolton: 11/6/2013
alopez: 7/24/2012
terry: 7/19/2012
mgross: 12/16/2011
mgross: 10/27/2010
terry: 10/26/2010
mgross: 9/1/2010
terry: 8/26/2010
mgross: 10/18/2007
terry: 10/18/2007
terry: 10/12/2005
alopez: 4/18/2005
carol: 3/5/2003
alopez: 9/20/2002
alopez: 8/20/2002
terry: 8/20/2002
alopez: 3/18/2002
psherman: 10/28/1999
carol: 9/20/1999
carol: 10/9/1998
terry: 10/5/1998
alopez: 7/23/1998
carol: 7/14/1998
dholmes: 7/13/1998
terry: 7/1/1998
alopez: 2/10/1998
alopez: 8/27/1997
alopez: 6/27/1997
mark: 6/4/1997
mark: 12/17/1996